Funding opportunities

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
Principle Investigator: 
Funds requested: 
$19 999 563
Funding Recommendations: 
Grant approved: 
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.

Review Summary: 

The goal of this proposal is to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) for a stem cell gene therapy for treating metastatic melanoma and to conduct a phase I clinical trial. The disease team proposes to redirect the patient’s immune response to specifically attack the cancer by delivering genetically modified antigen-specific mature lymphocytes and hematopoietic stem cells (HSC) to patients with advanced forms of the aggressive skin cancer malignant melanoma. Genetic modifications will include a reporter such that the investigators can evaluate immune system reconstitution, effectiveness and immune response during treatment with Positron Emission Tomography (PET) scans. The applicant hypothesizes that since HSCs have the ability to self-renew, a sustained, high frequency anti-tumor cellular immune response will provide a benefit to these melanoma patients, for whom there are currently limited therapeutic options.

Significance and Impact
-The targeted patient population has few alternatives and represents a population with a clear and significant unmet medical need. All current therapies for malignant melanoma have significant limitations.

-The proposed therapeutic approach builds on prior experience, incorporates lessons learned from clinical research using mature T cells to target melanoma and will likely benefit the subset of melanoma patients eligible for this therapy.

-Impact may be limited due to complexity of the proposed approach as it may not be easily exportable to clinical sites on a wider scale. However, given the great unmet medical need in this patient population, a commercially viable product may be pursued in the event the therapy is efficacious.

-Although autologous cell based therapies are a difficult business model, the proposed approach offers a pathway to commercialization through a business entity founded by the PI.

-The strong scientific rational is based upon previous clinical studies.

-The use of HSCs is innovative and represents an efficient and potentially long-term solution to the limitations of adult immune system cells based immunotherapies. The applicants are uniquely positioned to inform the field as to whether one can achieve long-term engraftment and expression using this approach.

-Reviewers were concerned about the choice of the tumor antigen, which is also expressed to a lesser extant on some normal cells, and thought another tumor-specific antigen might be better.

-Reviewers pointed out the possibility that, since the proposed antigen is expressed on some normal tissue, engineered T cells may undergo negative selection in the thymus and be eliminated.

Therapeutic Development Readiness
-The preclinical studies are appropriate and support the project plan.

-The gene therapy vector required for the proposed studies has been produced at research scale.

-The proposed timelines for IND-enabling studies and a Phase I clinical study are achievable.

Feasibility of the Project Plan
-Project plan is feasible and likely to be achievable according to the proposed timelines. Though the plan depends on successful completion of IND-enabling studies, it is likely that those studies will be completed in the indicated timeframe. Reviewers noted that the proposed patient enrollment plan might make completion of the clinical study, with all the proposed patients and by the target date, a challenge.

-The team’s clinical experience in measuring objective responses to immunotherapy of melanoma as well as ex vivo immune assays to monitor surrogate end points supports the feasibility of the clinical plan.

-Reviewers appreciated the use of non-invasive imaging for in vivo monitoring and, if necessary, elimination of genetically modified immune system cells. There were, however, a lack of details on how imaging will be performed and limited evaluation of the readiness of the technology in the proposed setting. Reviewers cautioned that, depending on the expression of the transgene and sensitivity of the assay, imaging might be difficult to implement.

-Enthusiasm of some reviewers was dampened because of the complexity of combining two separate gene modified cells in the proposed study. It might be difficult to know if any efficacy or toxicity seen is from gene modified HSC or adult cell transplant.

-It will be challenging to define an appropriate conditioning regimen for the patient population, considering the known toxicities associated with the proposed myeloablative regimen.

Principal Investigator (PI) and Development Team
-The team was considered extraordinary and possesses stem cell experience and other essential attributes that should enable accomplishment of the proposed goals.

-The PI is an established translational investigator and a clinical expert in melanoma biology and clinical care.

-The development team includes a number of distinguished clinicians and scientists.

-The team is committed to advancing a stem cell based immunotherapy approach for melanoma and has a demonstrated track record for translating scientific discoveries into clinical development.

Collaborations, Resources and Environment
-Resources and environment were considered outstanding.

-The applicant institution has committed funds to support this proposal should it get approved for funding by CIRM.

-The IP position for this approach and antigen requires clarification.

-Details of collaboration with the NIH on specific memory immune cells and alternative suicide gene is not well described and was considered by some reviewers as a distraction from the primary goals and directions of the application.

Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding. )

- Costs associated with preparation of the regulatory packages (which includes pre IND, RAC, IRB and FDA IND) have significant overlap and are excessive.

- Costs associated with manufacturing of the gene therapy vector were assessed to be excessive.

- Estimated per patient cost for the clinical studies was assessed to be excessive.

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