Cancer

Coding Dimension ID: 
280
Coding Dimension path name: 
Cancer
Funding Type: 
Genomics Centers of Excellence Awards (R)
Grant Number: 
GC1R-06673-A
Investigator: 
Institution: 
Type: 
PI
Type: 
Co-PI
ICOC Funds Committed: 
$40 000 000
Disease Focus: 
Brain Cancer
Cancer
Developmental Disorders
Heart Disease
Cancer
Genetic Disorder
Stem Cell Use: 
iPS Cell
Embryonic Stem Cell
Adult Stem Cell
Cancer Stem Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 

The Center of Excellence in Stem Cell Genomics will bring together investigators from seven major California research institutions to bridge two fields – genomics and pluripotent stem cell research. The projects will combine the strengths of the center team members, each of whom is a leader in one or both fields. The program directors have significant prior experience managing large-scale federally-funded genomics research programs, and have published many high impact papers on human stem cell genomics. The lead investigators for the center-initiated projects are expert in genomics, hESC and iPSC derivation and differentiation, and bioinformatics. They will be joined by leaders in stem cell biology, cancer, epigenetics and computational systems analysis. Projects 1-3 will use multi-level genomics approaches to study stem cell derivation and differentiation in heart, tumors and the nervous system, with implications for understanding disease processes in cancer, diabetes, and cardiac and mental health. Project 4 will develop novel tools for computational systems and network analysis of stem cell genome function. A state-of-the-art data management program is also proposed. This research program will lead the way toward development of the safe use of stem cells in regenerative medicine. Finally, Center resources will be made available to researchers throughout the State of California through a peer-reviewed collaborative research program.

Statement of Benefit to California: 

Our Center of Excellence for Stem Cell Genomics will help California maintain its position at the cutting edge of Stem Cell research and greatly benefit California in many ways. First, diseases such as cardiovascular disease, cancer, neurological diseases, etc., pose a great financial burden to the State. Using advanced genomic technologies we will learn how stem cells change with growth and differentiation in culture and can best be handled for their safe use for therapy in humans. Second, through the collaborative research program, the center will provide genomics services to investigators throughout the State who are studying stem cells with a goal of understanding and treating specific diseases, thereby advancing treatments. Third, it will employ a large number of “high tech” individuals, thereby bringing high quality jobs to the state. Fourth, since many investigators in this center have experience in founding successful biotech companies it is likely to “spin off” new companies in this rapidly growing high tech field. Fifth, we believe that the iPS and information resources generated by this project will have significant value to science and industry and be valuable for the development of new therapies. Overall, the center activities will create a game-changing network effect for the state, propelling technology development, biological discovery and disease treatment in the field.

Progress Report: 
  • This grant has enabled a plethora of activities in California Stem Cell Genomics. The Stanford Administrative Core for the Center of Excellence in Stem Cell Genomics (CESCG) has been established and is responsible for overseeing joint center activities, and the administration of center-initiated projects (CIP) 1 and 2, and several collaborative research projects (CRP). In the first year of the award the CESCG administration organized monthly telephone conference calls to share research progress and coordinate activities across the Center. On May 1, 2015 the CESCG held its first center-wide retreat in a one-day event at Clark Center on the campus of the Stanford Medical School. The two CIPs have made significant progress. CIP1 has generated a valuable resource of 38 induced pluripotent stem cell lines and established a reliable platform for high throughput derivation of human induced pluripotent stem cell-derived cardiomyocytes for use in downstream high throughput toxicity and drug pharmacology screening assays. CIP2 has completed the first human single cell brain analysis and is in the process of deriving a single cell pancreatic map. We have launched our collaborative research progress grant. Following on the receipt of applications in October 2014 and successful review in January 2015, the Administrative Core at Stanford has also issued subcontract awards for 3 CRPs managed by the CESCG from the Northern California site – two comprehensive project awards CRP-C2 to Daniel Geschwind of UCLA and CRP-C3 to Arnold Kriegstein of UCSF, and a regular project award CRP-R4 to Jeremy Sanford of UCSC. These activities will transform stem cell research in California and continue its preeminence in this area.
Funding Type: 
Disease Team Therapy Development III
Grant Number: 
DR3-06965
Investigator: 
Institution: 
Type: 
PI
Institution: 
Type: 
Co-PI
Institution: 
Type: 
Partner-PI
ICOC Funds Committed: 
$12 726 396
Disease Focus: 
Cancer
Solid Tumor
Blood Cancer
Collaborative Funder: 
UK
Stem Cell Use: 
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 

Most normal tissues are maintained by a small number of stem cells that can both self-renew to maintain stem cell numbers, and also give rise to progenitors that make mature cells. We have shown that normal stem cells can accumulate mutations that cause progenitors to self-renew out of control, forming cancer stem cells (CSC). CSC make tumors composed of cancer cells, which are more sensitive to cancer drugs and radiation than the CSC. As a result, some CSC survive therapy, and grow and spread. We sought to find therapies that include all CSC as targets. We found that all cancers and their CSC protect themselves by expressing a ‘don’t eat me’ signal, called CD47, that prevents the innate immune system macrophages from eating and killing them. We have developed a novel therapy (anti-CD47 blocking antibody) that enables macrophages to eliminate both the CSC and the tumors they produce. This anti-CD47 antibody eliminates human cancer stem cells when patient cancers are grown in mice. At the time of funding of this proposal, we will have fulfilled FDA requirements to take this antibody into clinical trials, showing in animal models that the antibody is safe and well-tolerated, and that we can manufacture it to FDA specifications for administration to humans.

Here, we propose the initial clinical investigation of the anti-CD47 antibody with parallel first-in-human Phase 1 clinical trials in patients with either Acute Myelogenous Leukemia (AML) or separately a diversity of solid tumors, who are no longer candidates for conventional therapies or for whom there are no further standard therapies. The primary objectives of our Phase I clinical trials are to assess the safety and tolerability of anti-CD47 antibody. The trials are designed to determine the maximum tolerated dose and optimal dosing regimen of anti-CD47 antibody given to up to 42 patients with AML and up to 70 patients with solid tumors. While patients will be clinically evaluated for halting of disease progression, such clinical responses are rare in Phase I trials due to the advanced illness and small numbers of patients, and because it is not known how to optimally administer the antibody. Subsequent progression to Phase II clinical trials will involve administration of an optimal dosing regimen to larger numbers of patients. These Phase II trials will be critical for evaluating the ability of anti-CD47 antibody to either delay disease progression or cause clinical responses, including complete remission. In addition to its use as a stand-alone therapy, anti-CD47 antibody has shown promise in preclinical cancer models in combination with approved anti-cancer therapeutics to dramatically eradicate disease. Thus, our future clinical plans include testing anti-CD47 antibody in Phase IB studies with currently approved cancer therapeutics that produce partial responses. Ultimately, we hope anti-CD47 antibody therapy will provide durable clinical responses in the absence of significant toxicity.

Statement of Benefit to California: 

Cancer is a leading cause of death in the US accounting for approximately 30% of all mortalities. For the most part, the relative distribution of cancer types in California resembles that of the entire country. Current treatments for cancer include surgery, chemotherapy, radiation therapy, biological therapy, hormone therapy, or a combination of these interventions ("multimodal therapy"). These treatments target rapidly dividing cells, carcinogenic mutations, and/or tumor-specific proteins. A recent NIH report indicated that among adults, the combined 5-year relative survival rate for all cancers is approximately 68%. While this represents an improvement over the last decade or two, cancer causes significant morbidity and mortality to the general population as a whole.

New insights into the biology of cancer have provided a potential explanation for the challenge of treating cancer. An increasing number of scientific studies suggest that cancer is initiated and maintained by a small number of cancer stem cells that are relatively resistant to current treatment approaches. Cancer stem cells have the unique properties of continuous propagation, and the ability to give rise to all cell types found in that particular cancer. Such cells are proposed to persist in tumors as a distinct population, and because of their increased ability to survive existing anti-cancer therapies, they regenerate the tumor and cause relapse and metastasis. Cancer stem cells and their progeny produce a cell surface ‘invisibility cloak’ called CD47, a ‘don’t eat me signal’ for cells of the native immune system to counterbalance ‘eat me’ signals which appear during cancer development. Our anti-CD47 antibody counters the ‘cloak’, enabling the patient’s natural immune system to eliminate the cancer stem cells and cancer cells. Our preclinical data provide compelling support that anti-CD47 antibody might be a treatment strategy for many different cancer types, including breast, bladder, colon, ovarian, glioblastoma, leiomyosarcoma, squamous cell carcinoma, multiple myeloma, lymphoma, and acute myelogenous leukemia.

Development of specific therapies that target all cancer stem cells is necessary to achieve improved outcomes, especially for sufferers of metastatic disease. We hope our clinical trials proposed in this grant will indicate that anti-CD47 antibody is a safe and highly effective anti-ancer therapy that offers patients in California and throughout the world the possibility of increased survival and even complete cure.

Funding Type: 
Early Translational III
Grant Number: 
TR3-05641
Investigator: 
Institution: 
Type: 
PI
Institution: 
Type: 
Co-PI
ICOC Funds Committed: 
$5 217 004
Disease Focus: 
Brain Cancer
Cancer
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 

While current treatment strategies for high-grade glioma can yield short term benefits, their inability to eradicate the highly tumorigenic cancer stem cell population results in disease recurrence in the vast majority of patients. Stem cells and some cancer cells (the targets of our therapy) share many common characteristics, including the ability to self-renew and grow indefinitely. These cancer stem cells are also resistant to many standard therapies including radiation and chemotherapy, creating a critical need for novel therapies that will efficiently eliminate this cell population. We propose here to develop and optimize a therapeutic strategy, termed “adoptive T cell therapy", that will eliminate the brain tumor stem cell population by re-directing a patient’s immune cells, specifically T cells, to recognize and destroy tumor stem cells. Our goal is a therapy in which a single administration of tumor-specific T cells results in long-term anti-glioma protection. Our approach builds on previous findings that T cells, when reprogrammed, can potently kill glioma stem cells. Furthermore, we will exploit the self-renewing stem cell-like properties of a defined T cell population (central memory T cells) to establish reservoirs of long-lasting tumor-directed T cells in patients with glioma, and thereby achieve durable tumor regression with a glioma-specific T cell product. Our findings can then be applied to cancers besides glioma, including tumors that metastasize to brain.

Statement of Benefit to California: 

The goal of this project is to develop a novel and promising immunotherapy utilizing genetically modified T cells to target glioma stem cells in order to improve cure rates for patients with high-grade malignant glioma. Our strategy, in which a single administration of tumor-specific T cells results in long-term anti-glioma protection, has the potential to provide significant therapeutic benefit to patients with brain tumors, for which there is a dearth of effective treatment options. Further, the tumor-specificity of this therapy is intended to improve the quality of life for patients with high-grade gliomas by reducing treatment related side-effects of conventional therapies. Moreover, due to the high cost hospital stays and treatments usually required for patients with advanced disease, this therapy, by generating long-lasting anti-cancer immunity, has the potential to significantly reduce the costs of health care to California and its citizens. Carrying out these proposed studies will have further economic benefit for California through the creation and maintenance of skilled jobs, along with the purchasing of equipment and supplies from in-state companies. This project will also yield long-reaching benefit through continuing to build the larger CIRM community that is establishing California as a leader in stem-cell and biomedical research both nationally and internationally.

Progress Report: 
  • While current treatment strategies for high-grade glioma can yield short term benefits, their inability to eradicate the highly tumorigenic cancer stem cell population results in disease recurrence in the vast majority of patients. Stem cells and some cancer cells (the targets of our therapy) share many common characteristics, including the ability to self-renew and grow indefinitely. These stem cell-like cancer cells are also resistant to many standard therapies including radiation and chemotherapy, creating a critical need for novel therapies that will efficiently eliminate this cell population. The goal of this project is to develop and optimize a therapeutic strategy, termed “adoptive T cell therapy,” that will eliminate the brain tumor stem cell population by re-directing a patient’s immune cells, specifically T cells, to recognize and destroy tumor stem cells. Our goal is a therapy in which a single administration of tumor-specific T cells results in long-term anti-glioma protection. Our approach builds on our previous pre-clinical and clinical findings that T cells, when reprogrammed, can potently kill glioma stem cells.
  • Over the past year, our group has developed and characterized an optimized next-generation adoptive T cell therapy platform for targeting the glioma-associated antigen IL13Rα2. As such, T cells were modified to express a chimeric antigen receptor (CAR) to recognize and kill IL13Rα2-expressing glioma cells. This T cell platform incorporates several improvements in CAR design and T cell engineering, including improved receptor signaling and the utilization of central memory T cells (Tcm) as the starting cell population for CAR-engineering for enhanced long-term persistence of the cells after they are administered to patients. Importantly, we now demonstrate that this optimized IL13Rα2-specific CAR Tcm therapeutic product mediates superior antitumor efficacy and improved T cell persistence as compared to our previous first-generation IL13Rα2-specific T cells. These findings are significant as they suggest the potential for improving the transient anti-glioma responses for patients, as observed in two Phase I clinical trials by our group at City of Hope, with this optimized next-generation platform.
  • The variability of gliomas, including the known differences between populations of glioma stem-like cells, is a critical barrier to the development of a therapy with the potential to mediate complete and durable remission of this disease. We have therefore hypothesized that a multi-targeted therapeutic approach will be required to achieve elimination of glioma stem-like cells and achieve longer lasting regression of high-grade glioma. To devise an effective multi-target therapy, one must first identify the potentially useful T cell target antigens and variations in their expression between patients and within individual tumors. The ideal target will be highly expressed on tumor cells, including stem-like cells, and not found on normal brain or other tissues. To this end, we have assembled a cohort of 35 patient samples in commercial tissue arrays and 45 patient specimens from the CoH Department of Pathology. Within this group of 80 patient tumors we have begun to examine expression of potential T cell targets, such as IL13Rα2, HER2, EGFR, and others. The goal is to find a set of target antigens that would encompass the maximum number of tumors and, in particular, the cancer stem-like cells within an individual tumor.
  • Our progress thus far has set the stage for our team to develop a potent multi-antigen specific T cell therapy that can “box-in” tumor variability. This clinically translatable platform has the potential to provide new treatment options for this devastating disease.
  • While current treatment strategies for glioblastoma (GBM) can yield short term benefits, their inability to eradicate the highly tumorigenic cancer stem cell population results in disease recurrence in the vast majority of patients. Stem cells and some cancer cells (the targets of our therapy) share many common characteristics, including the ability to self-renew and grow indefinitely. These stem cell-like cancer cells are also resistant to many standard therapies including radiation and chemotherapy, creating a critical need for novel therapies that will efficiently eliminate this cell population. The goal of this project is to develop and optimize a therapeutic strategy, termed “adoptive T cell therapy,” that will eliminate the brain tumor stem cell population by re-directing a patient’s immune cells, specifically T cells, to recognize and destroy tumor stem cells. Our goal is a therapy in which administration of tumor-specific T cells targeting combinations of antigens expressed on the cell surface of glioma stem-like cells results in long-term anti-glioma protection. Our approach builds on our previous pre-clinical and clinical findings that T cells, when reprogrammed, can potently kill glioma stem cells.
  • Thus far, our group has developed and characterized an optimized next-generation adoptive T cell therapy platform for targeting the glioma-associated antigen IL13Rα2. As such, T cells were modified to express a chimeric antigen receptor (CAR) to recognize and kill IL13Rα2-expressing glioma cells. This T cell platform incorporates several improvements in CAR design and T cell engineering over previous versions, including improved receptor signaling and the utilization of central memory T cells (Tcm) as the starting cell population for CAR-engineering (enhancing long-term persistence of the cells after they are administered to patients). Importantly, we now demonstrate that this optimized IL13Rα2-specific CAR Tcm therapeutic product mediates superior antitumor efficacy and improved T cell persistence as compared to our previous first-generation IL13Rα2-specific T cells. We further demonstrate that intracranial (i.c.) delivery of the IL13Rα2-specific CAR T cells outperforms intravenous (i.v.) delivery in orthtotopic mouse models of human glioblastoma, providing the clinical rational for local i.c. delivery. These findings are significant as they suggest the potential of this optimized next-generation platform to improve upon the transient anti-glioma patient responses observed in two Phase I clinical trials completed by our group at City of Hope. Based on these earlier results we have submitted an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) to initiate a single agent IL13Rα2-specific CAR T cell clinical trial. This clinical trial will provide a foundation for the ultimate goal of this CIRM ET award: development of a combination CAR T cell approach to overcome the high-degree of GBM heterogeneity.
  • This antigenic variability of gliomas, including differences between populations of glioma stem-like cells, is a critical barrier to the development of an immunotherapy with the potential to mediate complete and durable disease remission. We hypothesize that a multi-targeted therapeutic approach will be required to achieve elimination of glioma stem-like cells and achieve longer lasting regression of high-grade glioma. To devise an effective multi-target therapy, we are first identifying potentially useful T cell target antigens, and assessing variations in their expression between patients and within individual tumors. Ideal targets will be highly expressed on tumor cells, including stem-like cells, and not found on normal brain or other tissues. To this end, we have assembled a cohort of 35 patient samples in commercial tissue arrays and 45 patient specimens from the CoH Department of Pathology. Within this group of 80 patient tumors we have been examining expression of potential T cell targets, such as IL13Rα2, HER2, EGFR/EGFRvIII, and others. Our goal is to define a set of target antigens encompassing the maximum number of tumors and, in particular, the cancer stem-like cells within individual tumors. Based on this analysis, we are currently developing and optimizing CAR T cells targeting HER2 and EGFRvIII.
  • Our progress is thus continuing to set the stage for developing a potent multi-antigen specific T cell therapy that can “box-in” tumor variability. Our clinically translatable platform has the potential to provide new treatment options for this devastating disease.
Funding Type: 
Early Translational II
Grant Number: 
TR2-01816-B
Investigator: 
Institution: 
Type: 
Partner-PI
ICOC Funds Committed: 
$3 607 305
Disease Focus: 
Blood Cancer
Cancer
Collaborative Funder: 
Germany
Stem Cell Use: 
Cancer Stem Cell
Cell Line Generation: 
Adult Stem Cell
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 

Leukemia is the most frequent form of cancer in children and teenagers, but is also common in adults. Chemotherapy has vastly improved the outcome of leukemia over the past four decades. However, many patients still die because of recurrence of the disease and development of drug-resistance in leukemia cells.
In preliminary studies for this proposal we discovered that in most if not all leukemia subtypes, the malignant cells can switch between an “proliferation phase” and a “quiescence phase”. The “proliferation phase” is often driven by oncogenic tyrosine kinases (e. g. FLT3, JAK2, PDGFR, BCR-ABL1, SRC kinases) and is characterized by vigorous proliferation of leukemia cells. In this phase, leukemia cells not only rapidly divide, they are also highly susceptible to undergo programmed cell death and to age prematurely. In contrast, leukemia cells in “quiescence phase” divide only rarely. At the same time, however, leukemia cells in "quiescence phase" are highly drug-resistant. These cells are also called 'leukemia stem cells' because they exhibit a high degree of self-renewal capacity and hence, the ability to initiate leukemia. We discovered that the BCL6 factor is required to maintain leukemia stem cells in this well-protected safe haven. Our findings demonstrate that the "quiescence phase" is strictly dependent on BCL6, which allows them to evade cell death during chemotherapy treatment. Once chemotherapy treatment has ceased, persisting leukemia stem cells give rise to leukemia clones that reenter "proliferation phase" and hence initiate recurrence of the disease. Pharmacological inhibition of BCL6 using inhibitory peptides or blocking molecules leads to selective loss of leukemia stem cells, which can no longer persist in a "quiescence phase".
In this proposal, we test a novel therapeutic concept eradicate leukemia stem cells: We propose that dual targeting of oncogenic tyrosine kinases (“proliferation”) and BCL6 (“quiescence”) represents a powerful strategy to eradicate drug-resistant leukemia stem cells and prevent the acquisition of drug-resistance and recurrence of the disease. Targeting of BCL6-dependent leukemia stem cells may reduce the risk of leukemia relapse and may limit the duration of tyrosine kinase inhibitor treatment in some leukemias, which is currently life-long.

Statement of Benefit to California: 

Leukemia represents the most frequent malignancy in children and teenagers and is common in adults as well. Over the past four decades, the development of therapeutic options has greatly improved the prognosis of patients with leukemia reaching 5 year disease-free survival rates of ~70% for children and ~45% for adults. Despite its relatively favorable overall prognosis, leukemia remains one of the leading causes of person-years of life lost in the US (362,000 years in 2006; National Center of Health Statistics), which is attributed to the high incidence of leukemia in children.
In 2008, the California Cancer Registry expected 3,655 patients with newly diagnosed leukemia and at total of 2,185 death resulting from fatal leukemia. In addition, ~23,300 Californians lived with leukemia in 2008, which highlights that leukemia remains a frequent and life-threatening disease in the State of California despite substantial clinical progress. Here we propose the development of a fundamentally novel treatment approach for leukemia that is directed at leukemia stem cells. While current treatment approaches effectively diminish the bulk of proliferating leukemia cells, they fail to eradicate the rare leukemia stem cells, which give rise to drug-resistance and recurrence of the disease. We propose a dual targeting approach which combines targeted therapy of the leukemia-causing oncogene and the newly discovered leukemia stem cell survival factor BCL6. The power of this new therapy approach will be tested in clinical trials to be started in the State of California.

Progress Report: 
  • During the past reporting period (months 18-24 of this grant), we have made progress towards all three milestones. Major progress in Milestone 1 was made by identifying 391 compounds in 10 lead classes that will be developed further in a secondary fragment-based screen. While the goal of identifying lead class compounds with BCL6 inhibitory activity has already been met, we propose to run a secondary, fragment-based screen to refine the existing lead compounds and prioritize a small number for cell-based validation in Milestone 2. The success in Milestone 1 was based on computational modeling, HTS of 200,000 compounds and Fragment-based drug discovery (FBDD).
  • For Milestone 2, we have successfully established POC analysis tools for validation of the ability of compounds to bind the BCL6 lateral groove and already produced 300 mg of BCL6-BTB domain protein needed for biochemical binding assays. Progress in Milestone 2 is based on surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) assays. In the coming months, we will use crystallographic fragment screening using a subset of our fragment library in addition to SPR and NMR, since crystallographic fragment screens have been shown to yield complimentary hits. For Milestone 3, we have now set up a reliable method to measure disease-modifying activity of BCL6-inhibitory compounds based on a newly generated knockin BCL6 reporter mouse model, in which transcriptional activation of the endogenous BCL6 promoter drives expression of mCherry. This addresses a main caveat of these measurements was that they were strongly influenced by the copy number of lentivector integrations. The BCL6fl/+-mCherry knockin BCL6 reporter system will provide a stable platform to study BCL6-expressing leukemia cells and effects of BCL6 small molecule inhibitors on survival and proliferation on BCL6-dependent leukemia cell populations. This will be a key requirement to measure disease-modifying activity of inhibitory compounds in large-scale assays in Milestone 3. Other requirements (e.g. leukemia xenografts) are already in place. 
  • During the past two years of this grant, we have generated compounds that have the ability to block the function of BCL6. In previous work, we had identified BCL6 as a key requirement for persistence of leukemia stem cells, which are the root cause of leukemia relapse and drug-resistance in patients. Over the past six months, we have focused on validating the new compounds based on functional tests that allow us to measure the depth and durability of BCL6 blockade in cell-based assay. To this end, we designed a large-scale petri-dish system in which we measured the efficacy of 11 lead compounds and their derivatives to abrogate the ability of leukemia cells to form colonies, a capability that reflects the activity of leukemia stem cells. This assay allowed us to prioritize 4 compounds for further testing. In parallel, we developed a biological assay to verify that the compounds are actually hitting their target, i.e. BCL6, by measuring the activity of genes that are typically regualted by BCL6. These genes include tumor suppressors like p53 and Arf and we measured the ability of our compounds to re-instate p53 and Arf expression. We found that p53 and Arf were reinstated only by 2 of our 4 lead candidates, so current trouble-shooting efforts will attempt to clarify why this is the case and whether we can modify these two compounds to improve their on-target efficacy. The other two compounds will move forward in the next derivative screen, in which we perform a fragment-based, screen, i.e. test multiple derivative based on addition and removal of small structural changes (fragments). Other caveats to address in the next year will be stability (half-life) of the lead compounds, bioavailability (how much and how long the compound will be available in the blood stream) and toxicity (how much of the compound will be tolerated by mice, is there indication of damage to tissues upon long-term treatment?).The goal of these studies will be to make a strong case for IND-enabling studies, i.e. to enter a formal, government-regulated process to convert the strongest of our compound into an FDA-approved drug for potential clinical testing in patients with drug-refractory AML and ALL.
Funding Type: 
Research Leadership
Grant Number: 
LA1-01747
Investigator: 
ICOC Funds Committed: 
$5 919 616
Disease Focus: 
Brain Cancer
Cancer
Cell Line Generation: 
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 

Stem cells have the remarkable ability to renew themselves and to generate multiple different cell types. This allows them to generate normal tissues during development and to repair tissues following injury, but at the same time, renders them highly susceptible to mutations that can result in cancer. Only by understanding the signals that control growth and differentiation of stem cells can we learn to harness their regenerative capacity and restrain their malignant potential. The research described in this proposal is aimed at elucidating the role of neural stem cells in development, regeneration and tumor formation in the cerebellum.
Our previous studies identified a population of neural stem cells in the developing cerebellum. We now propose to use genetic approaches to mark these cells and identify the cell types that they generate during normal development. In addition, we plan to examine the capacity of these cells to regenerate the cerebellum following radiation. Finally, we propose to study the ability of these cells to give rise to brain tumors, and use the models that result from these studies to develop and test novel approaches to therapy. These studies will pave the way towards use of stem cells for repair of neurological damage and help develop more effective treatments for patients with brain tumors.

Statement of Benefit to California: 

We have previously identified a novel population of neural stem cells in the cerebellum. This proposal is focused on understanding the role of these cells in normal development, regeneration and tumor formation. It has the potential to benefit California in a number of important ways.

1. Treatment of Brain Damage: Radiation is the most commonly used treatment for brain tumors, and children who receive this treatment often suffer severe side effects, including a progressive loss of intellectual function. By studying the ability of cerebellar stem cells to repair brain tissue, we will advance the treatment of patients suffering from brain damage due to radiation therapy. The knowledge we gain may also be more broadly applicable, advancing the use of stem cells to repair damage due to congenital brain disorders, trauma and stroke.

2. Treatment of Brain Tumors: Medulloblastoma and astrocytoma are the most common brain tumors in children. By examining the role of stem cells in development of these tumors, we will deepen our understanding of how brain tumors form, and develop novel approaches to treating them. Moreover, we will create new model systems that can be used to test these therapies, with the hope of moving the most effective ones forward towards trials in patients.

3. Technology: Our research will culminate in the invention and generation of new drugs and approaches to therapy that will be made available for licensing by the academic institutions in California, such as {REDACTED} and its collaborators, and developed by pharmaceutical companies based in the State.

4. Collaboration: Our work is multidisciplinary and translational in nature. As such, it will require collaboration with other investigators, including stem cell biologists, neurobiologists, cancer biologists and chemists involved in experimental therapeutics. Once discoveries are made that may be of benefit to patients, we will also work with clinicians to move these discoveries towards the clinic. Californians will be the likely first beneficiaries of these therapies because the clinical trials will be conducted here and we will make an effort to make sure that Californians have immediate access to these therapies when they become standard. By bringing together investigators from various fields and focusing their attention on clinically relevant problems, our studies will advance the translational potential of stem cell research in California.

Progress Report: 
  • The goal of our studies is to determine the role of neural stem cells in the development, regeneration and tumor formation in the cerebellum. By understanding the role of stem cells, we hope to learn to use them for repair of neurological damage and to develop more effective treatments for patients with brain tumors.
  • The aims of our studies are: (1) To identify the cell types generated by cerebellar stem cells during normal development; (2) To determine the capacity of cerebellar stem cells to repair damage caused by radiation or disease; and (3) To determine whether cerebellar stem cells can give rise to the pediatric brain tumor medulloblastoma.
  • We have made significant progress toward our goals over the last year. In particular, we have identified genetic markers that allow us to trace the fate of cerebellar stem cells during normal development. In addition, we have demonstrated that cerebellar stem cells carrying cancer-causing genes can give rise to medulloblastoma. Importantly, this finding has allowed us to create stem cell-based models of medulloblastoma that can be used to test drugs that may be useful for treating the disease. Over the next few years, we hope to use this information to develop more effective therapies for children suffering from medulloblastoma.
  • The goal of our studies is to determine the role of neural stem cells in the development, regeneration and tumor formation in the cerebellum. By understanding the role of stem cells, we hope to learn to use them for repair of neurological damage and to develop more effective treatments for patients with brain tumors.
  • The aims of our studies are: (1) To identify the cell types generated by cerebellar stem cells during normal development; (2) To determine the capacity of cerebellar stem cells to repair damage caused by radiation or disease; and (3) To determine whether cerebellar stem cells can give rise to the pediatric brain tumor medulloblastoma.
  • We have made significant progress toward our goals over the last year. In particular, we have identified genetic markers that allow us to trace the fate of cerebellar stem cells during normal development. In addition, we have demonstrated that cerebellar stem cells carrying cancer-causing genes can give rise to medulloblastoma. Importantly, this finding has allowed us to create stem cell-based models of medulloblastoma that can be used to test drugs that may be useful for treating the disease. Our screening efforts over the past year have begun to identify compounds that inhibit the growth of human medulloblastoma tumor cells. Over the next few years, we hope to use this information to develop more effective therapies for children suffering from medulloblastoma.
  • The goal of our studies is to determine the role of neural stem cells in development, regeneration, and tumor formation in the cerebellum. By understanding the role of stem cells, we hope to learn to use them for repair of neurological damage and to develop more effective treatments for patients with brain tumors.
  • We have made significant progress towards our goals during the past year. We have identified new drugs that potently inhibit the growth of medulloblastoma, the most common malignant brain tumor in children. This work could lead to development of new, more effective therapies for medulloblastoma in patients. In addition, we have developed new models for several types of brain tumors, including one that resembles the most aggressive form of medulloblastoma, and several that model choroid plexus tumors. These models are valuable resources for studying the biology and therapeutic responsiveness of these diseases. Over the next few years, we will continue in our efforts to develop more effective therapies for children suffering from aggressive brain tumors.
  • The goal of our studies is to elucidate the role of neural stem cells in development, regeneration, and tumor formation in the cerebellum. By understanding the role of stem cells, we hope to learn to use them for repair of neurological damage and to develop more effective treatments for patients with brain tumors.
  • We have made significant progress towards our goals in the past year. Using animal models developed in our lab, we have uncovered new mechanisms and pathways that drive the growth and metastasis of medulloblastoma, the most common malignant brain tumor in children. In addition, we have identified molecular pathways that are de-regulated in choroid plexus carcinoma, a rare brain tumor with a poor prognosis that occurs most frequently in children. Our work has also led to the identification of new drugs that inhibit the growth of medulloblastoma and choroid plexus carcinoma. In the coming year, we will continue in our efforts to understand these aggressive cancers and develop new, more effective therapies for children who suffer from them.
Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01421
Investigator: 
Institution: 
Type: 
PI
Institution: 
Type: 
Co-PI
Institution: 
Type: 
Co-PI
ICOC Funds Committed: 
$18 015 429
Disease Focus: 
Brain Cancer
Cancer
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 

Despite aggressive multimodal therapy and advances in imaging, surgical and radiation techniques, malignant brain tumors (high-grade gliomas) remain incurable, with survival often measured in months. Treatment failure is largely attributable to the diffuse and invasive nature of these brain tumor cells, ineffective delivery of chemotherapeutic agents to tumor sites, and toxic side-effects to the body, which limits the dose of drug that can be given. Therefore, new tumor-selective therapies are critically needed. Neural stem cells (NSCs) offer an unprecedented advantage over conventional treatment approaches because of their unique ability to target tumor cells throughout the brain. This ability allows NSCs to be used to deliver prodrug-activating enzymes to tumors, where these enzymes will generate high concentrations of powerful anti-cancer agents selectively at tumor sites.

We will use an established human NSC line to develop a novel NSC-based product to deliver the enzyme carboxylesterase (CE), which will activate a systemically administered prodrug, CPT-11, to a powerful chemotherapeutic agent, SN-38, selectively at tumor sites, destroying invasive glioma cells while sparing normal tissues. Based on our preliminary data, we hypothesize that CE-expressing NSCs will home to tumor sites in the brain, and, in combination with CPT-11, will generate high concentrations of SN-38 specifically at tumor sites. Thus, in addition to potentially improving lifespan by concentrating the powerful chemotherapeutic agent selectively at tumor sites, this NSC-mediated treatment strategy should significantly decrease toxic side-effects to normal tissues, thus preserving or improving the patient’s quality of life.

Our research, regulatory and clinical teams have the collective expertise and experience to conduct the preclinical studies necessary to optimize the efficacy of this innovative treatment approach. Specifically, we will determine the optimal dose and route of NSC administration; the optimal prodrug dosing regimen; and assess the safety of this treatment approach. We will perform these studies and analyses, generate clinical grade products, and file and obtain all appropriate regulatory documents and approvals. Completion of these activities will lead to the filing of a new Investigational New Drug (IND) proposal to the FDA, for a first-in-human Phase I clinical trial of this pioneering NSC-mediated treatment in patients with recurrent high-grade gliomas.

Importantly, our NSC line can be further modified for tumor-localized delivery of a variety of therapeutic agents, and can be given serially or in combination to maximize therapeutic benefit. Thus, the potential medical impact of this innovative NSC-mediated therapeutic approach may be very far-reaching, as it can be developed for application to other types of malignant brain tumors, as well as for metastatic cancers.

Statement of Benefit to California: 

Despite aggressive multimodality therapy and advances in imaging, surgical and radiation techniques, high-grade gliomas remain incurable, with survival often measured in months. Approximately, 22,500 malignant brain tumors are diagnosed annually in the U.S., of which more than 2,600 cases are in California. New therapies are desperately needed to improve both the survival and quality of life of these brain tumor patients and to reduce the economic impact of billions of dollars in related healthcare costs.

We propose to develop a novel neural stem cell (NSC)-based treatment method that will selectively target glioma cells with a potent chemotherapy agent, locally activated by the NSCs at tumor sites to destroy neighboring tumor cells. Our tumor-selective approach also has the advantage of minimizing toxicity to normal tissues, thereby decreasing systemic side effects and damage to normal brain. This new therapeutic strategy, therefore, not only has the potential to improve survival, but, by preserving cognitive function and quality of life, it could also enable adult Californians diagnosed with brain tumors to continue making societal contributions that would benefit all Californians.

Important for clinical translation of this novel therapeutic approach, we have established the NSC line to be used in this study as a fully characterized cGMP Master Cell Bank. The NSC line is thus expandable, easily distributed to other medical centers, and cost-effective, which will allow this therapeutic approach to be quickly adopted. Importantly, this NSC line can be further modified for tumor-localized delivery of a variety of therapeutic agents, which may be given serially or in combination to maximize therapeutic benefit. There is tremendous potential for developing NSC-mediated treatment applications for other types of malignant brain tumors, as well as for metastatic solid tumors throughout the body. Therefore, the impact of these proposed studies to advance NSC-mediated treatment of glioma may be very far-reaching and may significantly contribute to reducing healthcare costs.

Finally, the combined strengths and experience of our research team will enable us to advance this NSC-meditated therapeutic approach in a timely, streamlined, and cost-effective manner to submit a new IND application for initiating first-in-human clinical trials in California, providing benefit to state taxpayers by efficient use of tax dollars and initial access to this novel therapy. In addition, our CIRM Disease Team NSC-mediated cancer treatment studies would stimulate and advance collaborative partnerships and alliances with other cancer centers and affiliates, pharmaceutical companies, academic institutions, and philanthropic societies within California, which would further enhance local and state economies.

Progress Report: 
  • Primary brain tumors are among the most difficult cancers to treat. High-grade gliomas, the most common primary brain tumors in adults, remain incurable with current therapies. These devastating tumors present significant treatment challenges for several reasons: 1) surgical removal runs the risk of causing permanent neurologic damage and does not eliminate cancer cells that have migrated throughout the brain; 2) most anti-cancer drugs are prevented from entering the brain because of the presence of the blood-brain barrier, which often does not allow enough chemotherapy into the brain to kill the cancer cells; and 3) typically, the amount of chemotherapy that can be given to cancer patients is limited by intolerable or harmful side effects from these agents. If concentrated cancer therapies could be specifically localized to sites of tumor, damage to healthy tissues would be avoided.
  • The long-range goal of this research project is to develop a neural stem cell (NSC)-based treatment strategy that produces a potent, localized anti-tumor effect while minimizing toxic side effects. NSCs hold the promise of improved treatment for brain cancers because they have the natural ability to distribute themselves within a tumor, as well as seek out other sites of tumor in the brain. Because they can home to the tumor cells, NSCs may offer a new way to bring more chemotherapy selectively to brain tumor sites. After modifying the NSCs by transferring a therapeutic gene into them, NSCs can serve as vehicles to deliver anti-cancer treatment directly to the primary tumor, as well as potentially to malignant cells that have spread away from the original tumor site. With funding from CIRM, we are studying the ability of NSCs, that carry an activating protein called carboxylesterase (CE) to convert the chemotherapy agent CPT-11 (irinotecan) to its more potent form, SN-38, at sites of tumor in the brain.
  • During the first year of funding we have determined that 1) when administered directly into the brain or into a peripheral vein (intravenous injection) of mice with brain tumors, NSCs will travel to several different subtypes of gliomas; 2) we can engineer the NSCs to consistently produce high levels of more powerful forms of CE: rCE and hCE1m6; 3) glioma cells die when they are exposed to very low (nanomolar) concentrations of SN-38, and 4) although glioma cells survive when exposed to a relatively high concentration of CPT-11 alone, they do die when the same concentration of CPT-11 is administered in combination with either rCE or hCE1m6. These results suggest that the engineered NSCs are expressing relatively high levels of CE enzymes and that the CE enzymes are converting CPT-11 into SN-38. We have also been able to label our NSCs with iron particles, so that we can track their movement in real-time by magnetic resonance imaging (MRI), and follow their location and distribution in relation to the tumor.
  • All of our data thus far support the original hypothesis that effective, tumor-specific therapy for glioma patients can be developed using NSCs that express rCE or hCE1 and the prodrug CPT-11. During the second year of CIRM funding, we will further analyze our data to make a final determination regarding the best form of CE to develop towards clinical trials, and the best dose range and route of delivery of NSCs to achieve maximal tumor coverage. We will then begin our therapeutic studies and start discussions with the Food and Drug Administration, to define the safety studies necessary to obtain approval for testing this new treatment strategy in patients with brain tumors.
  • High-grade gliomas, the most common primary brain tumors in adults, have a poor prognosis and remain incurable with current therapies. These devastating tumors present significant treatment challenges: 1) surgery may cause permanent neurologic damage; 2) surgery misses cancer cells that have invaded beyond the edge of the tumor or to other sites in the brain; 3) many, if not most, chemotherapy drugs cannot enter the brain because of the blood-brain barrier; and 4) due to the highly toxic nature of chemotherapy agents the therapeutic window (the difference between the dose that kills the tumor and the dose that causes toxic side effects) is very small, resulting in undesirable side-effects. Therefore, if therapeutic agents could be localized and concentrated selectively to the tumor sites, treatment efficacy may be improved while toxic side effects are minimized.
  • The overarching goal of this project is to develop a human Neural Stem Cell (NSC)-based treatment strategy that produces potent localized anti-tumor effects while minimizing toxic side effects. NSCs hold the promise of improved treatment for brain cancers because they have an innate ability to distribute within and around a tumor mass and to seek out tumor cells that have invaded further into surrounding brain tissue. By homing to cancer cells, NSCs offer a way to selectively deliver concentrated chemotherapy to brain tumor sites. We are modifying NSCs to make the protein carboxylesterase (CE), which will convert a systemically administered prodrug, CPT-11 (irinotecan) to an active, potent anti-cancer drug, SN38 at the tumor sites.
  • Our second year of funding was highly productive and informative. We validated key elements of our system, successfully negotiating Go/No Go milestones, yielding substantial progress:
  • (1) We have selected the optimal genetically modified human CE to efficiently convert CPT-11 to SN-38. This CE is being developed for clinical grade use.
  • (2) We have determined the volume of tumor coverage by NSCs injected directly into the brain versus injecting them intravenously. We found that we achieve more tumor coverage with direct injection of the NSCs into the brain, and will focus on developing this approach for initial NSC.CE/CPT-11 clinical trials. However, following intravenous injections we found the NSCs localize prominently at the invasive tumor edges, which may prove therapeutically efficacious as well. Due to the significant clinical and commercial advantages that intravenous administration presents, this approach will also be developed toward patient trials. We have determined the starting NSC dose range for both approaches.
  • (3) We have shown that CPT-11 + CE is1,000 fold more toxic to glioma cells than CPT-11 alone. Importantly, microdialysis studies in our preclinical models have confirmed the conversion of CPT-11 to SN-38 by our CE-secreting NSCs in the brain.
  • (4) We have completed studies labeling our NSCs with iron (Feraheme) nanoparticles, which allows for non-invasive cell tracking by Magnetic Resonance Imaging (MRI). Safety studies for clinical use of this iron-labeling method were completed and submitted to the FDA, for consideration of use in brain tumor patients enrolled in our current NSC.CD/5-FC recurrent glioma clinical trial. This would be the first-in-human use of Feraheme-labeled stem cells for MRI tracking.
  • Our results to date robustly support the original hypothesis that an effective, glioma-specific therapy can be developed using NSCs that home to tumors and express CE to convert CPT-11 to the potent anti-cancer agent SN-38. Pre-clinical therapeutic efficacy studies to optimize CPT-11 regimens are now in progress.
  • High-grade gliomas, the most common primary brain tumors in adults, have a poor prognosis and remain incurable with current therapies. These devastating tumors present significant treatment challenges; 1) surgery may cause permanent neurologic damage; 2) surgery misses cancer cells that have invaded beyond the edge of the tumor or disseminated to other sites in the brain; 3) many, if not most, chemotherapy drugs cannot enter the brain because of the blood-brain barrier; and 4) due to the highly toxic nature of chemotherapy agents the therapeutic window (the difference between the dose that kills the tumor and the dose that causes toxic side effects) is very small. Therefore, if therapeutic agents could be concentrated and localized to the tumor sites, treatment efficacy may be improved while toxic side effects are minimized.
  • The overarching goal of this project is to develop a human Neural Stem Cell (NSC)-based treatment strategy that produces potent localized anti-tumor effects while minimizing toxic side effects. NSCs hold the promise of improved treatment for brain cancers because they have an innate ability to distribute within and around a tumor mass and to seek out other, secondary and smaller tumor nodules in the brain. By homing to cancer cells, NSCs offer a way to selectively deliver concentrated chemotherapy to brain tumor sites. After modifying NSCs by adding the gene to make the protein carboxylesterase (CE), NSCs deliver CE to convert the drug CPT-11 (irinotecan) to its more potent form, SN-38 at primary and secondary brain tumor sites.
  • The major milestone in our third year of funding was that we completed our pre-IND package and held our pre-IND meeting with the FDA. To this end, we validated the following:
  • (1) NSCs can potentiate the in vivo efficacy of irinotecan (CPT-11) using a low dose (7.5 mg/kg) daily x 5 schedule. Both real time Xenogen and integrated morphometric analysis of immunohistochemically stained sections of tumor were used to determine tumor volumes.
  • (2) In vivo pharmacokinetics demonstrated increased accumulation of SN-38 in tumor over that of tumor interstitium. The concentrations of tumor SN-38 were approximately 3-fold higher in tumor-bearing brain tissue than in corresponding normal tissue supporting the hypothesis that NSCs can direct toxic chemotherapy in a tumor localized manner.
  • (3) Following FDA approval of the incorporation of iron (Feraheme) into NSCs, three patients were treated with FeHe-labeled HB1.F3.CD, the first generation NSCs undergoing clinical trial. There were no adverse effects from the treatment demonstrating relative safety and lack of toxicity of this method.
  • Our results to date robustly support the original hypothesis that an effective, glioma-specific therapy can be developed using NSCs that home to tumors and express CE to convert CPT-11 to SN-38. During the fourth and coming year of CIRM funding, we will conduct experiments to determine the optimal schedule for NSC/CPT-11 therapy and demonstrate the safety and lack of toxicity of the treatment schema in rodents to fulfill requirements for IND submission and clinical trial in humans.
  • High-grade gliomas, the most common primary brain tumors in adults, have a poor prognosis and remain incurable with current therapies. These devastating tumors present significant treatment challenges; 1) surgery may cause permanent neurologic damage; 2) surgery misses cancer cells that have invaded beyond the tumor edge to other sites in the brain; 3) many, if not most, chemotherapy drugs cannot enter the brain because of the blood-brain barrier; and 4) chemotherapy drugs are toxic to normal tissues as well as tumor, causing undesirable side effects. Therefore, if therapeutic agents could be concentrated and localized to the tumor sites, treatment efficacy may improve while side effects are minimized.
  • Our goal is to bring to the clinic a human Neural Stem Cell (NSC)-based treatment strategy that produces potent localized anti-tumor effects while minimizing toxic side effects. NSCs have a natural ability to home to invasive brain tumor cells throughout the brain. NSCs, used as a delivery vehicle, offer a novel way to selectively target chemotherapy to brain tumor sites. NSCs are modified to express a certain enzyme (carboxylesterase; CE), that converts systemically administered prodrug (irinotecan) to a much more potent form (SN-38), that is up to 1000 times more effective at killing brain tumor cells.
  • Milestones reached in our fourth year include:
  • (1) receiving regulatory approval from the NIH/OBA following a public form in September, 2013.
  • (2) determining the dose and timing of NSC and irinotecan administration for optimal therapeutic efficacy in pre-clinical brain tumor models.
  • (3) demonstrating that the CE-expressing NSCs can increase concentrations of the toxic drug SN-38 by > 6-fold compared to giving irinotecan alone. Furthermore, SN-38 concentrations were dose proportional to administered irinotecan concentrations.
  • (4) Safety-toxicity studies required by the FDA for Investigational New Drug (IND) approval were completed. These studies demonstrated no significant toxicities and safety of our NSC treatment protocol in preclinical brain tumor models.
  • Our results to date support our hypothesis that a safe and effective NSC-mediated therapy can be developed for clinical use in patients with high-grade glioma, with potential application to other types of brain tumor and brain tumor metastases. We hope to initiate clinical trials with our CE-expressing NSCs and irinotecan by the end of 2014.
  • High-grade gliomas, the most common primary brain tumors in adults, have a poor prognosis and remain incurable with current therapies. These devastating tumors present significant treatment challenges; 1) surgery may cause permanent neurologic damage; 2) surgery cannot remove the cancer cells that have invaded beyond the main tumor site; 3) most chemotherapy drugs cannot enter the brain because of the blood-brain barrier; and 4) chemotherapy drugs are toxic to normal tissues as well as tumor, causing undesirable side effects. Therefore, if therapeutic agents could be concentrated and localized to the tumor sites, treatment efficacy may improve while side effects are minimized.
  • Our goal is to bring to the clinic a human Neural Stem Cell (NSC)-based treatment strategy that produces potent localized anti-tumor effects while minimizing toxic side effects. NSCs have a natural ability to home to invasive brain tumor cells throughout the brain. NSCs, used as a delivery vehicle, offer a novel way to selectively target chemotherapy to brain tumor sites. NSCs are modified to express a certain enzyme (carboxylesterase; CE), that converts systemically administered prodrug (irinotecan) to a much more potent form (SN-38), that is up to 1000 times more effective at killing brain tumor cells.
  • Milestones reached in our fifth (final) year include:
  • (1) completion of safety/tox and efficacy study data analysis reports
  • (2) completion of clinical protocol
  • (3) completion of clinical lot for initiation of patient trial
  • (4) Regulatory documents including IBC, IRB, SCRO, NIH-RAC Protocol #13071241 all approved
  • (5) submission of final IND package to the FDA
  • (6) phase I trial initiation pending
  • Our results to date support our hypothesis that a safe and effective NSC-mediated therapy can be developed for clinical use in patients with high-grade glioma, with potential application brain tumor metastases, as well as metastatic cancers.
Funding Type: 
Disease Team Therapy Development III
Grant Number: 
DR3-06924
Investigator: 
Type: 
PI
Type: 
Co-PI
ICOC Funds Committed: 
$4 179 600
Disease Focus: 
Blood Cancer
Cancer
oldStatus: 
Active
Public Abstract: 

Cancer is a leading cause of death in California. Research has found that many cancers can spread throughout the body and resist current anti-cancer therapies because of cancer stem cells, or CSC. CSC can be considered the seeds of cancer; they can resist being killed by anti-cancer drugs and can lay dormant, sometimes for long periods, before growing into active cancers at the original tumor site, or at distant sites throughout the body. Required are therapies that can kill CSC while not harming normal stem cells, which are needed for making blood and other cells that must be replenished. We have discovered a protein on the surface of CSC that is not present on normal cells of healthy adults. This protein, called ROR1, ordinarily is found only on cells during early development in the embryo. CSC have co-opted the use of ROR1 to promote their survival, proliferation, and spread throughout the body. We have developed a monoclonal antibody that is specific for ROR1 and that can inhibit these functions, which are vital for CSC. Because this antibody does not bind to normal cells, it can serve as the “magic bullet” to deliver a specific hit to CSC. We will conduct clinical trials with the antibody, first in patients with chronic lymphocytic leukemia to define the safety and best dose to use. Then we plan to conduct clinical trials involving patients with other types of cancer. To prepare for such clinical trials, we will use our state-of-the-art model systems to investigate the best way to eradicate CSC of other intractable leukemias and solid tumors. Finally, we will investigate the potential for using this antibody to deliver toxins selectively to CSC. This selective delivery could be very active in killing CSC without harming normal cells in the body because they lack expression of ROR1. With this antibody we can develop curative stem-cell-directed therapy for patients with any one of many different types of currently intractable cancers.

Statement of Benefit to California: 

The proposal aims to develop a novel anti-cancer-stem-cell (CSC) targeted therapy for patients with intractable malignancies. This therapy involves use of a fully humanized monoclonal antibody specific for a newly identified, CSC antigen called ROR1. This antibody was developed under the auspices of a CIRM disease team I award and is being readied for phase I clinical testing involving patients with chronic lymphocytic leukemia (CLL). Our research has revealed that the antibody specifically reacts with CSC of other leukemias and many solid-tumor cancers, but does not bind to normal adult tissues. Moreover, it has functional activity in blocking the growth and survival of CSC, making it ideal for directing therapy intended to eradicate CSC of many different cancer types, without affecting normal adult stem cells or other normal tissues. As such, treatment could avoid the devastating physical and financial adverse effects associated with many standard anti-cancer therapies. Also, because this therapy attacks the CSC, it might prove to be a curative treatment for California patients with any one of a variety different types of currently intractable cancers.

Beyond the significant benefit to the patients and families that are dealing with cancer, this project will also strengthen the position of the California Institute of Regenerative Medicine as a leader in cancer stem cell biology, and will deliver intellectual property to the state of California that may then be licensed to pharmaceutical companies.

In summary, the benefits to the citizens of California from the CIRM disease team 3 grant are:

(1) Direct benefit to the thousands of patients with cancer
(2) Financial savings through definitive treatment that obviates costly maintenance or salvage therapies for patients with intractable cancers
(3) Potential for an anti-cancer therapy with a high therapeutic index
(4) Intellectual property of a broadly active uniquely targeted anti-CSC therapeutic agent.

Progress Report: 
  • Dormant cancer stem cells (CSC) evade therapies that target dividing cells and promote drug-resistance, relapse, and metastasis. Despite advances in molecularly targeted therapy, therapeutic resistance and relapse, driven by self-renewing CSC, remain major therapeutic challenges in common hematologic malignancies like chronic lymphocytic leukemia (CLL). As a result of a CIRM HALT leukemia disease team grant, we were able to pre-clinically inhibit CSC survival in CLL and a broad array of other advanced malignancy models by developing a monoclonal antibody, cirmtuzumab (UC-961), which targets the Wnt5A receptor, ROR1. Cirmtuzumab is a humanized monoclonal antibody (mAb) that binds with high-affinity to a proprietary, extracellular epitope of ROR1, which we defined as an onco-embryonic antigen. While ROR1 is not expressed on adult hematopoietic stem cells or other normal post-partum tissues, it is highly expressed on the cell-surface of CSC in CLL. Cirmtuzumab does not bind to normal adult tissues, but has unique functional activity against CSC by targeting ROR1, which acts in a niche-dependent fashion. In preclinical models, shRNA-silencing of ROR1 was shown to impair activation of phospho-AKT/CREB, increases spontaneous apoptosis, and inhibit the proliferation, migration, and metastatic potential of CSC in a manner similar to cirmtuzumab. In addition, cirmtuzumab inhibits the capacity of CSC to to propagate CLL in immune-deficient mice. Finally, cirmtuzumab induced rapid internalization of ROR1, thereby inhibiting CSC survival. Based on these unique features, we proceeded with the cirmtuzumab clinical development plan under the auspices of the CIRM disease team 3 grant.
  • Over the last year, this CIRM Disease team grant has enabled filing and FDA approval of an investigational new drug application (IND) for cirmtuzumab as well as the implementation and administration of an ongoing first-in-human Phase 1A clinical trial to assess safety and tolerability in patients with CLL who are not amenable to standard therapy. In keeping with the FDA IND-approved intra-patient dose escalation schema and related cirmtuzumab administration timeline, our team has enrolled 8 patients to the Phase lA clinical trial at UC San Diego for patients with relapsed or refractory CLL since 8/29/15. In particular, we have now completed enrollment of the first and second dose cohorts (doses: 15 mcg/kg and 30 mcg/kg for cohort 1; 60 mcg/kg, 120 mcg/kg, and 240 mcg/kg for cohort 2). There have been no observed grade 2 or higher adverse events attributed to cirmtuzumab. Two patients have now enrolled and initiated therapy in the third dose cohort (planned doses 500 mcg/kg and 1 mg/kg). While durable clinical responses have not been observed at these low doses, there has been evidence of biological activity and clinical benefit with stabilization of disease in some patients. This has prompted the development of a Phase 1B clinical trial, currently under review at our IRB and at CIRM, to allow patients that have derived some benefit from cirmtuzumab treatment to receive additional doses and to determine if longer term treatment provides for enhanced clinical benefit while retaining an excellent safety profile.
  • Correlative biomarkers include flow cytometric analyses that address disease heterogeneity and are suggestive of decreased ROR1 expression in the more recent dosing cohorts that may be used in the future to predict clinical outcome. In cohorts that demonstrate signs of sustained clinical responses, we will examine the activity of cirmtuzumab-based treatments in eradicating ROR1+ CSC by flow cytometry. Pharmacokinetic assessments are ongoing but cirmtuzumab plasma levels appear to correlate with response in the more recent higher dose cohort. In addition, we will examine the activity and anticipated therapeutic index (TI) of cirmtuzumab in relapsed/refactory CLL. If one or more of these tests meet milestones, then clinical studies of regimens with the highest apparent TI will be conducted in years 3-4. Upon completion of our program, we will deliver a cirmtuzumab-based therapeutic that will be suitable for registration and/or pivotal clinical trials and facilitate commercialization of this novel cancer stem-cell targeted therapy for Californians with cancer.
Funding Type: 
Alpha Stem Cell Clinics
Grant Number: 
AC1-07659
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$8 000 000
Disease Focus: 
Blood Disorders
Blood Cancer
Cancer
HIV/AIDS
Solid Tumor
Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

As the largest provider of bone marrow cell transplants in California, and the second largest in the nation, our institution has great expertise and an excellent record of safety in the delivery of stem cell treatments. We now propose to create the Alpha Clinic for Cell Therapy and Innovation (ACT-I) in which new, state-of-the-art, stem cell treatments for cancer and devastating blood-related diseases will be conducted and evaluated. As these experimental therapies prove to be effective, and become routine practice, our ACT-I Program will serve as the clinical center for delivery of these treatments. ACT-I will be an integral part of our Hematologic Malignancy and Stem Cell Transplantation Institute, placing it in the center of our institutional strengths, expertise, infrastructure and investment over the next decade. To move quickly once the CIRM award is made, ACT-I can be launched within our institution’s Day Hospital, a brand new, outpatient blood stem cell transplantation center opened in late 2013 with California Department of Health approval for 24 hour a day operation. This will ensure that ACT-I will have all the clinical and regulatory expertise, trained personnel, state-of-the-art facilities and other infrastructure in place to conduct first-in-human clinical trials and to deliver future, stem cell-based therapies for cancer and blood-related diseases, including AIDS. When our new Ambulatory Treatment Center is complete in 2018, it will double our capacity for patient visits and allow for expansion of the ACT-I pipeline of new stem cell products in a state-of-the-art facility.

Beyond our campus, we operate satellite clinics covering an area that includes urban, suburban and rural sites. More than 17.7 million people live in this area, and represent some of the greatest racial and ethnic diversity seen in any part of the country. Our ACT-I is prepared to serve a significant, diverse and underserved portion of the population of California.

CLINICAL TRIALS. Our proposal has two lead clinical trials that will be the first to be tested in ACT-I. One will deliver transplants of blood stem cells that have been modified to treat patients suffering from AIDS and lymphoma. The second will use neural stem cells to deliver drugs directly to cancer cells hiding in the brain. These studies represent some of the new and exciting biomedical technologies being developed at our institution. In addition to the two lead trials, we have several additional clinical studies poised to use and be tested in this special facility for clinical trials. In summary, ACT-I is well prepared to accommodate the long list of clinical trials and begin to fulfill the promise of providing new stem cell therapies for the citizens of California.

Statement of Benefit to California: 

California’s citizens voted for the California Stem Cell Research and Cures Act to support the development of stem cell-based therapies that treat incurable diseases and relieve human suffering. To achieve this goal, we propose to establish an Alpha Clinic for Cellular Therapies and Innovation (ACT-I) as an integral part of our Hematological Malignancies and Stem Cell Transplantation Institute, and serve as the clinical center for the testing and delivery of new, cutting-edge, cellular treatments for cancer and other blood-related diseases. Our institution is uniquely well-suited to serve as a national leader in the study and delivery of stem cell therapeutics because we are the largest provider of stem cell transplants in California, and the second largest in the country. According to national benchmarking data, our Hematopoietic Cell Transplantation program is the only program in the nation to have achieved survival outcomes above expectation for each of the past nine years. This program currently offers financially sustainable, research-driven clinical care for patients with cancer, HIV and other life-threatening diseases. CIRM funding will allow the ACT-I clinic to ramp up quickly, drawing upon institutionally established protocols, personnel and infrastructure to conduct first-in-human clinical trials for assessment of efficacy. As CIRM funding winds down, ACT-I will have institutional support to offer proven cellular therapeutics to patients. The lead studies at the forefront of the ACT-I pipeline of clinical trials focus on treatments for HIV-1 infection and brain tumors, two devastating and incurable conditions. These first trials are closely followed by a robust queue of other stem cell therapeutics for leukemia, lymphoma, prostate cancer, brain cancers and thalassemia.

Our long list of proposed treatments addresses diseases that have a major impact on the lives of Californians. Thalassemia is found in up to 1 in 2,200 children born in California; prostate cancer affects 211,300 men, and HIV-1 infection occurs in 111,000 of our citizens. From 2008 to 2010, 6,705 Californians were diagnosed with brain cancers, 4,580 of whom died. In considering hematological malignancies during this same period, 2,800 patients were diagnosed with Hodgkin lymphoma (416 died), 20,351 with non-Hodgkin lymphoma (6,241 died), 13,358 with leukemia (6,961 died), 3,900 with acute myelogenous leukemia (2,972 died), 2,129 with acute lymphoblastic leukemia (648 died) and 4,198 with chronic lymphocytic leukemia (1,271 died). Standard of care fails in many cases; mortality rates for patients with hematological malignancies range from 25% to 76%. Successful stem cell therapeutics hold the promise to reduce disease-related mortality while improving disease-related survival and quality of life for the citizens of California, and for those affected by these diseases worldwide.

Funding Type: 
Disease Team Therapy Development III
Grant Number: 
DR3-07067
Investigator: 
Type: 
Co-PI
ICOC Funds Committed: 
$6 924 317
Disease Focus: 
Cancer
oldStatus: 
Active
Public Abstract: 

Cancer is a major cause of morbidity and mortality worldwide. Many believe that progress in drug development has not been as rapid as one would have predicted based on the significant technological advancements that have led to improved molecular understanding of this disease. There are numerous explanations for the lag in clinical success with new therapeutics. However, work in the past decade has provided support for what has become known as the cancer stem cell hypothesis. This model suggests that there is a class of cells that are the main drivers of tumor growth that are resistant to standard treatments. In one model the cancer stem cells inhabit an anatomical “niche” that prevents drug efficacy. Another view is one in which tumors can achieve resistance by cell fate decisions in which some tumor cells are killed by therapeutics, while other cells avoid this fate by choosing to become cancer stem cells. These stem cells are thought to be capable of both cancer stem cell renewal and repopulation of the tumor.
Our proposal aims to conduct a Phase I clinical trial of a first-in-class mitotic inhibitor. The target is a serine/threonine kinase that was originally selected because blocking this target affects both tumor cell lines and tumor initiating cells (TICs). Our data suggest that the target kinase functions at the intersection of mitotic regulation, DNA damage and repair, and cell fate decisions associated with stem cell renewal. Preclinical work has begun to segregate “sensitive” and “resistant” groups of tumor cell lines and TICs after treatment with the drug candidate as a single agent and in combination with standard-of-care therapeutics. Our data also support the model in which cancer stem cell resistance is likely to arise, at least in some cases, due to stem cell fate decisions that happen in response to therapeutic intervention.
This grant is a natural progression of work partially funded by CIRM that enabled the isolation of Tumor Initiating Cells (TICs)from tumors in different tissue types. This facilitated the development and assessment of drug candidates that target both bulk tumor cells and TICs and has now led to the development of a potential anti-cancer drug which we are now preparing to test in humans. The goal of the Phase I trial is to determine the maximum tolerated dose, the recommended Phase II dose, and any dose-limiting toxicities. We will also characterize safety, pharmacokinetic, and pharmacodynamic profiles along with any antitumor activity. Once the maximum tolerated dose has been identified, a biomarker expansion cohort will be opened in order to determine whether appropriately selected biomarkers are associated with a predictable patient response. This will allow a rational approach to study single agent and combination studies that perturb this network and allow us the opportunity to facilitate a targeted clinical development plan.

Statement of Benefit to California: 

It has been estimated, by the California Department of Public Health, that in 2013 about 145,000 Californians will be diagnosed with cancer and more than 55,000 of these will ultimately succumb to their disease. Furthermore, more than 1.3 million Californians are living today with a history of cancer. Therefore, innovative research programs that are able to impact this devastating disease burden are likely to have a large potential benefit to the state of California and its residents.
This grant application proposes a Phase I clinical trial for a first-in-class inhibitor of a target that has never been tested in patients. The aim of this trial is to determine the maximum tolerated dose in humans, the recommended dose for phase II trials, and evaluate any dose-limiting toxicities. The trial will also characterize safety, pharmacokinetics, and pharmacodynamic properties. It will also provide early insight into any antitumor activity.
Our group has developed a comprehensive unbiased platform that facilitates the segregation of sensitive and resistant populations of cancer based on their molecular subtypes. This capability has the promise to improve the success rate and reduce the cost of oncology clinical trials by focusing on the subsets that are most likely to benefit while avoiding unnecessarily treating patients that would otherwise benefit from alternative treatments. Our preliminary pre-clinical work, funded by CIRM in the context of a Disease Team I award, suggests that this approach can be successfully applied to the networks associated with mitotic regulation, DNA repair, and stem-cell fate decisions. Our ongoing research has tested a number of chemical compounds that are able to block pathways that are critical to the growth and proliferation of many cancer models. These compounds have all been tested in multiple in vitro and in vivo systems and have been found to inhibit the ability of the cancer stem cell to repopulate. Now that our pre-clinical enabling studies have been completed, we have submitted an Investigational New Drug (IND) application to the FDA for a first-in-human phase I clinical trial. In the current proposal, we will be able to test our hypotheses in a clinical setting, which if successful will lead to confirmation of safety and the establishment of the appropriate dose with which to test in later stage trials. This trial will set the stage for a new class of agents that has not yet been tested in clinical settings.
We believe that the proposal described herein has the promise to expand the reach of targeted therapies into mechanisms that in most cases have been resistant to innovation. Finally, it is reasonable to expect that our preclinical work and the proposed clinical trials will validate a number of potential biomarkers that will identify susceptible patient subpopulations.

Progress Report: 
  • Over the last several years, it has become increasingly clear that cancer is a diverse disease where the treatments must be individualized. In the last year alone, 8 new drugs have received FDA approvals to treat cancers ranging from those that originate in the bone marrow (lymphoma, or myeloma) to “solid” tumors (eg breast or lung cancer). Most new drug development focuses on identifying subgroups that are more likely to respond and therefore derive benefit from these new agents. Along these lines, the attraction of attacking the cancer stem cell has become a priority. The cancer stem cell model suggests that there is a class of cells that are the main drivers of tumor growth that are resistant to standard treatments. This model even implies that tumors can achieve resistance by cell fate decisions in which some tumor cells are killed by therapeutics which makes the relevance of new drug development even more critical.
  • In our proposal, we are conducting a first in human Phase I clinical trial of a first-in-class mitotic inhibitor. The target is a serine/threonine kinase that was originally selected because blocking this target affects both tumor cell lines and tumor initiating cells (TICs). But, compared to chemotherapy, it appears to decrease more of the tumor initiating cell population in many cancer models. We have been able to identify those pre-clinical models that will predict which cancer are sensitive and which are resistant. The goal of our Phase I trial is to determine the maximum tolerated dose, the recommended Phase II dose, and any dose-limiting toxicities. We will further characterize safety, pharmacokinetic, and pharmacodynamic profiles along with any antitumor activity. In the last year, we have enrolled many patients and we are starting to develop a sense of how this drug works and in which cancers it may have the most potential relevance. Once the maximum tolerated dose has been identified, a biomarker expansion cohort will be opened in order to determine whether appropriately selected biomarkers are associated with a predictable patient response. This will allow a rational approach to study single agent and combination studies and allow us the opportunity to facilitate a targeted clinical development plan.
Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06479
Investigator: 
ICOC Funds Committed: 
$3 084 000
Disease Focus: 
Blood Disorders
Blood Cancer
Cancer
Stem Cell Use: 
iPS Cell
Directly Reprogrammed Cell
Cell Line Generation: 
Directly Reprogrammed Cell
oldStatus: 
Active
Public Abstract: 

The current roadblocks to hematopoietic stem cell (HSC) therapies include the rarity of matched donors for bone marrow transplant, engraftment failures, common shortages of donated blood, and the inability to expand HSCs ex vivo in large numbers. These major obstacles would cease to exist if an extensive, bankable, inexhaustible, and patient-matched supply of blood were available. The recent validation of hemogenic endothelium (blood vessel cells lining the vessel wall give rise to blood stem cells) has introduced new possibilities in hematopoietic stem cell therapy. As the phenomenon of hemogenic endothelium only occurs during embryonic development, we aim to understand the requirements for the process and to re-engineer mature human endothelium (blood vessels) into once again producing blood stem cells (HSCs). The approach of re-engineering tissue specific de-differentiation will accelerate the pace of discovery and translation to human disease. Engineering endothelium into large-scale hematopoietic factories can provide substantial numbers of pure hematopoietic stem cells for clinical use. Higher numbers of cells, and the ability to grow cells from matched donors (or the patients themselves) will increase engraftment and decrease rejection of bone marrow transplantation. In addition, the ability to program mature lineage restricted cells into more primitive versions of the same cell lineage will capitalize on cell renewal properties while minimizing malignancy risk.

Statement of Benefit to California: 

Bone marrow transplantation saves the lives of millions with leukemia and other diseases including genetic or immunologic blood disorders. California has over 15 centers serving the population for bone marrow transplantation. While bone marrow transplantation can be seen as a standard to which all stem cell therapies should aspire, there still remains the difficulty of finding matched donors, complications such as graft versus host disease, and the recurrence of malignancy. While cord blood has provided another donor source of stem cells and improved engraftment, it still requires pooling from multiple donors for sufficient cell numbers to be transplanted, which may increase transplant risk. By understanding how to reprogram blood vessels (such as those in the umbilical cord) for production of blood stem cells (as it once did during human development), it could eventually be possible to bank umbilical cord vessels to provide a patient matched reproducible supply of pure blood stem cells for the entire life of the patient. Higher numbers of cells, and the ability to grow cells from matched donors (or the patients themselves) will increase engraftment and decrease rejection of bone marrow transplantation. In addition, the proposed work will introduce a new approach to engineering human cells. The ability to turn back the clock to near mature cell specific stages without going all the way back to early embryonic stem cell stages will reduce the risk of malignancy.

Progress Report: 
  • We aim to understand how blood stem cells develop from blood vessels during development. We are also interested in learning whether the blood-making program can be turned back on in blood vessel cells for blood production outside the human body. During the past year we have been able to extract and culture blood vessel cells that once had blood making capacity. We have also started experiments that will help uncover the regulation of the blood making program. In addition, we have developed tools to help the process of understanding whether iPS technology can "turn back time" in mature blood vessels and turn on the blood making program.
  • We aim to understand how blood stem cells develop from blood vessels during development. We are also interested in learning whether the blood-making program can be turned back on in blood vessel cells for bloodproduction outside the human body. During the past year we have made progress in understanding early human hematopoiesis such that we have designed new tools that may enable us to try and generate hematopoietic cells in culture. We have also gained ground in refining our screening strategy that we hope to adapt for finding new regulators of blood development that can be used for culturing hematopoietic stem cells.

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