Cancer

Coding Dimension ID: 
280
Coding Dimension path name: 
Cancer

Genetic Re-programming of Stem Cells to Fight Cancer

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05309
ICOC Funds Committed: 
$19 999 563
Disease Focus: 
Melanoma
Cancer
Collaborative Funder: 
NIH
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
Science has made great progress in the treatment of certain cancers with targeted and combination therapies, yet prolonged remissions or cures are rare because most cancer therapies only inhibit cell growth and/or reduce such growth but do not stop the cancer. The study investigators propose to develop an Investigational New Drug (IND) and fully enroll a phase I clinical trial within the grant period to genetically redirect the patient’s immune response to specifically attack the cancer starting from hematopoietic (blood) stem cells (HSC) in patients with advanced forms of the aggressive skin cancer malignant melanoma. Evaluation of immune system reconstitution, effectiveness and immune response during treatment will use imaging with Positron Emission Tomography (PET) scans. The HSC treatment approach has been validated in extensive studies in the laboratory. The investigators of this grant have recently initiated a clinical trial where adult immune cells obtained from blood are genetically modified to become specific killer cells for melanoma. These cells are administered back to patients. The early data from this study is encouraging in terms of the ability to generate these cells, safely administer them to patients leading to beneficial early clinical effects. However, the adult immune cells genetically redirected to attack cancer slowly decrease over time and lose their killer activity, mainly because they do not have the ability to self-renew. The advantage of the proposed HSC method over adult blood cells is that the genetically modified HSC will continuously generate melanoma-targeted immune killer cells, hopefully providing prolonged protection against the cancer. The IND filing with the FDA will use the modified HSC in advanced stage melanoma patients. By the end of year 4, we will have fully accrued this phase 1 clinical trial and assessed the value of genetic modification of HSCs to provide a stable reconstitution of a cancer-fighting immune system. The therapeutic principles and procedures we develop will be applicable to a wide range of cancers and transferrable to other centers that perform bone marrow and HSC transplants. The aggressive milestone-driven IND timeline is based on our: 1) Research that led to the selection and development of a blood cell gene for clinical use in collaboration with the leading experts in the field, 2) Wealth of investigator-initiated cell-based clinical research and the Human Gene Medicine Program (largest in the world with 5% of all patients worldwide), 3) Experience filing a combined 15 investigator initiated INDs for research with 157 patients enrolled in phase I and II trials, and 4) Ability to have leveraged significant institutional resources of on-going HSC laboratory and clinical research contributed ~$2M of non-CIRM funds to pursue the proposed research goals, including the resulting clinical trial.
Statement of Benefit to California: 
Cancer is the leading cause of death in the US and melanoma incidence is increasing fastest (~69K new cases/year). Treatment of metastatic melanoma is an unmet local and national medical need (~9K deaths/year) striking adults in their prime (20-60 years old). Melanoma is the second greatest cancer cause of lost productive years given its incidence early in life and its high mortality once it metastasizes. The problem is severe in California, with large populations with skin types sensitive to the increased exposure to ultraviolet light. Most frequently seen in young urban Caucasians, melanoma also strikes other ethnicities, i.e., steady increases of acral melanoma in Latinos and African-Americans over the past decades. Although great progress has been made in the treatment of certain leukemias and lymphomas with targeted and combination therapies, few options exist for the definitive treatment of late stage solid tumors. When cancers like lung, breast, prostate, pancreas, and melanoma metastasize beyond surgical boundaries, prolonged remissions or cures are rare and most cancer therapies only inhibit cell growth and/or reduce such growth but do not stop the cancer. Our proposal, the filing of an IND and the conduct of a phase 1 clinical trial using genetically modified autologous hematopoietic stem cells (HSC) for the immunotherapy of advanced stage melanoma allowing sustained production of cancer-reactive immune cells, has the potential to address a significant and serious unmet clinical need for the treatment of melanoma and other cancers, increase patient survival and productivity, and decrease cancer-related health care costs. The advantage of the proposed HSC methodology over our current work with peripheral blood cells is that genetically modified stem cells will continuously generate melanoma-targeted immune cells in the patient’s body providing prolonged protection against the cancer. The therapeutic principles and procedures developed here will be applicable to a wide range of cancers. Good Manufacturing Practices (GMP) reagents and clinical protocols developed by our team will be transferable to other centers where bone marrow and peripheral blood stem cell transplantation procedures are done.

White matter neuroregeneration after chemotherapy: stem cell therapy for “chemobrain”

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06510
ICOC Funds Committed: 
$2 800 536
Disease Focus: 
Neurological Disorders
Brain Cancer
Cancer
Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Chemotherapy for cancer is often life saving, but it also causes a debilitating syndrome of impaired cognition characterized by deficits in attention, concentration, information processing speed, multitasking and memory. As a result, many cancer survivors find themselves unable to return to work or function in their lives as they had before their cancer therapy. These cognitive deficits, colloquially known as "chemobrain" or "chemofog," are long-lasting and sometimes irreversible. For example, breast cancer survivors treated with chemotherapy suffer from cognitive disability even 20 years later. These cognitive problems occur because chemotherapy damages the neural stem and precursor cells necessary for the health of the brain's infrastructure, called white matter. We have discovered a powerful way to recruit the stem/precursor cells required for white matter repair that depends on an interaction between the electrical cells of the brain, neurons, and these white matter stem/precursor cells. In this project, we will determine the key molecules responsible for the regenerative influence of neurons on these white matter stem cells and will develop that molecule (or molecules) into a drug to treat chemotherapy-induced cognitive dysfunction. If successful, this will result in the first effective treatment for a disease that affects at least a million cancer survivors in California.
Statement of Benefit to California: 
Approximately 100,000 Californians are diagnosed with cancer each year, and the majority of these people require chemotherapy. While cancer chemotherapy is often life saving, it also causes a debilitating neurocognitive syndrome characterized by impaired attention, concentration, information processing speed, multitasking and memory. As a result, many cancer survivors find themselves unable to return to work or function in their lives as they had before their cancer therapy. These cognitive deficits, colloquially known as "chemobrain" or "chemofog" are long-lasting; for example, cognitive deficits have been demonstrated in breast cancer survivors treated with chemotherapy even 20 years later. With increasing cancer survival rates, the number of people living with cognitive disability from chemotherapy is growing and includes well over a million Californians. Presently, there is no known therapy for chemotherapy-induced cognitive decline, and physicians can only offer symptomatic treatment with medications such as psychostimulants. The underlying cause of "chemobrain" is damage to neural stem and precursor cell populations. The proposed project may result in an effective regenerative strategy to restore damaged neural precursor cell populations and ameliorate or cure the cognitive syndrome caused by chemotherapy. The benefit to California in terms of improved quality of life for cancer survivors and restored occupational productivity would be immeasurable.
Progress Report: 
  • Cancer chemotherapy can be lifesaving but frequently results in long-term cognitive deficits. This project seeks to establish a regenerative strategy for chemotherapy-induced cognitive dysfunction by harnessing the potential of the interactions between active neurons and glial precursor cells that promote myelin plasticity in the healthy brain. In the first year of this award, we have made on-track progress towards establishing a working experimental model system of chemotherapy-induced neurotoxicity that faithfully models the human disease both in terms of the cellular damage as well as functional deficits in cognition. We have also been able to identify several therapeutic candidate molecules that we will be studying in the coming years of the project to ascertain which of these candidates are sufficient to promote OPC population repletion and neuro-regeneration after chemotherapy exposure.

Center of Excellence for Stem Cell Genomics

Funding Type: 
Genomics Centers of Excellence Awards (R)
Grant Number: 
GC1R-06673-A
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.

CD61-driven stemness program in epithelial cancer

Funding Type: 
Basic Biology V
Grant Number: 
RB5-06978
ICOC Funds Committed: 
$1 161 000
Disease Focus: 
Solid Tumor
Cancer
Stem Cell Use: 
Cancer Stem Cell
oldStatus: 
Closed
Public Abstract: 
Tumors contain a heterogeneous mix of cancer cells with distinct features, including subsets of particularly aggressive stem-like cells. Since a single cancer stem cell can self-renew, divide, and differentiate to reconstitute the heterogeneity of an entire tumor, the ability of one cell to evade therapy or surgical resection could lead to tumor re-growth and disease relapse. Few, if any, individual markers have been capable of identifying cancer stem cells among distinct tumor types. It is therefore remarkable that we have detected enrichment of CD61 on stem-like cells within tumor biopsies from many different drug-resistant samples of lung, breast, pancreatic, and brain tumors from mice or humans. CD61 promotes a stem-like reprogramming event, since ectopic expression CD61 induces stemness, including self-renewal, tumor-forming ability, and resistance to therapy. CD61 drives these behaviors by activating a signaling pathway which can be inhibited to reverse stemness and sensitize tumors to therapy. Our project is focused on learning how CD61 drives this cancer stem cell program, and how the increase in CD61 could be prevented or reversed. If successful, our work will provide valuable new insight into a cancer stem cell program that is unexpectedly shared among a variety of solid tumor types.
Statement of Benefit to California: 
The American Cancer Society estimates 171,330 new cancer cases will be diagnosed in California this year, a 10th of the national total. As part of an NCI-designated comprehensive cancer, we are uniquely positioned to translate our basic science research into clinical impact for the cancer patients within our community. From a clinical perspective, the understanding gained from our proposed studies will broadly benefit patients in California who will be diagnosed with an epithelial cancer this year, including 25,360 new breast cancer patients and 18,720 new lung cancer patients. Gaining fundamental insight into how these cancers are reprogrammed to become more stem cell-like as they acquire resistance to therapy will facilitate development of new strategies to prevent or reverse this behavior to benefit these large numbers of patients who live in California. In addition, our work will also yield new diagnostic tools that could identify which patients might respond to certain therapies. At the basic science level, our project will also serve to elucidate the mechanisms by which cancer stem cells contribute to cancer progression and response to therapy. During the course of our project, we will be able to train more people in California to work on this cutting-edge research, and to establish a foundation for the logical design of anti-cancer therapies targeting this unique cancer stem cell population.

Clinical Investigation of a Humanized Anti-CD47 Antibody in Targeting Cancer Stem Cells in Hematologic Malignancies and Solid Tumors

Funding Type: 
Disease Team Therapy Development III
Grant Number: 
DR3-06965
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.

Therapeutic Eradication of Cancer Stem Cells

Funding Type: 
Disease Team Therapy Development III
Grant Number: 
DR3-06924
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.

Trop2 dependent and independent mechanisms of self-renewal in human cancer stem cells

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06209
ICOC Funds Committed: 
$1 382 400
Disease Focus: 
Cancer
Prostate Cancer
Stem Cell Use: 
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 
Progress from our group and others has led to the identification of normal prostate tissue stem cells and the definition of important signaling pathways that regulate their growth and maintenance. Human cancers utilize these same pathways to promote malignancy and drive tumor progression. Our recent studies have uncovered an important regulatory molecule (Trop2) that is expressed on a subset of prostate cancer cells capable of regenerating tumors. Trop2 expression is selected for in advanced disease and predicts poor prognosis for many tumors including prostate, ovarian, pancreatic, breast, gastric and colorectal cancer. We predict that blocking Trop2 and other regulatory signaling pathways will be an effective strategy to prevent disease progression in prostate and other human cancers.
Statement of Benefit to California: 
In 2012 alone in the state of California, an estimated 29,000 men will be diagnosed with prostate cancer and almost 3,400 men will die from the disease. The advanced stages of prostate cancer are treated with hormonal therapy which causes significant changes in mood, body weight and composition, impotence and gynecomastia in addition to the pain and suffering from the disease. Our proposed experiments will define new therapeutic targets and combinatorial therapies with the potential to significantly extend life and minimize suffering of men with advanced prostate cancer. Many of the molecules that we are investigating are implicated in a range of tumors, suggesting that our findings may provide benefit to patients suffering from numerous cancers.
Progress Report: 
  • Stem cells are characterized by longevity, self-renewal throughout the lifetime of a tissue or organism and the ability to generate all lineages of a tissue. Pathways involved in stem cell function are commonly dysregulated in cancer. Emerging evidence in leukemias and epithelial cancers suggests that tumors can be maintained by self-renewing cancer stem cells (CSCs), defined functionally by their ability to regenerate tumors. Delineating mechanisms that regulate self-renewal in human CSCs are essential to design new therapeutic strategies to combat cancer.
  • We have developed an in vivo tissue-regeneration model of primary human prostate cancer and identified two distinct populations of CSCs that can self-renew and serially propagate tumors. Both CSC subsets express the transmembrane protein Trop2. We have previously shown that Trop2 is a marker and a new regulator of stem/progenitor activity in the prostate. Trop2 controls self-renewal, proliferation and tissue hyperplasia through two cleavage products—intracellular domain (ICD) and extracellular domain (ECD) generated by regulated intramembrane proteolysis (RIP). RIP of Trop2 is carried out by TACE metalloprotease and gamma-secretase complex.
  • We have also demonstrated that cleaved Trop2 ICD is found in human prostate cancer but not in the cancer-adjacent benign tissue, suggesting a role for Trop2 cleavage in tumorigenesis. Now we are generating antibodies that will block Trop2 cleavage and activation. Blocking Trop2 signaling will be an effective strategy to prevent disease progression not only in the prostate but also in other epithelial cancers.
  • Stem cells are characterized by longevity, self-renewal throughout the lifetime of a tissue or organism and the ability to generate all lineages of a tissue. Pathways involved in stem cell function are commonly dysregulated in cancer. Emerging evidence in leukemias and epithelial cancers suggests that tumors can be maintained by self-renewing cancer stem cells (CSCs), defined functionally by their ability to regenerate tumors. Delineating mechanisms that regulate self-renewal in human CSCs are essential to design new therapeutic strategies to combat cancer.
  • We have developed an in vivo tissue-regeneration model of primary human prostate cancer and identified two distinct populations of CSCs that can self-renew and serially propagate tumors. Both CSC subsets express the transmembrane protein Trop2. We have previously shown that Trop2 is a marker and a new regulator of stem/progenitor activity in the prostate. Trop2 controls self-renewal, proliferation and tissue hyperplasia through two cleavage products—intracellular domain (ICD) and extracellular domain (ECD) generated by regulated intramembrane proteolysis (RIP). RIP of Trop2 is carried out by TACE metalloprotease and gamma-secretase complex.
  • We have also demonstrated that cleaved Trop2 ICD is found in human prostate cancer but not in the cancer-adjacent benign tissue, suggesting a role for Trop2 cleavage in tumorigenesis. So far we generated seventeen antibodies against Trop2. Currently we are testing the inhibitory effect of the antibodies on Trop2 cleavage and activation. Blocking Trop2 signaling will be an effective strategy to prevent disease progression not only in the prostate but also in other epithelial cancers.

Targeting glioma cancer stem cells with receptor-engineered self-renewing memory T cells

Funding Type: 
Early Translational III
Grant Number: 
TR3-05641
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.

Recombinant Bispecific Antibody Targeting Cancer Stem Cells for the Therapy of Glioblastoma

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05373
ICOC Funds Committed: 
$109 750
Disease Focus: 
Brain Cancer
Cancer
oldStatus: 
Closed
Public Abstract: 
Glioblastoma multiforme is the most prevalent and aggressive type of brain tumor, and devastating to any patient unfortunate enough to receive its diagnosis. As the most populous state in the nation, more Californians are diagnosed with glioblastoma multiforme than any other state. Over the past 20 years, surgery, radiation therapy and chemotherapy have been utilized with frustrating results. Today, even with the most advanced treatments available, survival rates average only 14-15 months. Our proposed research focuses on a new theory that brain tumor cells are initiated and maintained by a small fraction of cells with stem cell-like properties. This “cancer stem cell” hypothesis states that if this small subset of cancer stem cells could be eliminated then the tumor would cease to grow. Cancer stem cells in glioblastoma have been identified using CD133, a well known marker for isolating normal neural stem cells. The fact that CD133 is present on normal stem cells means that only targeting this molecule would be potentially dangerous. To enhance targeting, we reasoned that a cancer-specific alteration found in glioblastoma could be used as a potential marker for cancer stem cells. EGFRvIII is a specific variant of the normal EGF receptor and is widely found in glioblastoma but is rarely present in normal tissues. We have now shown that tumor cells that express both CD133 and EGFRvIII have the most cancer stem cell properties—more so than cells that have CD133 or EGFRvIII alone. We then developed a “bispecific” antibody that simultaneously recognizes both of these markers and we have shown that this bispecific selectively kills the cancer cells in glioblastoma tumors that express both CD133 and EGFRvIII. However, the bispecific did not kill normal stem cells. These results are very promising and suggest that bispecific can be tested as a therapeutic for glioblastoma. To move this into patients, we will produce large quantities of the bispecific and perform rigorous tests to ensure that it is uniform and has the required properties. We will also determine that it is safe through a combination of cell based and animal studies. Extensive planning will be made for the correct format for the clinical trial to test this molecule. Once the properties of the bispecific are certified and plans for the clinical trial are finalized, we will submit the drug to the FDA for an Investigational New Drug application. Once approved by the FDA, we can then move forward with testing this compound in glioblastoma patients. We are particularly excited about the bispecific as it could serve as the paradigm for a new class of drugs that specifically target cancer stem cells.
Statement of Benefit to California: 
Glioblastoma is a devastating diagnosis. The most common and malignant form of brain cancer, the most aggressive treatments currently available yield an average survival of only 14-15 months. As the most populous state in the nation, more Californians are diagnosed with glioblastoma each year than any other state, with a consequent significant economic toll to the state as well as its emotional toll. As the leader in cutting edge biomedical research, California through CIRM has recognized the unmet need to provide a roadmap for the translation of stem cell research to clinical applications. Through CIRM there is an unparalleled opportunity to foster clearly-defined discovery that will not only benefit Californians with glioblastomas, but potentially those with many other cancers, and ultimately all Californians, through healthier citizens, increased employment opportunities, and reduced economic burdens. We have previously shown that two markers of cancer stem cells, CD133 and EGFRvIII, are tightly associated in glioblastoma tumors. We created a recombinant bispecific antibody (BsAb) selectively targeting CD133 and EGFRvIII. This antibody selectively kills glioblastoma tumor cells but not healthy cells. When glioblastoma cells pre-treated with BsAb were injected into mice, tumor formation was significantly reduced, strongly suggesting that targeting of the EGFRvIII/CD133 cancer stem cell population can inhibit glioblastoma formation. The key objective of our project is to identify efficient and high yield methods for BsAb production, identify an effective dose and route of delivery for the treatment of brain tumors, and evaluate any potential effects on cells/tissues that express CD133. Our goal is to ready the BsAb for investigational new drug-related development. Californians will benefit from this research project in several significant ways. 1) Most importantly, this research has the promise to dramatically extend the long-term survival rates for Californians with glioblastomas, with potential applications to multiple other human cancers. 2) The research will take place in California with direct benefit to the California economy through the hiring of employees and purchase of supplies and reagents. 3) With successful completion of the proposed project, a clinical trial will be the direct next step, requiring additional employees along with associated expenditures. 4) If the therapeutic BsAb generated is commercialized, profits derived from the production of the BsAbs by CIRM policy will result in improved treatments to insured patients and lower cost treatments to the uninsured, thus ultimately benefiting all Californians. 5) Finally, funding this research will help raise awareness of California’s prominence as a national and international leader in stem cell research with the potential to benefit glioblastoma patients world-wide.
Progress Report: 
  • During the funding period, we were able to identify a project manager, Mauri Okamoto-Kearney, MBA who was then able to engage various consultants for all areas needed to write the Disease Team Proposal. We held various meetings with several CROs and CMOs to identify the best facility and processes for carrying out the manufacture and testing of the product. Following our fact gathering process, we used further personnel to write and assemble the final proposal.

Genetic Re-programming of Stem Cells to Fight Cancer

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05309
ICOC Funds Committed: 
$110 000
Disease Focus: 
Melanoma
Cancer
oldStatus: 
Closed
Public Abstract: 
Science has made great progress in the treatment of certain cancers with targeted and combination therapies, yet prolonged remissions or cures are rare because most cancer therapies only inhibit cell growth and/or reduce such growth but do not stop the cancer. The study investigators propose to develop an Investigational New Drug (IND) and fully accrue a phase I clinical trial within the grant period to genetically redirect the patient’s immune response to specifically attack the cancer starting from hematopoietic (blood) stem cells (HSC) in patients with advanced forms of the aggressive skin cancer malignant melanoma. Evaluation of immune system reconstitution, effectiveness and immune response during treatment will use imaging with Positron Emission Tomography (PET) scans. The HSC treatment approach has been validated in extensive studies in the laboratory. The investigators of this grant have recently initiated a clinical trial where adult immune cells obtained from blood are genetically modified to become specific killer cells for melanoma. These cells are administered back to patients. The early data from this study is encouraging in terms of the ability to generate these cells, safely administer them to patients leading to beneficial early clinical effects. However, the adult immune cells genetically redirected to attack cancer slowly decrease over time and lose their killer activity, mainly because they do not have the ability to self-renew. The advantage of the proposed HSC method over adult blood cells is that the genetically modified HSC will continuously generate melanoma-targeted immune killer cells, hopefully providing prolonged protection against the cancer. The IND filing with the FDA will use the modified HSC in advanced stage melanoma patients. By the end of year 4, we will have fully accrued this phase 1 clinical trial and assessed the value of genetic modification of HSCs to provide a stable reconstitution of a cancer-fighting immune system. The therapeutic principles and procedures we develop will be applicable to a wide range of cancers and transferrable to other centers that perform bone marrow and HSC transplants. The aggressive milestone-driven IND timeline is based on our: 1) Research that led to the selection and development of a blood cell gene for clinical use in collaboration with the leading experts in the field, 2) Our wealth of investigator-initiated cell-based clinical research and the Human Gene Medicine Program (largest in the world with 5% of all patients worldwide), 3) Experience filing a combined 15 investigator initiated INDs for research with 157 patients enrolled in phase I and II trials, and 4) Ability to leverage significant institutional resources of on-going HSC laboratory and clinical research and contribute ~$1M of non-CIRM funds to pursue the proposed research goals, including the resulting clinical trial.
Statement of Benefit to California: 
Cancer is the leading cause of death in the US and melanoma incidence is increasing fastest (~69K new cases/year). Treatment of metastatic melanoma is an unmet local and national medical need (~9K deaths/year) striking adults in their prime (20-60 years old). Melanoma is the second greatest cancer cause of lost productive years given its incidence early in life and its high mortality once it metastasizes. The problem is severe in California, with large populations with skin types sensitive to the increased exposure to ultraviolet light. Most frequently seen in young urban Caucasians, melanoma also strikes other ethnicities, i.e., steady increases of acral melanoma in Latinos and African-Americans over the past decades. Although great progress has been made in the treatment of certain leukemias and lymphomas with targeted and combination therapies, few options exist for the definitive treatment of late stage solid tumors. When cancers like lung, breast, prostate, pancreas, and melanoma metastasize beyond surgical boundaries, prolonged remissions or cures are rare and most cancer therapies only inhibit cell growth and/or reduce such growth but do not stop the cancer. Our proposal, the filing of an IND and the conduct of a phase 1 clinical trial using genetically modified autologous hematopoietic stem cells (HSC) for the immunotherapy of advanced stage melanoma allowing sustained production of cancer-reactive immune cells, has the potential to address a significant and serious unmet clinical need for the treatment of melanoma and other cancers, increase patient survival and productivity, and decrease cancer-related health care costs. The advantage of the proposed HSC methodology over our current work with peripheral blood cells is that genetically modified stem cells will continuously generate melanoma-targeted immune cells in the patient’s body providing prolonged protection against the cancer. The therapeutic principles and procedures developed here will be applicable to a wide range of cancers. Good Manufacturing Practices (GMP) reagents and clinical protocols developed by our team will be transferable to other centers where bone marrow and peripheral blood stem cell transplantation procedures are done.
Progress Report: 
  • The planning award funds were entirely dedicated to the establishment of the disease team for the full award submission. This has included:
  • - Hiring the project leader, Dr. Phyllis Wu.
  • - Organization of the cell therapy manufacturing, quality assurance, and clinical groups.
  • - A meeting of the external advisory board.
  • - A site visit to the lentiviral vector manufacturing facility.
  • With these activities we were able to assemble and submit the full CIRM DT-2 application to pursue a translational research project based on the genetic programming of hematopoietic stem cells to become cancer-targeted by the insertion of T cell receptor (TCR) genes.

Pages

Subscribe to RSS - Cancer

© 2013 California Institute for Regenerative Medicine