Funding opportunities

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
Principle Investigator: 
Funds requested: 
$110 000
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 accrue a phase I clinical trial within the grant period to genetically redirect the patient’s immune response to specifically attack the cancer starting from hematopoietic (blood) stem cells (HSC) in patients with advanced forms of the aggressive skin cancer malignant melanoma. Evaluation of immune system reconstitution, effectiveness and immune response during treatment will use imaging with Positron Emission Tomography (PET) scans.

The HSC treatment approach has been validated in extensive studies in the laboratory. The investigators of this grant have recently initiated a clinical trial where adult immune cells obtained from blood are genetically modified to become specific killer cells for melanoma. These cells are administered back to patients. The early data from this study is encouraging in terms of the ability to generate these cells, safely administer them to patients leading to beneficial early clinical effects. However, the adult immune cells genetically redirected to attack cancer slowly decrease over time and lose their killer activity, mainly because they do not have the ability to self-renew.

The advantage of the proposed HSC method over adult blood cells is that the genetically modified HSC will continuously generate melanoma-targeted immune killer cells, hopefully providing prolonged protection against the cancer. The IND filing with the FDA will use the modified HSC in advanced stage melanoma patients. By the end of year 4, we will have fully accrued this phase 1 clinical trial and assessed the value of genetic modification of HSCs to provide a stable reconstitution of a cancer-fighting immune system. The therapeutic principles and procedures we develop will be applicable to a wide range of cancers and transferrable to other centers that perform bone marrow and HSC transplants.

The aggressive milestone-driven IND timeline is based on our:
1) Research that led to the selection and development of a blood cell gene for clinical use in collaboration with the leading experts in the field,
2) Our wealth of investigator-initiated cell-based clinical research and the Human Gene Medicine Program (largest in the world with 5% of all patients worldwide),
3) Experience filing a combined 15 investigator initiated INDs for research with 157 patients enrolled in phase I and II trials, and
4) Ability to leverage significant institutional resources of on-going HSC laboratory and clinical research and contribute ~$1M of non-CIRM funds to pursue the proposed research goals, including the resulting clinical trial.

Statement of Benefit to California: 

Cancer is the leading cause of death in the US and melanoma incidence is increasing fastest (~69K new cases/year). Treatment of metastatic melanoma is an unmet local and national medical need (~9K deaths/year) striking adults in their prime (20-60 years old). Melanoma is the second greatest cancer cause of lost productive years given its incidence early in life and its high mortality once it metastasizes. The problem is severe in California, with large populations with skin types sensitive to the increased exposure to ultraviolet light. Most frequently seen in young urban Caucasians, melanoma also strikes other ethnicities, i.e., steady increases of acral melanoma in Latinos and African-Americans over the past decades.

Although great progress has been made in the treatment of certain leukemias and lymphomas with targeted and combination therapies, few options exist for the definitive treatment of late stage solid tumors. When cancers like lung, breast, prostate, pancreas, and melanoma metastasize beyond surgical boundaries, prolonged remissions or cures are rare and most cancer therapies only inhibit cell growth and/or reduce such growth but do not stop the cancer.

Our proposal, the filing of an IND and the conduct of a phase 1 clinical trial using genetically modified autologous hematopoietic stem cells (HSC) for the immunotherapy of advanced stage melanoma allowing sustained production of cancer-reactive immune cells, has the potential to address a significant and serious unmet clinical need for the treatment of melanoma and other cancers, increase patient survival and productivity, and decrease cancer-related health care costs.

The advantage of the proposed HSC methodology over our current work with peripheral blood cells is that genetically modified stem cells will continuously generate melanoma-targeted immune cells in the patient’s body providing prolonged protection against the cancer. The therapeutic principles and procedures developed here will be applicable to a wide range of cancers. Good Manufacturing Practices (GMP) reagents and clinical protocols developed by our team will be transferable to other centers where bone marrow and peripheral blood stem cell transplantation procedures are done.

Review Summary: 


Project Synopsis
The goal of this proposal is to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) for an immunotherapy approach to treating melanoma and to conduct a Phase I clinical trial testing the safety of the proposed therapeutic in advanced stage melanoma patients. The proposed immunotherapeutic is genetically modified hematopoietic stem cells (HSCs) engineered to produce mature cytolytic T cell (CTL) progeny expressing a tumor reactive T cell receptor (TCR) and a Positron Emission Tomography (PET) reporter gene. 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.

- The proposed therapeutic is extremely complex. The applicant does not articulate nor is it obvious how it can go from a clinical experiment to a commercializable or widely available therapy. In the absence of a clear plan to make this therapy widely available, impact is limited.

- Impact is limited as only a subset of patients will qualify for the therapy and myeloablative conditioning is required. However, the proposed therapy is likely to provide some benefit to qualifying patients and has the potential to complement other therapeutic approaches. This is also a population with no alternative where any successful therapeutic would be of great impact.

- The target product profile (TPP) is not an aspirational TPP. Reviewers recommended that the applicant utilize the FDA guidance document (Guidance for Industry and Review Staff Target Product Profile — A Strategic Development Process Tool for instructions on how to prepare a TPP) in preparing the TPP should a full application be submitted.

- The proposal is only moderately responsive to the RFA. A single development candidate that meets the required criteria is proposed. However, the applicant is still in the process of optimizing the therapeutic vector and has not yet selected the final development candidate.

Project Rationale and Feasibility
- There is a strong clinical and preclinical rationale for initiating these studies.

- The use of HSCs is innovative and represents an efficient and potentially long-term solution to providing ongoing immunotherapy, a demonstrated limitation of previous approaches using genetically modified adult immune system cells.

- The proposal is ambitious but feasible and likely to be achievable in the proposed timeline.

- Enthusiasm of some reviewers was dampened based on the complexity of the proposed product, a major challenge to commercialization and/or availability of the therapy. However, other reviewers felt that the proposed complexity is necessary for the efficacy of the therapeutic and, given the limited options for the targeted patient population, thought this approach should be tested in a clinical setting.

- The inclusion of a PET reporter and suicide gene are significant innovations that allow in vivo tracking and, if necessary, elimination of the genetically modified cells.

- The proposed technology is likely the most efficient way to induce long-term anti-tumor T cell responses, though some obstacles still exist relating to transduction and sustained expression of the transgenes.

- The preclinical studies that will be carried out to demonstrate the safety and dosing of the proposed vectors were not adequately described and should be elaborated upon in a full application, if submitted.

Principal Investigator (PI) and Planning Leader
- The PI is an established translational investigator and a known immunotherapy expert with appropriate experience in obtaining IND clearance and running this type of clinical trial.

- The team is entirely appropriate, capable of providing critical basic science insights, is experienced with regulatory agencies, and has appropriate experience in translating this type of therapy from the bench to bedside.

- The previous experience of this group demonstrates they can achieve what they propose.

- An external advisory committee is proposed, which is an innovative step and important for these kinds of high-risk projects.

- The experience of the planning leader is not clear and s/he seems more experienced in the discovery phase of research. The biosketch indicates very little experience that is obviously translational. The single noted experience for a drug program does not indicate the phase of development.