Cancer

Coding Dimension ID: 
280
Coding Dimension path name: 
Cancer
Funding Type: 
Clinical Trial Stage Projects
Grant Number: 
CTS1-08289
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$8 521 441
Disease Focus: 
HIV/AIDS
Blood Cancer
Cancer
Stem Cell Use: 
Adult Stem Cell
Public Abstract: 
Statement of Benefit to California: 

In California, the number of HIV infected individuals continues to increase. As anti-retroviral drugs are not curative, these individuals still have to deal with the emotional, financial, and medical consequences. Our HIV stem cell gene therapy approach comprises the transplantation of a purified population of HIV-resistant blood forming stem cells which would generate an HIV-resistant immune system in a patient’s body. This would be significantly compelling to the state of California.

Funding Type: 
Clinical Trial Stage Projects
Grant Number: 
CTS1-08239
Investigator: 
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: 
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
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.
Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01421
Investigator: 
Institution: 
Type: 
PI
Institution: 
Type: 
Co-PI
Institution: 
Type: 
Co-PI
ICOC Funds Committed: 
$18 015 429
Disease Focus: 
Brain Cancer
Cancer
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 

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

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

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

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

Statement of Benefit to California: 

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

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

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

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

Progress Report: 
  • Primary brain tumors are among the most difficult cancers to treat. High-grade gliomas, the most common primary brain tumors in adults, remain incurable with current therapies. These devastating tumors present significant treatment challenges for several reasons: 1) surgical removal runs the risk of causing permanent neurologic damage and does not eliminate cancer cells that have migrated throughout the brain; 2) most anti-cancer drugs are prevented from entering the brain because of the presence of the blood-brain barrier, which often does not allow enough chemotherapy into the brain to kill the cancer cells; and 3) typically, the amount of chemotherapy that can be given to cancer patients is limited by intolerable or harmful side effects from these agents. If concentrated cancer therapies could be specifically localized to sites of tumor, damage to healthy tissues would be avoided.
  • The long-range goal of this research project is to develop a neural stem cell (NSC)-based treatment strategy that produces a potent, localized anti-tumor effect while minimizing toxic side effects. NSCs hold the promise of improved treatment for brain cancers because they have the natural ability to distribute themselves within a tumor, as well as seek out other sites of tumor in the brain. Because they can home to the tumor cells, NSCs may offer a new way to bring more chemotherapy selectively to brain tumor sites. After modifying the NSCs by transferring a therapeutic gene into them, NSCs can serve as vehicles to deliver anti-cancer treatment directly to the primary tumor, as well as potentially to malignant cells that have spread away from the original tumor site. With funding from CIRM, we are studying the ability of NSCs, that carry an activating protein called carboxylesterase (CE) to convert the chemotherapy agent CPT-11 (irinotecan) to its more potent form, SN-38, at sites of tumor in the brain.
  • During the first year of funding we have determined that 1) when administered directly into the brain or into a peripheral vein (intravenous injection) of mice with brain tumors, NSCs will travel to several different subtypes of gliomas; 2) we can engineer the NSCs to consistently produce high levels of more powerful forms of CE: rCE and hCE1m6; 3) glioma cells die when they are exposed to very low (nanomolar) concentrations of SN-38, and 4) although glioma cells survive when exposed to a relatively high concentration of CPT-11 alone, they do die when the same concentration of CPT-11 is administered in combination with either rCE or hCE1m6. These results suggest that the engineered NSCs are expressing relatively high levels of CE enzymes and that the CE enzymes are converting CPT-11 into SN-38. We have also been able to label our NSCs with iron particles, so that we can track their movement in real-time by magnetic resonance imaging (MRI), and follow their location and distribution in relation to the tumor.
  • All of our data thus far support the original hypothesis that effective, tumor-specific therapy for glioma patients can be developed using NSCs that express rCE or hCE1 and the prodrug CPT-11. During the second year of CIRM funding, we will further analyze our data to make a final determination regarding the best form of CE to develop towards clinical trials, and the best dose range and route of delivery of NSCs to achieve maximal tumor coverage. We will then begin our therapeutic studies and start discussions with the Food and Drug Administration, to define the safety studies necessary to obtain approval for testing this new treatment strategy in patients with brain tumors.
  • High-grade gliomas, the most common primary brain tumors in adults, have a poor prognosis and remain incurable with current therapies. These devastating tumors present significant treatment challenges: 1) surgery may cause permanent neurologic damage; 2) surgery misses cancer cells that have invaded beyond the edge of the tumor or to other sites in the brain; 3) many, if not most, chemotherapy drugs cannot enter the brain because of the blood-brain barrier; and 4) due to the highly toxic nature of chemotherapy agents the therapeutic window (the difference between the dose that kills the tumor and the dose that causes toxic side effects) is very small, resulting in undesirable side-effects. Therefore, if therapeutic agents could be localized and concentrated selectively to the tumor sites, treatment efficacy may be improved while toxic side effects are minimized.
  • The overarching goal of this project is to develop a human Neural Stem Cell (NSC)-based treatment strategy that produces potent localized anti-tumor effects while minimizing toxic side effects. NSCs hold the promise of improved treatment for brain cancers because they have an innate ability to distribute within and around a tumor mass and to seek out tumor cells that have invaded further into surrounding brain tissue. By homing to cancer cells, NSCs offer a way to selectively deliver concentrated chemotherapy to brain tumor sites. We are modifying NSCs to make the protein carboxylesterase (CE), which will convert a systemically administered prodrug, CPT-11 (irinotecan) to an active, potent anti-cancer drug, SN38 at the tumor sites.
  • Our second year of funding was highly productive and informative. We validated key elements of our system, successfully negotiating Go/No Go milestones, yielding substantial progress:
  • (1) We have selected the optimal genetically modified human CE to efficiently convert CPT-11 to SN-38. This CE is being developed for clinical grade use.
  • (2) We have determined the volume of tumor coverage by NSCs injected directly into the brain versus injecting them intravenously. We found that we achieve more tumor coverage with direct injection of the NSCs into the brain, and will focus on developing this approach for initial NSC.CE/CPT-11 clinical trials. However, following intravenous injections we found the NSCs localize prominently at the invasive tumor edges, which may prove therapeutically efficacious as well. Due to the significant clinical and commercial advantages that intravenous administration presents, this approach will also be developed toward patient trials. We have determined the starting NSC dose range for both approaches.
  • (3) We have shown that CPT-11 + CE is1,000 fold more toxic to glioma cells than CPT-11 alone. Importantly, microdialysis studies in our preclinical models have confirmed the conversion of CPT-11 to SN-38 by our CE-secreting NSCs in the brain.
  • (4) We have completed studies labeling our NSCs with iron (Feraheme) nanoparticles, which allows for non-invasive cell tracking by Magnetic Resonance Imaging (MRI). Safety studies for clinical use of this iron-labeling method were completed and submitted to the FDA, for consideration of use in brain tumor patients enrolled in our current NSC.CD/5-FC recurrent glioma clinical trial. This would be the first-in-human use of Feraheme-labeled stem cells for MRI tracking.
  • Our results to date robustly support the original hypothesis that an effective, glioma-specific therapy can be developed using NSCs that home to tumors and express CE to convert CPT-11 to the potent anti-cancer agent SN-38. Pre-clinical therapeutic efficacy studies to optimize CPT-11 regimens are now in progress.
  • High-grade gliomas, the most common primary brain tumors in adults, have a poor prognosis and remain incurable with current therapies. These devastating tumors present significant treatment challenges; 1) surgery may cause permanent neurologic damage; 2) surgery misses cancer cells that have invaded beyond the edge of the tumor or disseminated to other sites in the brain; 3) many, if not most, chemotherapy drugs cannot enter the brain because of the blood-brain barrier; and 4) due to the highly toxic nature of chemotherapy agents the therapeutic window (the difference between the dose that kills the tumor and the dose that causes toxic side effects) is very small. Therefore, if therapeutic agents could be concentrated and localized to the tumor sites, treatment efficacy may be improved while toxic side effects are minimized.
  • The overarching goal of this project is to develop a human Neural Stem Cell (NSC)-based treatment strategy that produces potent localized anti-tumor effects while minimizing toxic side effects. NSCs hold the promise of improved treatment for brain cancers because they have an innate ability to distribute within and around a tumor mass and to seek out other, secondary and smaller tumor nodules in the brain. By homing to cancer cells, NSCs offer a way to selectively deliver concentrated chemotherapy to brain tumor sites. After modifying NSCs by adding the gene to make the protein carboxylesterase (CE), NSCs deliver CE to convert the drug CPT-11 (irinotecan) to its more potent form, SN-38 at primary and secondary brain tumor sites.
  • The major milestone in our third year of funding was that we completed our pre-IND package and held our pre-IND meeting with the FDA. To this end, we validated the following:
  • (1) NSCs can potentiate the in vivo efficacy of irinotecan (CPT-11) using a low dose (7.5 mg/kg) daily x 5 schedule. Both real time Xenogen and integrated morphometric analysis of immunohistochemically stained sections of tumor were used to determine tumor volumes.
  • (2) In vivo pharmacokinetics demonstrated increased accumulation of SN-38 in tumor over that of tumor interstitium. The concentrations of tumor SN-38 were approximately 3-fold higher in tumor-bearing brain tissue than in corresponding normal tissue supporting the hypothesis that NSCs can direct toxic chemotherapy in a tumor localized manner.
  • (3) Following FDA approval of the incorporation of iron (Feraheme) into NSCs, three patients were treated with FeHe-labeled HB1.F3.CD, the first generation NSCs undergoing clinical trial. There were no adverse effects from the treatment demonstrating relative safety and lack of toxicity of this method.
  • Our results to date robustly support the original hypothesis that an effective, glioma-specific therapy can be developed using NSCs that home to tumors and express CE to convert CPT-11 to SN-38. During the fourth and coming year of CIRM funding, we will conduct experiments to determine the optimal schedule for NSC/CPT-11 therapy and demonstrate the safety and lack of toxicity of the treatment schema in rodents to fulfill requirements for IND submission and clinical trial in humans.
  • High-grade gliomas, the most common primary brain tumors in adults, have a poor prognosis and remain incurable with current therapies. These devastating tumors present significant treatment challenges; 1) surgery may cause permanent neurologic damage; 2) surgery misses cancer cells that have invaded beyond the tumor edge to other sites in the brain; 3) many, if not most, chemotherapy drugs cannot enter the brain because of the blood-brain barrier; and 4) chemotherapy drugs are toxic to normal tissues as well as tumor, causing undesirable side effects. Therefore, if therapeutic agents could be concentrated and localized to the tumor sites, treatment efficacy may improve while side effects are minimized.
  • Our goal is to bring to the clinic a human Neural Stem Cell (NSC)-based treatment strategy that produces potent localized anti-tumor effects while minimizing toxic side effects. NSCs have a natural ability to home to invasive brain tumor cells throughout the brain. NSCs, used as a delivery vehicle, offer a novel way to selectively target chemotherapy to brain tumor sites. NSCs are modified to express a certain enzyme (carboxylesterase; CE), that converts systemically administered prodrug (irinotecan) to a much more potent form (SN-38), that is up to 1000 times more effective at killing brain tumor cells.
  • Milestones reached in our fourth year include:
  • (1) receiving regulatory approval from the NIH/OBA following a public form in September, 2013.
  • (2) determining the dose and timing of NSC and irinotecan administration for optimal therapeutic efficacy in pre-clinical brain tumor models.
  • (3) demonstrating that the CE-expressing NSCs can increase concentrations of the toxic drug SN-38 by > 6-fold compared to giving irinotecan alone. Furthermore, SN-38 concentrations were dose proportional to administered irinotecan concentrations.
  • (4) Safety-toxicity studies required by the FDA for Investigational New Drug (IND) approval were completed. These studies demonstrated no significant toxicities and safety of our NSC treatment protocol in preclinical brain tumor models.
  • Our results to date support our hypothesis that a safe and effective NSC-mediated therapy can be developed for clinical use in patients with high-grade glioma, with potential application to other types of brain tumor and brain tumor metastases. We hope to initiate clinical trials with our CE-expressing NSCs and irinotecan by the end of 2014.
  • High-grade gliomas, the most common primary brain tumors in adults, have a poor prognosis and remain incurable with current therapies. These devastating tumors present significant treatment challenges; 1) surgery may cause permanent neurologic damage; 2) surgery cannot remove the cancer cells that have invaded beyond the main tumor site; 3) most chemotherapy drugs cannot enter the brain because of the blood-brain barrier; and 4) chemotherapy drugs are toxic to normal tissues as well as tumor, causing undesirable side effects. Therefore, if therapeutic agents could be concentrated and localized to the tumor sites, treatment efficacy may improve while side effects are minimized.
  • Our goal is to bring to the clinic a human Neural Stem Cell (NSC)-based treatment strategy that produces potent localized anti-tumor effects while minimizing toxic side effects. NSCs have a natural ability to home to invasive brain tumor cells throughout the brain. NSCs, used as a delivery vehicle, offer a novel way to selectively target chemotherapy to brain tumor sites. NSCs are modified to express a certain enzyme (carboxylesterase; CE), that converts systemically administered prodrug (irinotecan) to a much more potent form (SN-38), that is up to 1000 times more effective at killing brain tumor cells.
  • Milestones reached in our fifth (final) year include:
  • (1) completion of safety/tox and efficacy study data analysis reports
  • (2) completion of clinical protocol
  • (3) completion of clinical lot for initiation of patient trial
  • (4) Regulatory documents including IBC, IRB, SCRO, NIH-RAC Protocol #13071241 all approved
  • (5) submission of final IND package to the FDA
  • (6) phase I trial initiation pending
  • Our results to date support our hypothesis that a safe and effective NSC-mediated therapy can be developed for clinical use in patients with high-grade glioma, with potential application brain tumor metastases, as well as metastatic cancers.
Funding Type: 
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 III
Grant Number: 
DR3-07067
Investigator: 
Type: 
Co-PI
ICOC Funds Committed: 
$6 924 317
Disease Focus: 
Cancer
oldStatus: 
Active
Public Abstract: 

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

Statement of Benefit to California: 

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

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

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

Statement of Benefit to California: 

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

Progress Report: 
  • We aim to understand how blood stem cells develop from blood vessels during development. We are also interested in learning whether the blood-making program can be turned back on in blood vessel cells for blood production outside the human body. During the past year we have been able to extract and culture blood vessel cells that once had blood making capacity. We have also started experiments that will help uncover the regulation of the blood making program. In addition, we have developed tools to help the process of understanding whether iPS technology can "turn back time" in mature blood vessels and turn on the blood making program.
  • We aim to understand how blood stem cells develop from blood vessels during development. We are also interested in learning whether the blood-making program can be turned back on in blood vessel cells for bloodproduction outside the human body. During the past year we have made progress in understanding early human hematopoiesis such that we have designed new tools that may enable us to try and generate hematopoietic cells in culture. We have also gained ground in refining our screening strategy that we hope to adapt for finding new regulators of blood development that can be used for culturing hematopoietic stem cells.
Funding Type: 
Research Leadership
Grant Number: 
LA1-01747
Investigator: 
ICOC Funds Committed: 
$5 919 616
Disease Focus: 
Brain Cancer
Cancer
Cell Line Generation: 
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 

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

Statement of Benefit to California: 

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

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

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

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

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

Progress Report: 
  • The goal of our studies is to determine the role of neural stem cells in the development, regeneration and tumor formation in the cerebellum. By understanding the role of stem cells, we hope to learn to use them for repair of neurological damage and to develop more effective treatments for patients with brain tumors.
  • The aims of our studies are: (1) To identify the cell types generated by cerebellar stem cells during normal development; (2) To determine the capacity of cerebellar stem cells to repair damage caused by radiation or disease; and (3) To determine whether cerebellar stem cells can give rise to the pediatric brain tumor medulloblastoma.
  • We have made significant progress toward our goals over the last year. In particular, we have identified genetic markers that allow us to trace the fate of cerebellar stem cells during normal development. In addition, we have demonstrated that cerebellar stem cells carrying cancer-causing genes can give rise to medulloblastoma. Importantly, this finding has allowed us to create stem cell-based models of medulloblastoma that can be used to test drugs that may be useful for treating the disease. Over the next few years, we hope to use this information to develop more effective therapies for children suffering from medulloblastoma.
  • The goal of our studies is to determine the role of neural stem cells in the development, regeneration and tumor formation in the cerebellum. By understanding the role of stem cells, we hope to learn to use them for repair of neurological damage and to develop more effective treatments for patients with brain tumors.
  • The aims of our studies are: (1) To identify the cell types generated by cerebellar stem cells during normal development; (2) To determine the capacity of cerebellar stem cells to repair damage caused by radiation or disease; and (3) To determine whether cerebellar stem cells can give rise to the pediatric brain tumor medulloblastoma.
  • We have made significant progress toward our goals over the last year. In particular, we have identified genetic markers that allow us to trace the fate of cerebellar stem cells during normal development. In addition, we have demonstrated that cerebellar stem cells carrying cancer-causing genes can give rise to medulloblastoma. Importantly, this finding has allowed us to create stem cell-based models of medulloblastoma that can be used to test drugs that may be useful for treating the disease. Our screening efforts over the past year have begun to identify compounds that inhibit the growth of human medulloblastoma tumor cells. Over the next few years, we hope to use this information to develop more effective therapies for children suffering from medulloblastoma.
  • The goal of our studies is to determine the role of neural stem cells in development, regeneration, and tumor formation in the cerebellum. By understanding the role of stem cells, we hope to learn to use them for repair of neurological damage and to develop more effective treatments for patients with brain tumors.
  • We have made significant progress towards our goals during the past year. We have identified new drugs that potently inhibit the growth of medulloblastoma, the most common malignant brain tumor in children. This work could lead to development of new, more effective therapies for medulloblastoma in patients. In addition, we have developed new models for several types of brain tumors, including one that resembles the most aggressive form of medulloblastoma, and several that model choroid plexus tumors. These models are valuable resources for studying the biology and therapeutic responsiveness of these diseases. Over the next few years, we will continue in our efforts to develop more effective therapies for children suffering from aggressive brain tumors.
  • The goal of our studies is to elucidate the role of neural stem cells in development, regeneration, and tumor formation in the cerebellum. By understanding the role of stem cells, we hope to learn to use them for repair of neurological damage and to develop more effective treatments for patients with brain tumors.
  • We have made significant progress towards our goals in the past year. Using animal models developed in our lab, we have uncovered new mechanisms and pathways that drive the growth and metastasis of medulloblastoma, the most common malignant brain tumor in children. In addition, we have identified molecular pathways that are de-regulated in choroid plexus carcinoma, a rare brain tumor with a poor prognosis that occurs most frequently in children. Our work has also led to the identification of new drugs that inhibit the growth of medulloblastoma and choroid plexus carcinoma. In the coming year, we will continue in our efforts to understand these aggressive cancers and develop new, more effective therapies for children who suffer from them.
Funding Type: 
Alpha Stem Cell Clinics
Grant Number: 
AC1-07659
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$8 000 000
Disease Focus: 
Blood Disorders
Blood Cancer
Cancer
HIV/AIDS
Solid Tumor
Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

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

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

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

Statement of Benefit to California: 

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

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

Funding Type: 
Disease Team Therapy Development - 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.

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