Funding opportunities

EXECUTIVE SUMMARY Project Synopsis The goal of this project is to file an IND and obtain appropriate regulatory approvals for a novel cell and gene therapy approach against human immunodeficiency virus (HIV) disease. The investigators propose to identify a combination of anti-HIV T cell receptors that will be introduced into the patient’s own blood-forming (hematopoietic) stem cells. The manipulated cells, the proposed product, will then be transplanted back to the patient. These cells will contribute to the patient’s immune system and lead to the generation of cytotoxic T cells that will target and kill cells infected with HIV. Proposed project activities include completion of preclinical studies including identification of anti-HIV receptors, cell process development, investigational new drug (IND)-enabling studies and obtaining appropriate regulatory approvals for a Phase 1 clinical trial. Significance and Impact - While current anti-retroviral therapy has been extremely effective in the vast majority of HIV positive patients, these medications can be costly, must be taken for life and can be associated with toxicity and other complications. The proposed strategy to genetically enhance the patient’s own immune response to HIV, if successful, has the potential to have significant impact by providing benefit for an extended period of time since hematopoietic stem cells have the capacity to self renew. - The intended patient population represents a minority of HIV patients but this population is sufficiently large to warrant development of this approach. - The proposal is responsive to the RFA in that the proposed therapeutic meets the criteria for an eligible cell type. However, the proposed target product profile is not yet complete, and a development candidate has not yet been defined. For instance, a number of in vitro and in vivo studies to screen for additional anti-HIV T cell receptors and to identify their optimum combination and the gene delivery system have yet to be completed. Furthermore, the disease stage at which subjects would be treated is not yet specified. Project Rationale and Feasibility - Due to the fact that studies to inform the target product profile have yet to be performed before IND-enabling studies can be initiated, the proposed time lines are unrealistic and it is questionable whether an IND submission can be achieved within four years. - The scientific rationale is based on preclinical data. However, reviewers did not find the preclinical data to be compelling. - Reviewers noted that the type of hematopoietic stem cells used for preclinical studies are different from those that will be used in human clinical trials and thus preclinical studies will have to be repeated. - Reviewers cautioned that in the absence of any conditioning regimen it is unclear if the quantity of gene-modified cytotoxic T cells likely to be produced from the transplanted stem cells would be sufficient to have an impact on viral clearance. This is not adequately addressed in the proposal. - Since cytotoxic T cells require CD4 cells for help, it is not clear whether HIV patients will have sufficient CD4 cells available to facilitate the function of the engineered cytotoxic T effector cells. - A theoretical concern is whether impaired thymic function in HIV infected individuals would limit T cell differentiation. There is also the possibility that expression of HIV antigens in the thymus of infected patients could result in negative selection of HIV-specific T cells, thus decreasing the frequency of the desired cells. - Reviewers were concerned about insufficient attention to safety studies in the proposal. Principal Investigator (PI) and Planning Leader - The PI is highly experienced in research on HIV. He/She has previously participated in clinical trials of genetically modified hematopoietic stem cells in HIV positive subjects. He/She is well qualified to lead this translational project. - The Planning Leader has outstanding experience in clinical trials in HIV including gene therapy trials of strong relevance to those proposed in the application. He/She is extremely well qualified to serve the proposed role.