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Stem Cell-Based Targeted Immune Therapy for Cancer

Funding Type: 
Disease Team Research I
Grant Number: 
Funds requested: 
$17 452 288
Funding Recommendations: 
Not recommended
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 two Investigational New Drug (IND) applications within the grant period for the genetic modification of hematopoietic (blood) stem cells (HSC) from patients with advanced forms of an aggressive skin cancer (malignant melanoma) to genetically redirect the patient’s immune response to specifically attack the cancer. Evaluation of 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 cancer cells slowly decrease over time 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, providing prolonged protection against the cancer. The 1st IND filing (year 2/quarter 2) will use the modified HSC in end-stage melanoma patients. By the end of year 4, we will expand our efforts to a 2nd IND for a new engineered HSC clinical trial that will increase the specificity of the HSC to other cancers. 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 our Human Gene Medicine Program 3) Experience receiving a combined 15 investigator initiated INDs for research with 157 patients in Phase I and II trials 4) Ability to leverage significant institutional resources of on-going HSC laboratory and clinical research and co-support with over $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 the 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 (30-60 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 in large populations with skin types sensitive to the increased exposure of ultraviolet light. Most frequently seen in young urban Caucasians, melanoma also strikes other ethnicities with 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 which contains 2 INDs for the genetic modification of the patient’s own hematopoietic stem cells (HSC) for the immunotherapy of end-stage melanoma allowing sustained production of cancer-reactive blood 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 is that genetically modified stem cells in the patient’s body will continuously generate melanoma-targeted blood cells providing prolonged protection against the cancer. During the grant period we will also develop and produce a GMP quality second IND vector expressing a T cell receptor for NY-ESO, an antigen expressed by 10-30% of all cancers, thereby broadening the applicability of this approach. The therapeutic principles and procedures developed here will be applicable to a wide range of cancers. GMP reagents and clinical protocols developed by our team will be transferrable to other centers where bone marrow and peripheral blood stem cell transplantation procedures are done. Our institution, with its college and multiple professional schools, receives over $900M in extramural research support with a major economic impact throughout the region. The proposal will build upon a strong foundation of basic and clinical research and further solidify on-going institutional collaborations that will further link the activities of four premier research institutions.
Review Summary: 
The goal of this proposal is to engineer autologous hematopoietic stem cells (HSCs) to express tumor antigen-specific T cell receptors (TCRs) for transplantation into melanoma patients as an immunotherapeutic treatment. This research team has validated this approach and the efficacy of the first target antigen clinically using mature T cells and proposes to enhance the therapeutic benefit through the use of stem cells and by improving the gene therapy vector. The proposed therapy would be available to melanoma patients of the appropriate HLA haplotype with tumors expressing the targeted tumor antigens. Patients receiving the therapy would be appropriately conditioned prior to the adoptive transfer of engineered cells and would undergo post-adoptive transfer treatments to boost lymphocyte expansion. The vector would be designed to support Positron Emission Tomography (PET)-based imaging of the adoptively transferred cells and include a “suicide gene” as an additional safety mechanism. The applicants also propose to increase the potential impact of this therapeutic on melanoma patients by developing a second vector targeting a different tumor antigen. The second vector could be utilized to initiate a polyclonal anti-tumor immune response through adoptive transfer of both populations of engineered HSCs. The lead candidate for the second target antigen is expressed in melanoma and by a wide range of cancers and could potentially broaden the applicability of this therapy. The reviewers found this application to be a well-reasoned proposal targeting a highly resistant and generally fatal disease from an outstanding team of investigators with a proven track record. However, the reviewers were not convinced that the use of HSCs would offer a significant clinical advantage and were concerned that the applicants did not address several regulatory elements critical to the feasibility of the preclinical plan and the filing of the two proposed Investigational New Drug (IND) applications with the FDA. The reviewers were moderately enthusiastic about the significance of and scientific rationale for this therapy. While they agreed that the impact of advances in this therapeutic approach would be significant and that melanoma presents an unmet medical need, they questioned the number of patients this therapy could potentially reach. The potential patient population is limited by numerous factors as the patients would be restricted to those with a specific HLA haplotype who have tumors expressing the targeted antigens and who are able to tolerate the conditioning regiment. The scientific rationale for the proposed immunotherapy is sound, but reviewers were not convinced that the rationale for utilizing HSCs was well supported. The applicants included a wealth of data validating the approach, but there was little data provided to support the hypothesis that a renewing population of cancer-reactive T cells would provide a significant clinical benefit to melanoma patients as compared to the clinical trial this group recently initiated. The reviewers appreciated the ample preliminary data providing proof of concept for the use of engineered TCRs in treating melanoma and demonstrating the ability to apply this technology in HSCs. The clinical data was compelling and supportive for the anti-melanoma activity of cells transduced with a vector targeting the first proposed antigen. However, there was little preliminary data to support several feasibility and safety concerns. For example, the reviewers noted the lack of data addressing thymic selection following adoptive transfer of HSCs, immune evasion strategies employed by cancer cells, and the potential adverse effects viral transduction might have on other immune cells differentiated from transduced HSCs. The reviewers also questioned the lack of data demonstrating how the suicide gene might be utilized in potentially quiescent HSCs and its potential impact on the immune competence of the human host. The reviewers found the preclinical plan to lack several critical elements to achieve two IND filings within the four-year timeline. The reviewers did not agree with the applicant that the FDA would not require toxicology studies in animals with the GMP lentiviral construct and believed that the proposed use of two different vector systems in one patient would present a significant safety concern for the FDA. The regulatory expert suggested that it would be important to approach the FDA with data from animal models demonstrating the safety of this approach. The reviewers were also concerned that the use of self-renewing HSCs provided an additional regulatory burden that the applicants did not address. There was no apparent plan to generate data demonstrating the safety of this approach with HSCs, and the applicants did not address the difficult prospect that long-term tracking of the patient population might be necessary when using HSCs. The reviewers were also not confident that the FDA would allow the use of the PET component of the viral vector. There is no clinical benefit to the PET component, and it is likely to be perceived as increasing patient risk due to potential immunogenicity of the PET gene and the additional genetic modifications to the vector that are necessary for its inclusion. Furthermore, while the PET reporter gene can be used for non-invasive in vivo tracking, this does not offer an outcome measurement. The clinical endpoints the applicants hope to demonstrate are unclear. Despite these numerous regulatory concerns, the reviewers found the preclinical plan targeting the development of the HSCs transduced to express TCRs reactive to the first target antigen to be logical and achievable with reasonable milestones and timelines. However, this was not the case for the development of the vector targeting the second proposed antigen. The reviewers commented that this second part of the preclinical plan was not clearly delineated, and there was not sufficient data or details to indicate that increasing the immune response to the lead antigen target would be effective in treating melanoma patients. The milestones were vague, and the reviewers agreed that the only evidence that the timelines could be achieved was the excellent track record of the team. The reviewers also noted that the first component of the application was significantly stronger than the studies proposed for the second antigen target. The applicants indicated that the majority of the studies aimed at developing the first target antigen are already supported by outside sources, and it was therefore unclear to reviewers why CIRM funds were necessary for that portion of the proposal. The reviewers considered the qualifications of the primary investigator (PI), the Co-PIs, and the disease team to be the central strength of the proposal. The PI is highly qualified to lead this team of senior investigators and the collaborations are long standing and solid. The senior investigators on this team have impeccable track records with extensive experience in IND-enabling research. The group has all the necessary expertise and is perfectly suited for this research. The reviewers commented that there is clear commitment from the institutions and all the critical resources are in place. The reviewers praised the existing infrastructure and leadership plan and noted the inclusion of a project manager and a strong external advisory committee composed of the world experts in immunotherapy for cancer treatment. Overall, the reviewers felt that the applicants did not provide sufficient preliminary data to support their approach using HSCs and did not provide sufficient detail to support the feasibility of the research plan. This deficiency outweighed their great regard for the impressive quality of the assembled team and potential impact that advances in immunotherapy could have on cancer treatment.
  • John Rasko

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