Disease Team Therapy Planning I
AIDS/HIV disease is a viral infection that destroys the immune response. The disease can be treated with drugs, however these drugs do not eliminate the virus from the body. Hence currently the patient must remain on these drugs for the remainder of their life. These drugs are expensive and often cause toxicities, thus an improved treatment strategy for this disease is needed. Our project proposes pre-clinical studies to advance towards clinical trial a stem cell-based method of enhancing the patient's own immune response against the virus. This approach involves identifying anti-HIV receptors that will be introduced into the patient's own blood-forming stem cells. These cells will then be transplanted back into the patient, and the new receptors in those cells will direct those cells to turn into mature white blood cells that kill other cells infected by the AIDS virus (HIV). Since stem cells are stable following transplant, this approach has the potential to provide long-term immune control of virus replication, and may require only one or a few administrations. In this project we will perform all of the necessary pre-clinical development and characterization of this approach, and complete all of the necessary regulatory steps to achieve regulatory approval to begin testing of this strategy in humans.
Statement of Benefit to California:
The state of California and its economy are greatly impacted by AIDS/HIV disease. In 2007, the most recent year for which data is available, over 1100 Californians died from HIV disease. In 2008 nearly 68,000 Californians were living with an AIDS diagnosis. HIV infected individuals can be treated with anti-viral drugs, but these do not completely eradicate HIV from the body. Consequently HIV infected patients must remain on these drugs for the remainder of their life. These drugs agents are expensive and associated with toxicities. For these reasons a stem cell-based therapy that offered long-term control or elimination of HIV without the toxicities associated with current drug therapies would be advantageous. A stem cell-based treatment may have an additional advantage over current drug treatment in that it may need to be administered only once, or a limited number of times. Our proposed approach would provide a means to genetically engineer stem cells to enhance the patient's own immune response against the virus. It is possible that this approach could be used alone, or in conjunction with other therapies to provide improved control of HIV and prolong the life of the HIV infected patient.
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.