Cancer

Coding Dimension ID: 
280
Coding Dimension path name: 
Cancer
Funding Type: 
Tools and Technologies III
Grant Number: 
RT3-07683
Investigator: 
Institution: 
Type: 
PI
Institution: 
Type: 
Co-PI
ICOC Funds Committed: 
$1 452 708
Disease Focus: 
Blood Disorders
Blood Cancer
Cancer
Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

A goal of stem-cell therapy is to transplant into a patient “tissue-specific” stem cells, which can regenerate a particular type of healthy tissue (e.g., heart or blood cells). A major obstacle to this goal is obtaining tissue-specific stem cells that (1) are available in sufficient numbers; and (2) will not be rejected by the recipient. One approach to these challenges is to generate tissue-specific stem cells in the lab from “pluripotent” stem cells, which can produce all types of tissue-specific stem cells. The rationale is that pluripotent stem cells that will be tolerated are easier to directly obtain than tissue-specific stem cells that will be tolerated. Furthermore, descendants of a tolerated pluripotent stem cell will also be tolerated and can be produced abundantly.

The goal of the proposed project is to develop techniques for generating transplantable blood-forming stem cells from pluripotent stem cells. In pursuit of this goal, we will study how blood-forming stem cells arise during development. We will also test new methods--less toxic than current chemotherapy and radiation--for preparing recipients for transplantation of blood-forming stem cells.

Additional benefit: Successful transplantation of blood-forming stem cells allows the recipient to tolerate other tissue or organ transplants from the same donor. Thus, transplanted blood-forming stem cells could allow people to receive organs that they may otherwise reject, without taking immune-suppressing drugs.

Statement of Benefit to California: 

We aim to generate from stem cells that can produce all tissues of the body those stem cells that specifically form blood. We will also test new methods--less toxic than current chemotherapy and radiation--for pretreatment before transplantation of blood-forming stem cells. A large number of patients in California could benefit from advances in this field, primarily those with diseases affecting the production of blood and immune cells: leukemia, lymphoma, thalassemia, certain types of anemia, immune deficiency diseases, autoimmune diseases (e.g., lupus), etc. For leukemia and lymphoma alone, in 2014 in California, there will be an estimated 12,060 newly diagnosed cases, 103,400 existing cases, and 4,620 deaths (per the California Cancer Registry). The cost of these blood cancers are difficult to estimate but they account for 6% of cancers in women and 9% in men in California, where the estimated cost of cancer per year is $28.3 billion.

The reagents generated in these studies can be patented, forming an intellectual property portfolio shared by the state. The funds generated from the licensing of these technologies will provide revenue for the state, help increase hiring of faculty and staff (many of whom will bring in other, out-of-state funds to support their research) and could reduce the costs of related clinical trials. Only California businesses are likely to be able to license these reagents and to develop them into diagnostic and therapeutic entities.

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05309
Investigator: 
Name: 
Type: 
Co-PI
Type: 
Partner-PI
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.

Progress Report: 
  • A strategy in the treatment of cancer by harnessing the immune system, called adoptive cell therapy, is to use an individual’s own immune cells (T cells) and genetically modify them to target them to kill the cancer. Our emerging clinical data demonstrates that these gene-modified T cells are very active in killing tumor cells initially, but they lose their ability to function within a few weeks. This experience points to the need to have a continuous source of gene-modified cells to maintain the ability to kill cancer cells. In this study, we hypothesize that gene-modified stem cells will allow a sustained production of active T cells with antitumor activity. Since there is a delay in the appearance of the T cells that come from stem cells to get out of the bone marrow and into the blood, we will give patients both gene-modified T cells for a first wave of antitumor activity and gene-modified stem cells which will provide a bridge until the stem cells have produced more T cells. The purpose of the current study is to give gene-modified T cells in combination with gene-modified stem cells to reprogram the immune system to recognize and kill cancer cells that have the NY-ESO-1 protein with sustained killing activity. The patient’s own white blood cells and stem cells from their blood are modified in the laboratory using genetic techniques to express a specific receptor against cancer cells. Gene modification of cells involves the transfer of foreign genetic material (DNA) into a cell, in this case the immune system cells and stem cells. This process will endow the recipient immune cells and descendants of the stem cells with the ability to eliminate cancer cells that express the cancer specific protein, NY-ESO-1. The specific receptor against cancer cells that will be transferred to the immune cells and stem cells is called NY-ESO-1 T cell receptor (or TCR). In this study, the gene-modified immune cells will be given in combination with the gene-modified stem cells.
  • To date, we have manufactured a batch of the lentiviral vector necessary to transfer the NY-ESO-1 TCR into stem cells and have demonstrated that this vector can gene-modify human stem cells. Preclinical safety studies are currently ongoing. We have demonstrated that when mouse stem cells are gene-modified with this lentiviral vector, the stem cells take up residence in the bone marrow and produce appropriate blood cells. There is no detrimental effect on the blood cells that are derived from the stem cells. In vitro assays have also been performed to assess whether the lentiviral vector could potentially transform cells. These studies are ongoing but interim data suggests that there the lentiviral vector has no transforming potential. A preclinical study is also ongoing in mice to assess the safety of combining the gene-modified T cells and stem cells in mice. In addition, a preclinical study was performed to demonstrate that the stem cells are able to be specifically eliminated using ganciclovir, which provides a safety feature in case there was a problem when translating this research to humans. The vector includes a suicide gene which we have shown can be used to kill cells if necessary.
  • Preparations are ongoing towards opening a clinical trial. The manufacturing process is being optimized, and clinical documents have been submitted to internal committees for review.
Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06510
Investigator: 
Institution: 
Type: 
PI
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.
  • 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. Using this model, we have found that the oligodendroglial precursor cell population depletion following chemotherapy is due not only to a direct effect of the chemotherapy on the OPCs, but also due to alterations in the microenvironmental milieu of the brain that normally maintains this population of cells. 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.
Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01485
Investigator: 
Institution: 
Type: 
PI
Institution: 
Type: 
Co-PI
Institution: 
Type: 
Co-PI
Institution: 
Type: 
Partner-PI
ICOC Funds Committed: 
$19 999 996
Disease Focus: 
Blood Cancer
Cancer
Solid Tumor
Collaborative Funder: 
UK
Stem Cell Use: 
Cancer Stem Cell
Cell Line Generation: 
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 

Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow that is rapidly fatal within months if untreated. Even with aggressive treatment, including chemotherapy and bone marrow transplantation, five-year overall survival rates range between 30-40%. Evidence indicates that not all cells in this cancer are the same, and that there is a rare population of leukemia stem cells (LSC) that are responsible for maintaining the disease. Thus, in order to cure this cancer, all LSC must be eliminated, while at the same time sparing the normal blood forming stem cells in the bone marrow. We propose to develop therapeutic antibodies directed against surface markers present in much larger amounts on LSC than on the surface of normal blood forming stem cells. We recently identified and validated several such protein markers including CD47, which we determined contributes to leukemia development by blocking the ingestion and removal of leukemia cells by immune system cells called macrophages. In this way, CD47 acts as a “don’t eat me” signal on LSC. Moreover, we determined that monoclonal antibodies (mAbs) directed against CD47, able to block its interaction with macrophages, mask the “don’t eat me” signal resulting in ingestion and elimination of leukemia in mouse pre-clinical models. We propose a combination of clinical studies, basic research, and pre-clinical development to prepare a therapeutic antibody directed against CD47 and/or other LSC-specific proteins for Initial New Drug (IND) filing with the FDA, and then a Phase I clinical trial to be conducted at {REDACTED} and in the Collaborative Funding Partner country. In collaboration with the pioneering Collaborative Funding Partner country AML Working Group, we will track expression of the LSC proteins in patient samples and correlate with clinical outcomes. This will allow us to identify particular LSC proteins that must be targeted to achieve cure, thereby prioritizing candidate therapeutic antibodies for clinical development. Concurrently, we will conduct basic research and pre-clinical development to prepare these candidates. Basic research during years 1 and 2 will focus on the characterization of anti-CD47 mAb efficacy, investigation of mAb targeting of additional LSC molecules, and determination of efficacy in combinations with anti-CD47. Pre-clinical development during years 1 and 2 will focus on blocking anti-CD47 mAbs, including antibody humanization and large animal model pharmacologic and toxicity studies. Similar studies will be conducted with the most promising antibodies resulting from our basic research. During years 3-4, we will proceed with GMP grade production of the best candidate, followed by efficacy testing in mouse models and large animal models. Finally, in year 4, we will prepare an IND filing with the FDA/MHRA and develop a Phase I clinical trial with this antibody for the treatment of AML. Ultimately, therapeutic antibodies specifically targeting AML LSC offer the possibility of less toxicity with the potential for cure.

Statement of Benefit to California: 

Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow with nearly 13,000 new diagnoses annually in the US and 2,200 in the Collaborative Funding Partner country. Current standard of care for medically fit patients consists of several cycles of high dose chemotherapy, and often includes allogeneic hematopoietic cell transplantation. Even with these aggressive treatments, which cause significant morbidity and mortality, relapse is common and the five-year overall survival is 30-40%, but <10% in patients with relapsed or refractory disease or in the majority of AML patients who are over age 65. The goal of this research proposal is to prepare therapeutic antibodies directed against AML stem cell-specific antigens for IND filing with the FDA and a Phase I clinical trial. There are several potential benefits of this research for California: (1) most importantly, this research has the potential to revolutionize current clinical practice and provide a targeted therapy for AML that offers the possibility of less toxicity with the potential for cure; (2) this research will directly contribute to the California economy by funding a contract manufacturing organization to generate and produce GMP-grade clinical antibody, by employing several individuals who will be essential for the conduct of these studies, and through the purchase of equipment and reagents from California vendors; (3) additional clinical and economic benefits for California will derive from the potential application of clinical agents developed here to a number of other human cancers and cancer stem cells; (4) our animal models indicate that a significant fraction of patients with fatal AML can be cured, resulting in savings on their clinical care plus their return as productive contributors to the California economy; (5) if our therapeutic antibodies show clinical benefit in AML, they will be commercialized, and under CIRM policy, profits derived from treating insured patients and lower cost therapies for uninsured patients, would enrich the state and the lives of its citizens; (6) finally, this research has the potential to maintain California as the national and world-wide leader in stem cell technology.

Progress Report: 
  • Our program is focused on producing new therapeutic candidates to prolong remission and potentially cure highly lethal cancers where patients have few alternative treatment options. We have selected Acute Myelogenous Leukemia (AML) as the initial clinical indication for evaluating our novel therapeutics, but anticipate a full development program encompassing many other types of solid tumor cancers.
  • Our strategy is to develop an antibody that binds to and eliminates the cancer-forming stem cells in leukemia and other solid tumors. While current cancer treatments (e.g. surgery, chemotherapy, radiation) will frequently get rid of the bulk of the tumor, they rarely touch the tiny number of cancer stem cells that actually re-generate the masses of cancer cells that have been eliminated. When the latter occurs, the patient is described as having a relapse, leading to a disease recurrence with poor prognosis. Our strategy is to eliminate the small number of cancer-regenerating stem cells by targeting cell membrane proteins expressed by these cells.
  • We have discovered that many cancer cells coat themselves with a protein called CD47 that prevents them from being eaten and disposed of by the patient’s blood cells. In this context, CD47 can be considered a ‘don’t eat me’ signal that protects the cancer cells from being phagocytosed i.e. ‘eaten’. The antibody we are developing binds to and covers the ‘don’t eat me’ CD47 protein, so that the patient’s blood cells are now able to ‘eat’ the cancer cells by standard physiological responses, and eliminate them from the body.
  • Developing an antibody such as this for use in humans requires many steps to evaluate it is safe, while at the same ensuring it targets and eliminates the cancer forming stem cells. The antibody must also ‘look’ like a human antibody, or else the patient will ‘see’ it as a foreign protein and reject it. To achieve these criteria, we have made humanized antibodies that bind to human CD47. We have shown that the antibodies eliminate cancer cells in two ways: (i) blood cells from healthy humans rapidly “ate” and killed leukemia cells collected from separate cancer patients when the anti-human CD47 antibody was added to a mixture of both cell types in a research laboratory test tube; (ii) the anti-human CD47 antibody eliminates human leukemia cells collected from patients, then transferred into special immunodeficient mice which are unable to eliminate the human tumor cells themselves. In these experiments, the treated mice remained free of the human leukemia cells for many weeks post-treatment, and could be regarded as being cured of malignancy.
  • To show the antibodies were safe, we administered to regular mice large amounts of a comparable anti-mouse CD47 antibody on a daily basis for a period of many months. No adverse effects were noted. Unfortunately our antibody to human CD47 did not bind to mouse CD47, so it’s safety could not be evaluated directly in mice. Since the anti-human CD47 antibody does bind to non-human primate CD47, safety studies for our candidate therapeutic need to be conducted in non-human primates. These studies have been initiated and are in progress. Following administration of the anti-human CD47 antibodies, the non-human primates will be monitored for clinical blood pathology, which, as in humans, provides information about major organ function as well as blood cell function in these animals.
  • The next step after identifying an antibody with strong anti-cancer activity, but one that can be safely administered to non-human primates without causing any toxic effects, is to make large amounts of the antibody for use in humans. Any therapeutic candidate that will be administered to humans must be made according to highly regulated procedures that produce an agent that is extremely “clean”, meaning free of viruses, other infectious agents, bacterial products, and other contaminating proteins. This type of production work can only be performed in special facilities that have the equipment and experience for this type of clinical manufacturing. We have contracted such an organization to manufacture clinical grade anti-human CD47 antibodies. This organization has commenced the lengthy process of making anti-CD47 antibody that can be administered to humans with cancer. It will take another 18 months to complete the process of manufacturing clinical grade material in sufficient quantities to run a Phase I clinical trial in patients with Acute Myelogenous Leukemia.
  • Our program is focused on producing new therapeutic candidates to prolong remission and potentially cure highly lethal cancers where patients have few alternative treatment options. Our strategy is to develop an antibody that will eliminate the cancer stem cells which are the source of the disease, and responsible for the disease recurrence that can occur months-to-years following the remission achieved with initial clinical treatment. The cancer stem cells are a small proportion of the total cancer cell burden, and they appear to be resistant to the standard treatments of chemotherapy and radiation therapy. Therefore new therapeutic approaches are needed to eliminate them.
  • In year 2 of the CIRM award, we have continued to develop a clinical-grade antibody that will eliminate the cancer stem cells in Acute Myelogenous Leukemia (AML). We have identified several antibodies that cause human leukemia cells to be eaten and destroyed by healthy human white blood cells when tested in cell culture experiments. These antibodies bind to a protein called CD47 that is present on the outer surface of human leukemia cells. The anti-CD47 antibodies can eliminate leukemia growing in mice injected with AML cells obtained from patients. We have now extensively characterized the properties of our panel of anti-CD47 antibodies, and have identified the lead candidate to progress though the process of drug development. There are several steps in this process, which takes 18-24 months to fully execute. In the last 12 months, we have focused on the following steps:
  • (i) ‘Humanization’ of the antibody: The antibody needs to be optimized so that it looks like a normal human protein that the patient’s immune system will not eliminate because it appears ‘foreign’ to them.
  • (ii) Large scale production of the antibody: To make sufficient quantities of the antibody to complete the culture and animal model experiments required to progress to clinical safety trials with patients, we have contracted with a highly experienced manufacturing facility capable of such large-scale production. We have successfully transferred our antibody to them, and they have inserted it into a proprietary expression cell that will produce large amounts of the protein. This process is managed through weekly interactions with this contract lab. They send us small amounts of the material from each step of their manufacturing process and we test it in our models to ensure the antibody they are preparing retains its anti-cancer properties throughout production.
  • (iii) Pre-clinical safety studies: The antibody must be tested extensively in animals to ensure it does not cause serious limiting damage to any of the normal healthy tissues in the recipient. We have spent much of the last 12 months performing these types of safety experiments. The antibody has been administered to both mice and non-human primates and we have evaluated their overall health status, as well as analyzing their blood cells, blood enzyme levels, and urine, for up to 28 days. We have also collected samples of their organs and tissues to evaluate for abnormalities. Thus far, these assessments have appeared normal except for the development of a mild anemia a few days after the initial antibody injection. Subsequent experiments indicate that this anemia can be managed with existing approved clinical strategies
  • (iv) Determination of optimal dose: We have used mice injected with human cancer cells from AML patients, and determined how much antibody must be injected into these mice to produce a blood level that destroys the leukemia cells. This relationship between antibody dose and anti-cancer activity in the mouse cancer model enables us to estimate the dose to administer to patients.
  • Hematologic tumors and many solid tumors are propagated by a subset of cells called cancer stem cells. These cells appear to be resistant to the standard cancer treatments of chemotherapy and radiation therapy, and therefore new therapeutic approaches are needed to eliminate them. We have developed a monoclonal antibody (anti-CD47 antibody) that recognizes and causes elimination of these cancer stem cells and other cells in the cancer, but not normal blood-forming stem cells or blood cells. Cancer stem cells regularly produce a cell surface ‘invisibility cloak’ called CD47, a ‘don’t eat me signal’ for cells of the native immune system. Anti-CD47 antibody counters the ‘cloak, allowing the patient’s natural immune system eating cells, called macrophages, to eliminate the cancer stem cells.
  • As discussed in our two-year report, we optimized our anti-CD47 antibody so that it looks like a normal human protein that the patient’s immune system will not eliminate because it appears ‘foreign’. In this third year of the grant, we initiated the pre-clinical development of this humanized antibody, and assigned the antibody the development name of Hu5F9. Our major accomplishments in the third year of our grant are as follows:
  • (i) In addition to the hematological malignancies we have studied in previous years, we have now demonstrated the Hu5F9 is effective at inhibiting the growth and spread throughout the body [metastasis] of a large panel of human solid tumors, including breast, bladder, colon, ovarian, glioblastoma [a very aggressive brain cancer], leiomyosarcoma, head & neck squamous cell carcinoma, and multiple myeloma.
  • (ii) We have performed extensive studies optimizing the production and purification of Hu5F9 to standards compatible with use in humans, including that it is sterile, free of contaminating viruses, microorganisms, and bacterial products. We will commence manufacturing of Hu5F under highly regulated sterile conditions to produce what is known as GMP material, suitable for use in humans.
  • (iii) Another step to show Hu5F9 is safe to administer to humans is to administer it to experimental animals and observe its effects. We have demonstrated that Hu5F9 is safe and well tolerated when administered to experimental animals. Notably, no major abnormalities are detected when blood levels of the drug are maintained in the potentially therapeutic range for an extended duration of time.
  • (iv) We have initiated discussions with the FDA regarding the readiness of our program for initiating clinical trials, which we anticipate to start in the first quarter of 2014. To prepare for these trials we have established a collaboration between the Stanford Cancer Institute and the University of Oxford in the United Kingdom, currently our partners in this CIRM-funded program.
  • To our knowledge, CD47 is the first common target in all human cancers, one which has a known function that enables cancers to grow and spread, and one which we have successfully targeted for cancer therapy. Our studies show that Hu5F9 is a first-in-class therapeutic candidate that offers cancer treatment a totally new mechanism of enabling the patient’s immune system to remove cancer stem cells and their metastases.
  • Hematologic tumors and many solid tumors are driven by a subset of cells called cancer stem cells. These cancer stem cells must be eliminated for cures, however, they have been found to be resistant to the standard cancer treatments of chemotherapy and radiation therapy. Therefore, new therapeutic approaches are needed to target these abnormal stem cells. Previously, we found that cancer stem cells have developed a clever way to hide from the patient’s immune system. They display a protein called CD47 on their surface that signals to the immune system “don’t eat me”, thereby preventing their elimination. We have developed a monoclonal antibody (anti-CD47 antibody) that blocks this signal leading to elimination of these cancer stem cells, but not normal most normal cells, by the natural immune system. In our pre-clinical studies, we showed that anti-CD47 antibodies eliminates cancer cells and cancer stem cells from many different types of human cancer including: leukemia, breast cancer, colon cancer, prostate cancer, ovarian cancer, and others. In addition, anti-CD47 antibodies are effective at preventing and even eliminating metastases in animal models. These results indicate that anti-CD47 antibodies have great potential for the treatment of human cancer.
  • In order to develop this approach into a clinical therapeutic, we first optimized our anti-CD47 antibody so that it looks like a normal human protein that the patient’s immune system will not reject. Over the course of this grant project, we have conducted the pre-clinical development of this humanized antibody, termed Hu5F9-G4.
  • (1) Hu5F9-G4 has been manufactured according to Good Manufacturing Practices (GMP) as required by the United States Food and Drug Administration (FDA) for administration to humans. The drug product was manufactured and tested to be free of contaminants and is now ready for clinical use.
  • (2) Hu5F9-G4 has undergone extensive testing to investigate potential toxic effects in humans. According to FDA regulatory guidelines, Hu5F9-G4 was tested in experimental animals where it was given in various increasing doses. In all studies, Hu5F9-G4 was well-tolerated and caused no serious side effects.
  • (3) We have developed a phase 1 first-in-human clinical trial protocol for the investigation of Hu5F9-G4 in patients with solid tumors. In addition, we have prepared all the necessary documentation and clinical operations plans necessary to execute this clinical trial.
  • (4) We have submitted the necessary information on anti-cancer activity, manufacturing, safety, and clinical trial plans to the FDA in an Investigational New Drug (IND) application. This application was approved by FDA for the clinical trial in patients with solid tumors.
  • (5) We continue to develop parallel clinical trial plans for a phase 1 study in patients with acute myeloid leukemia (AML), and anticipate submitting our regulatory filing in 2015.
  • In summary, our studies show that Hu5F9-G4 is a first-in-class therapeutic candidate that offers cancer treatment through a totally new mechanism of enabling the patient’s immune system to remove cancer stem cells and prevent their metastases.
  • Hematologic tumors and many solid tumors are driven by a subset of cells called cancer stem cells. These cancer stem cells must be eliminated for cures, however, they have been found to be resistant to the standard cancer treatments of chemotherapy and radiation therapy. Therefore, new therapeutic approaches are needed to target these abnormal stem cells. Previously, we found that cancer stem cells have developed a clever way to hide from the patient’s immune system. They display a protein called CD47 on their surface that signals to the immune system “don’t eat me”, thereby preventing their elimination. We have developed a monoclonal antibody (anti-CD47 antibody) that blocks this signal leading to elimination of these cancer stem cells, but not normal most normal cells, by the natural immune system. In our pre-clinical studies, we showed that anti-CD47 antibodies eliminates cancer cells and cancer stem cells from many different types of human cancer including: leukemia, breast cancer, colon cancer, prostate cancer, ovarian cancer, and others. In addition, anti-CD47 antibodies are effective at preventing and even eliminating metastases in animal models. These results indicate that anti-CD47 antibodies have great potential for the treatment of human cancer.
  • In order to develop this approach into a clinical therapeutic, we first optimized our anti-CD47 antibody so that it looks like a normal human protein that the patient’s immune system will not reject. Over the course of this grant project, we have conducted the pre-clinical development of this humanized antibody, termed Hu5F9-G4.
  • (1) Hu5F9-G4 has been manufactured according to Good Manufacturing Practices (GMP) as required by the United States Food and Drug Administration (FDA) for administration to humans. The drug product was manufactured and tested to be free of contaminants and is now ready for clinical use.
  • (2) Hu5F9-G4 has undergone extensive testing to investigate potential toxic effects in humans. According to FDA regulatory guidelines, Hu5F9-G4 was tested in experimental animals where it was given in various increasing doses. In all studies, Hu5F9-G4 was well-tolerated and caused no serious side effects.
  • (3) Our stability studies have shown that refrigerated Hu5F9-G4 has a shelf life of at least 24 months and probably longer. This is an excellent storage life for any therapeutic.
  • (4) We have developed a phase 1 first-in-human clinical trial protocol for the investigation of Hu5F9-G4 in patients with solid tumors. In addition, we have prepared all the necessary documentation and clinical operations plans necessary to execute this clinical trial.
  • (5) We have submitted the necessary information on anti-cancer activity, manufacturing, safety, and clinical trial plans to the FDA in an Investigational New Drug (IND) application. This application was approved by FDA for the clinical trial in patients with solid tumors.
  • (6) We continue to develop parallel clinical trial plans for a phase 1 study in patients with acute myeloid leukemia (AML), and anticipate submitting our regulatory filing in 2015.
  • In summary, our studies show that Hu5F9-G4 is a first-in-class therapeutic candidate that approaches cancer treatment through a totally new mechanism of enabling the patient’s immune system to remove cancer stem cells and prevent their metastases. CIRM Grant DR1-01485 has provided us the resources to develop our new antibody to the point that it can be safely administered to human patients. Indeed we have started administering this drug to patients with advanced solid tumors that have failed all other treatments. Results to date indicate Hu5F9-G4 can be administered to cancer patients safely, enabling us to move on to studies to determine whether Hu5F9-G4 reduces or eliminates tumor burden.
Funding Type: 
Basic Biology V
Grant Number: 
RB5-06978
Investigator: 
Type: 
PI
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.

Progress Report: 
  • Cancers are often treated based on their underlying disease phenotype or molecular drivers. While these targeted strategies may provide some initial benefit, they tend to fail over time as tumors develop resistance mechanisms. Cancer stem cells, traditionally defined as a small population of “pre-existing” cells responsible for initiating a tumor, have been implicated as a major contributor to drug resistance. Although small in number, it is thought the population of cancer stem cells within a tumor could survive therapy to regenerate an entire tumor over time or spread to distant sites.
  • We suggest an alternate scenario in which any cell within a tumor could be “converted” into a cancer stem-like cell. We have now demonstrated that exposing epithelial cancer cells to different types of stress, including cancer therapies, induces a subset of markers and functions attributed to traditional cancer stem cells. The goal of our project is to understand how a protein called CD61 drives this reprogramming event so that we can design approaches to interfere with this pathway in order to lock cancer cells into a less aggressive and more therapy-responsive state.
  • In the past year, we have defined a common subset of cancer stem cell features that are induced by CD61 in response to multiple types of cellular stress. These stresses represent those that a tumor cell might encounter within its microenvironment, including nutrient deprivation, hypoxia, or cancer therapy. Interestingly, we have also discovered that these changes are reversible and that tumor cells can be “primed” to respond to stress so that they can rapidly adopt the stem-like features to evade the effects of therapy.
  • We have also identified specific upstream drivers required for the induction of CD61 by stress, and we have shown that they are necessary and sufficient to trigger CD61. In addition, we are beginning to understand how CD61 orchestrates the conversion of an epithelial cancer cell into a stem-like cancer cell by altering the location and function of downstream signaling proteins. Work in the upcoming year will focus on identifying specific steps along the pathway that could be manipulated therapeutically to prevent this reprogramming of cancer cells that contributes to drug resistance and disease progression.
Funding Type: 
Clinical Trial Stage Projects
Grant Number: 
CTS1-08239
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$17 725 734
Disease Focus: 
Melanoma
Cancer
Stem Cell Use: 
Cancer Stem Cell
Cell Line Generation: 
Other
Public Abstract: 
Statement of Benefit to California: 

Metastatic melanoma is a disease with no effective treatment and estimated 9,710 deaths in USA in 2014. An effective treatment will keep afflicted individuals productive, enhance State tax revenues and defray the healthcare cost burden to taxpayers. It will also lead to robust industry developments in the fields of stem cell treatments and biomarker discovery, effectively leading to job creation and tax benefits to the State as a result of consumption of research and clinical goods and services.

Funding Type: 
Early Translational II
Grant Number: 
TR2-01791
Investigator: 
ICOC Funds Committed: 
$3 370 607
Disease Focus: 
Brain Cancer
Cancer
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 

Modified viruses can be used to infect tumor cells and alter the tumor cell to make anti-tumor proteins. Most researchers use virus that can infect and modify the tumor cell it enters, but can not make more of itself to infect additional cells surrounding the original infected cell. This type of virus is called replication-incompetent virus. Use of replication-incompetent virus is considered safe because no additional virus, which potentially could get out of control, is generated inside of the tumor. However such therapies have been shown to have only limited beneficial effects, presumably because too many tumor cells never get infected.

Newer approaches investigate the use of replication-competent viruses to achieve highly efficient gene transfer to tumors. A successfully transduced tumor cell itself becomes a virus-producing cell, sustaining further transduction events even after initial administration. We propose here to use a type of replication-competent virus that only infects dividing cells and therefore will infect the rapidly dividing cancer cells but not normal brain cells.

The use of replication-competent virus is potentially more risky but is well justified in clinical scenarios involving highly aggressive and rapidly progressing metastatic tumor growth in the brain. To administer therapeutic virus into the brain, the virus is injected right into the center of the tumor. Yet, human brain tumors are often found as diffusely spreading foci in the brain and may be difficult to eliminate by locally-administered replication-competent retrovirus (RCR) vectors alone.

In this study we propose to use a type of adult stem cell called a "mesenchymal stem cell" (MSC) as a delivery system for the RCR vectors. Mesenchymal stem cells (MSCs) have been shown to have natural tumor-homing abilities, and can migrate to tumor foci and penetrate through into the interior of tumor masses. We propose to engineer them into "aircraft carriers" that release tumor-selective viruses, which can then efficiently spread suicide genes from one cancer cell to another in multiple tumor foci in the brain.

Statement of Benefit to California: 

This research is based on a solid foundation that combines two innovative technologies for the treatment of primary brain tumors, particularly glioblastoma multiforme (GBM) the most malignant form of brain tumor, which afflicts men, women, and children in California and elsewhere. Each of these technologies has been approved separately by FDA for clinical testing in humans: human mesenchymal stem cells (MSCs), and replication-competent retrovirus (RCR) vectors.

MSCs have been reported to exhibit a natural ability to migrate to solid tumors and penetrate into the tissue mass. Once inside a tumor, RCR vectors can spread selectively in the cancer cells and their replication can keep up with their uncontrolled proliferation, and their ability to integrate themselves into the cancer cell genome allows them to permanently "seed" tumor cells with therapeutic genes.

Here we propose to utilize the natural tumor homing ability of MSCs to deliver RCR vectors into brain tumors. This "virus vs. cancer" strategy takes advantage of the amplification process inherent in the spread of virus from cell to cell, and by using MSCs to initiate the virus infection efficiently in brain tumors, represents an approach that will have the potential to effectively treat this poor prognosis disease.

If successful, clinical application of this strategy can be implemented by an "off-the-shelf" mesenchymal stem cell (MSC) primary cell lines that have been pre-characterized for their tumor homing ability and virus production capability, and can be offered to patients without requiring an invasive procedure to harvest their own stem cells. Furthermore, this represents a treatment that could potentially be administered through a needle, thus making it unnecessary for patients to undergo major neurosurgical procedures entailing craniotomy at an advanced medical center. Hence this research could lead to a novel treatment approach that would particularly address the needs of brain tumor patients in California who are underserved due to socioeconomic and geographic constraints, as well as the elderly who are poor-risk for surgical interventions.

Progress Report: 
  • The goal of this project is to develop clinically translatable methods for engineering human mesenchymal stem cells (hMSC) to serve as tumor-homing cellular carriers that will deliver a replication-competent retrovirus (RCR) vector throughout primary brain tumors (gliomas). RCR vectors expressing a prodrug activator (also known as a "suicide gene"), which converts a non-toxic "pro-drug" compound into a potent chemotherapy drug directly generated within the infected tumor cells, have recently initiated testing in Phase I/II clinical trials for suicide gene therapy of recurrent high-grade gliomas. We are examining whether MSCs can serve as producer cells for this RCR vector, and whether the tumor transduction efficiency and therapeutic efficacy of this vector can be significantly enhanced, without compromising its safety profile, hMSC-based RCR producer cells (MSC-RCR) are used as a tumor-homing mobile carrier system that releases the virus as the cells migrate toward and within tumor masses in the brain. In particular, we are comparing this MSC-RCR cell-based carrier method against conventional delivery methods by direct intratumoral injection of 'naked' virus, in subcutaneous and intracranial brain tumor models.
  • To date, we have accomplished our milestone tasks for Year 1, by:
  • - successfully developing efficient methods to transduce hMSCs with RCR vectors and thereby convert them into vector producer cells
  • - developing and comparing in vitro and in vivo assays to evaluate the tumor-homing migratory activity of hMSCs
  • - applying these assays to screen and evaluate commercially available hMSC isolates
  • - demonstrating that the MSC-RCR delivery system can achieve significantly more efficient transduction of subcutaneous glioma models as compared to virus by itself
  • - confirming that enhanced transduction efficiency by MSC-RCR achieves more rapid tumor growth inhibition, as compared to 'naked' RCR alone, when applied to suicide gene therapy in subcutaneous tumor models of human glioma
  • - confirming that hMSC-mediated RCR delivery does not increase vector biodistribution to normal tissues, nor incur any increased risk of secondary leukemogenesis
  • Interestingly, through these studies we have found considerable variability in tumor-homing migration activity and intratumoral migration activity between hMSC isolates from different sources, a finding that may have significant implications for the development of hMSC-based clinical products. We are continuing to characterize additional hMSC isolates from various tissue sources, and are preparing a manuscript to publish these results.
  • Furthermore, based on our favorable results as described above, indicating the enhanced efficiency of tumor transduction and growth inhibitory effects when suicide gene therapy is delivered by MSC-RCR, as compared to RCR alone, we have fulfilled the success criteria for each of our milestone tasks in Year 1, and are currently proceeding with Year 2 studies.
  • Modified viruses can be used to infect tumor cells and alter the tumor cell to make anti-tumor proteins. We have developed a type of replication-competent virus that efficiently infects rapidly dividing cancer cells, but not normal brain cells. This virus is currently being tested clinically in patients with malignant brain tumors. However, to administer therapeutic virus into the brain, the virus is injected right into the center of the tumor, or in around the margins of the cavity after surgical removal of most of the tumor. Yet, human brain tumors are often found as diffusely spreading foci in the brain and may be difficult to eliminate by locally-administered replication-competent retrovirus (RCR) vectors alone. In this project, we propose to use a type of adult stem cell, called a "mesenchymal stem cell" (MSC), as a delivery system for the RCR vectors. Human mesenchymal stem cells (hMSCs) have been shown to have natural tumor-homing abilities, and can migrate to tumor foci and penetrate through into the interior of tumor masses.
  • During this project period, we have established and optimized manufacturing methods to engineer hMSCs into "aircraft carriers" that release our tumor-selective RCR vectors, which we then confirmed can efficiently spread a non-therapeutic marker gene to brain tumor cells. We have further confirmed that the use of hMSCs as a cellular delivery system for RCR vectors achieves more rapid spread of the vectors through the tumor mass, as compared to injecting the virus by itself, both in tumor models implanted under the skin as well as implanted in the brain. We have also obtained initial results demonstrating that hMSC delivery of RCR vectors does not result in unwanted spread of virus to normal tissues outside the brain. This stem cell-based RCR vector delivery system, which we have so far tested and validated using a marker gene, in our current studies is now being applied to delivery of a therapeutic anti-tumor 'suicide' gene. We have also initiated discussions with the UC Davis Stem Cell Institute to develop clinical grade manufacturing processes for hMSC-based RCR vector producer cells, and with a San Diego-based biotech partner, Tocagen Inc., toward the initiation of a clinical trial to test this strategy in brain tumor patients in the near future.
  • Modified viruses that have been engineered to serve as gene delivery vehicles ('vectors") can be used to infect tumor cells and alter the tumor cell to make anti-tumor proteins. We have developed a type of replication-competent virus that efficiently infects rapidly dividing cancer cells, but not normal brain cells. This virus is currently being tested clinically in patients with malignant brain tumors. However, to administer therapeutic virus into the brain, the virus is injected right into the center of the tumor, or in around the margins of the cavity after surgical removal of most of the tumor. Yet, human brain tumors are often found as diffusely spreading foci in the brain and may be difficult to eliminate by locally-administered replication-competent retrovirus (RCR) vectors alone. In this project, we propose to use a type of adult stem cell, called a "mesenchymal stem cell" (MSC), as a delivery system for the RCR vectors. Human mesenchymal stem cells (hMSCs) have been shown to have natural tumor-homing abilities, and can migrate to tumor foci and penetrate through into the interior of tumor masses.
  • Through this project, we have been able to establish and optimize manufacturing methods to engineer hMSCs into "aircraft carriers" that release our tumor-selective RCR vectors, which we then confirmed can efficiently spread a non-therapeutic marker gene to brain tumor cells. We have further confirmed that the use of hMSCs as a cellular delivery system for RCR vectors achieves more rapid spread of the vectors through the tumor mass, as compared to injecting the virus by itself, both in tumor models implanted under the skin as well as implanted in the brain. We have also confirmed that hMSC delivery of RCR vectors does not result in unwanted spread of virus to normal tissues outside the brain. We have now employed this stem cell-based RCR vector platform to deliver a therapeutic anti-tumor 'suicide' gene, and we have shown that stem cell-mediated vector delivery results in longer survival compared to delivery of the virus by itself. We have also initiated discussions with the UC Davis Stem Cell Institute to develop clinical grade manufacturing processes for hMSC-based RCR vector producer cells, and with a San Diego-based biotech partner, Tocagen Inc., toward developing a clinical trial to test this strategy in brain tumor patients in the near future.
  • Gene therapy can be used to alter the genome of cancer cells and induce them to make anti-tumor proteins. We have developed a highly efficient gene delivery vehicle (known as a “vector”) derived from a modified virus, which efficiently spreads though brain tumors and infects and permanently alters the genome of cancer cells, but does not infect normal brain cells. This modified virus, called a “replication-competent retrovirus (RCR) vector”, is currently being evaluated in clinical trials on-going at multiple sites throughout California to treat patients with malignant brain tumors, with highly encouraging results. However, to administer the therapeutic virus into brain tumors, the virus is injected directly into the center of the tumor, or around the margins of the cavity after surgical removal of most of the tumor. Yet, human brain tumors often diffusely spread into the surrounding normal brain tissue, and may be difficult to eliminate with a locally-injected RCR vector by itself. Therefore, in this project, we evaluated the use of a type of adult stem cell, called a "mesenchymal stem cell", as a delivery system for RCR vectors. Human mesenchymal stem cells (hMSCs) have been shown to have natural tumor-homing abilities, and can migrate to tumor foci and penetrate throughout the interior of tumor masses.
  • Through this project, we have established and optimized manufacturing methods to engineer hMSCs into "aircraft carriers" that release our tumor-selective RCR vectors, which we then confirmed can efficiently spread both a non-therapeutic “reporter gene”, as well as a therapeutic “suicide gene” to brain tumors. We have further confirmed that the use of hMSCs as a carrier system for delivery of RCR vectors results in more rapid spread of the vectors through the tumor mass, as compared to injecting the virus by itself, in human brain tumor models implanted both under the skin as well as in the brain. We have also confirmed that, when this hMSC -based RCR vector delivery system is employed to deliver an anti-tumor 'suicide' gene, the faster spread of the virus delivered by the stem cell carrier translates into more rapid shrinkage of tumors implanted under the skin, and prolongs survival in intracranial brain tumor models. In the final project period, we have also obtained results demonstrating that hMSC delivery of RCR vectors injected into intracranial brain tumors does not result in unwanted spread of virus to normal tissues outside the brain. We have initiated discussions with the UC Davis Stem Cell Institute to develop clinical grade manufacturing processes for hMSC-based RCR vector producer cells, and with a San Diego-based biotech partner, Tocagen Inc., toward the initiation of a clinical trial to test this strategy in brain tumor patients in the near future.
Funding Type: 
Genomics Centers of Excellence Awards (R)
Grant Number: 
GC1R-06673-C
Investigator: 
ICOC Funds Committed: 
$40 000 000
Disease Focus: 
Brain Cancer
Cancer
Developmental Disorders
Cancer
Toxicity
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: 
  • The CIRM Genomics Data Coordination and Management Center has made steady progress on our milestones over the last six months. We continued development of a database that stores files and descriptive tags for stem cell genomics projects, and developed a web site that allows authorized users controlled access to these data. The site includes a file browser that displays quality statistics, labels, and tags for each file. For many file types, the file browser provides a link to the UCSC Genome Browser where the data inside the file appears as a track. We imported test data sets from the labs of Stephen Quake (CIP2, Stanford) and Michael Snyder (CIP1, Stanford) into a test version of the database. We imported our first CIRM-funded dataset from the Kristin Baldwin lab (Scripps) into a firewall-protected production version of the database. We interviewed several additional labs, some of which may have data ready by the next reporting period, and have started building software in anticipation of their needs.
Funding Type: 
Early Translational IV
Grant Number: 
TR4-06867
Investigator: 
Name: 
Type: 
Co-PI
ICOC Funds Committed: 
$4 075 668
Disease Focus: 
Prostate Cancer
Cancer
Stem Cell Use: 
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 

Metastatic disease and the castration resistance remain tremendous challenges in the treatment of prostate cancer. New targeted treatments, such as the ant-testosterone medication enzalutamide, have improved the survival of men with advanced disease, but a majority develops treatment resistance. The field of cancer stem cells hypothesizes that treatment resistance emerges because stem cells are inherently resistant to our current therapies and eventually repopulate tumors. One mechanism by which cancer stem cells resist therapy is through acquisition of an epithelial to mesenchymal transition (EMT), a phenomenon of normal development used by cancers to survive and metastasize. Our laboratory has shown that prostate cancers undergo an EMT that leads to invasion, metastasis and treatment resistance. N-cadherin, a critical regulator of EMT, is expressed in most castration resistant prostate cancers (CRPC) and is sufficient to promote treatment resistance. We therefore developed antibodies against N-cadherin, which are able to inhibit growth, metastasis and progression of prostate cancers in vivo. The goal of this translational application is to move this promising treatment from the laboratory to the clinic by making the antibody human, making it bind more strongly, and then testing it for toxicity, behavior and anti-tumor activity. At the completion of this project, we will be poised to manufacture this lead molecule and move expeditiously to Phase I clinical studies.

Statement of Benefit to California: 

Prostate cancer is the second leading cause of cancer-related death in Californian men. With an aging population, this problem is expected to continue to grow despite recent advances in treatment. The goal of this application is to develop a novel antibody targeting a cancer stem cell target in hormone and treatment refractory prostate cancer. The benefit to the California, if successful, will be the development of a novel therapy against this common disease.

Progress Report: 
  • Metastatic disease and the castration resistance remain tremendous challenges in the treatment of prostate cancer. New targeted treatments, such as the anti-testosterone medication enzalutamide, have improved the survival of men with advanced disease, but a majority develops treatment resistance. The field of cancer stem cells hypothesizes that treatment resistance emerges because stem cells are inherently resistant to our current therapies and eventually repopulate tumors. One mechanism by which cancer stem cells resist therapy is through acquisition of an epithelial to mesenchymal transition (EMT), a phenomenon of normal development used by cancers to survive and metastasize. Our laboratory has shown that prostate cancers undergo an EMT that leads to invasion, metastasis and treatment resistance. N-cadherin, a critical regulator of EMT, is expressed in most castration resistant prostate cancers (CRPC) and is sufficient to promote treatment resistance. We therefore developed antibodies against N-cadherin, which are able to inhibit growth, metastasis and progression of prostate cancers in vivo. The goal of this translational application is to move this promising treatment from the laboratory to the clinic by making the antibody human, making it bind more strongly, and then testing it for toxicity, behavior and anti-tumor activity. At the completion of this project, we will be poised to manufacture this lead molecule and move expeditiously to Phase I clinical studies.
  • At this juncture in the project, we have made our two original lead antibodies into human ones that would not elicit an immune response in patients. We have begun to test these “humanized” antibodies and they appear to retain the properties of the mouse ones from which they were derived. We have also generated additional candidate antibody drugs through screening of a library containing millions of candidate antibodies. We have narrowed these candidates down to approximately 9, and are continuing to work to prioritize these based on activity. Finally, we have begun the process of maturing these lead candidates to bind more tightly to N-cadherin, the target, hypothesizing that this will further improve the efficacy of these drugs moving forward. Over the coming months, we will finalize selection of 2-3 lead antibodies and begin testing them in animal experiments as the next step toward realizing the goal of testing them in patients.
Funding Type: 
New Faculty II
Grant Number: 
RN2-00904
Investigator: 
ICOC Funds Committed: 
$2 381 572
Disease Focus: 
Lung Cancer
Cancer
Respiratory Disorders
Stem Cell Use: 
Adult Stem Cell
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 

Lung cancer is the most deadly cancer worldwide and accounts for more deaths than prostate cancer, breast cancer and colon cancer combined. Non small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. The current 5-year survival rate for all stages of NSCLC is only 15%. Although early stage lung cancer has a much better survival rate. Current therapeutic strategies of chemotherapy, radiation therapy and trials with new targeted therapies have only demonstrated, at best, extension in survival by a few months. Clearly, a novel approach is required to develop new therapies for this devastating disease and to detect the disease at an early stage. Cancer stem cells have been identified as the initial cell in the formation of carcinomas. Chemotherapy, radiation and even targeted therapies are all designed to eliminate dividing cells. However, cancer stem cells “hide out” in the quiescent phase of growth. This provides an explanation as to why our cancer therapies may produce an initial response but are often unsuccessful in curing patients. Lung cancer develops through a series of step wise changes that result in the progression of pre-malignant lesions to invasive lung cancer. The mechanisms of how lung cancer develops are not known and if we can prevent the formation of pre-malignant lesions, we will likely be able to prevent lung cancer. We have discovered a subpopulation of stem cells that circulates in the blood and is essential for normal lung repair. Blocking these cells from entering the lung results in a pre-malignant condition in the lungs. We have also identified a subpopulation of stem cells in the lung that is responsible for generating pre-malignant lung cancer lesions. We hypothesize that the interaction between the stem cells in the blood and the stem cells in the lung are critical to prevent lung cancer. We plan to use cutting edge technologies to characterize these different stem cell populations in the lung, and determine how they form pre-malignant lung cancer lesions. We also plan to use preclinical models to try to prevent lung cancer by giving additional stem cells derived from the blood as a therapy. Lastly, we plan to determine whether levels of stem cells in the blood in patients may be used as a blood test to measure the chance of recurrence of lung cancer after therapy. The long term goals of our work are to develop a screening test for lung cancer stem cells that can predict which patients are at high risk for developing lung cancer in order to diagnose lung cancer at an early stage, and to potentially develop a new stem cell based therapy for preventing and treating lung cancer.

Statement of Benefit to California: 

According to the Center for Health Statistics, California Department of Health Services, 13,427 people died of lung cancer in the state of California in 2005. This is more than the deaths attributed to breast, prostate and colon cancers combined. The devastating effects of this disease on the citizens of California and the health care costs involved are enormous. Most cases of lung cancer occur in smokers, but non smokers, people exposed to second hand smoke and ex-smokers are also at risk. In addition, of special concern to California residents, is that exposure to air pollution is associated with an increased risk of lung cancer. Current therapeutic strategies for lung cancer are in general only able to prolong survival by a few months, especially for late stage disease. One reason for this may be that the cancer initiating stem cell is resistant to these therapies. Understanding the stem cell populations involved in repair of the lung and how these cells may give rise to lung cancer is important for potentially generating new therapeutic targets for lung cancer. We propose to study the stem cell populations of the lung that are crucial for normal airway repair and characterize the putative cancer initiating stem cell in the lung. We have also found stem cells in the blood that are critical for normal airway repair and we plan to test their role in the prevention of premalignant lung cancer lesions. We also plan to test whether levels of these stem cells in the blood may be used as a biomarker of lung cancer. Ultimately, the ability to perform a screening test to detect lung cancer at an early stage, and the development of new therapies for lung cancer will be of major benefit to the citizens of California.

Progress Report: 
  • We identified a putative tumor-initiating stem/progenitor cell that goes rise to smoking-associated non small cell lung cancer (NSCLC). We examined 399 NSCLC samples for this tumor-initiating stem/progenitor cell and found that the presence of this cell in the tumor gave rise to a significantly worse prognosis and was associated with metastatic disease. This stem/progenitor cell is known to be important for repair of the airway and is present in precancerous lesions. We believe that this cell undergoes aberrant repair after smoking injury, which leads to lung cancer. We are currently trying to identify the genetic and epigenetic mechanisms involved in this aberrant repair as a means to identify a novel therapy to prevent the development of lung cancer. The presence of these stem/progenitor cells may also be used as a biomarker of poor prognostic NSCLC even in early stage disease.
  • We have identified markers on these stem/progenitor tumor-initiating cells and identified sub-populations of these cells. We are now determining the stem cell capabilities of each of these sub-populations. We are using a model of the development of lung cancer to determine if giving a stem/progenitor cell sub-population for repair can prevent NSCLC from developing.
  • We examined the blood of patients diagnosed with a lung nodule for circulating epithelial stem/progenitor cells. We found that the presence of these cells in the blood of patients predicted the presence of a subtype of NSCLC as compared to a benign lung nodule. We are currently obtaining many more blood samples from patients to further determine whether circulating epithelial stem/progenitor cells could be used as a biomarker of early NSCLC.
  • We have found a stem cell that is important for lung repair after injury that is located in a protected niche in the airway. After repeated injury, for example in smokers, these stem cells persist in an abnormal location on the surface of the airway and replicate and form precancerous areas in the lung. The presence of these stem cells in lung cancer tumors was associated with a poor prognosis with an increased chance of relapse and metastasis.This was especially true in current and former smokers. We therefore believe we have found a putative stem cell that is a tumor initiating cell for lung cancer. We developed a method to isolate these lung stem cells and to profile these cells and developed in vitro and in vivo models to assess their stem cell properties. Finally, we examined human blood samples to assess levels of surrogate markers of these stem cells to assess whether we could use this as a biomarker to predict the presence or absence of lung cancer in patients with a lung nodule.
  • We found a stem cell that is important for lung repair after injury that we believe may form precancerous areas in the lung. We are characterizing these stem cells and identifying pathways involved in normal repair and aberrant repair that leads to lung cancer. We are also isolating this stem cell population and other cell populations from the airway and inducing genetic changes to determine the tumor initiating cell/s for lung cancer. We are also examining the effect the environment may have on the regulation of genes in these stem cells, in precancerous areas and in lung cancers. Finally, we are examining human blood samples to assess levels of surrogate markers of these stem cells to assess whether we could use this as a biomarker to predict the presence or absence of lung cancer in patients with a lung nodule.
  • During this period of funding we discovered a method to reproducibly recover stem cells from human airways and grow them in a dish into mature airway cells. We also discovered the role that certain metabolic cell processes play in regulating the repair after airway injury. We believe that an inability to shut off these processes leads to abnormal repair and lung cancer and are actively investigating this. We are also determining whether the stem cells we isolate from the airways are the stem cells for lung cancer and how they might give rise to lung cancer.
  • In the last year of funding we identified a novel mechanism that tightly controls airway stem cell proliferation for repair after injury. We found that perturbing this pathway results in precancerous lesions that can ultimately lead to lung cancer. Correcting the abnormalities in this pathway that are seen in smokers could allow the development of targeted chemoprevention strategies to prevent the development of precancerous lesions and therefore lung cancer in at risk populations. We also continued our work on trying to identify a cell of origin for squamous lung cancer and identifying the critical drive mutations that are required for squamous lung cancer to develop.
  • During this reporting period we discovered and published on how reactive oxygen species drive proliferation of airway basal stem cells. We found that this pathway is critical for homeostasis of the airway epithelium and perturbing this pathway results in precancerous lesions. Interestingly, these precancerous lesions are able to resolve over time, which is similar to the situation in smokers who develop precancerous lesions that almost always resolve. We now have a model to study the driver mutations that take precancerous lesions to invasive squamous lung cancer and with this model we can start to identify novel therapies to prevent the development of precancerous lesions and/or progression of precancerous lesions. We also developed a model of precancerous lesions in a dish which allows us to screen for compounds that promote or resolve these premalignant lesions. Our overall goal is to use these models to develop a targeted chemoprevention strategy for squamous lung cancer.

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