The AIDS virus infects and destroys cells of the immune system such that the bodies of infected individuals cannot fight infections or some cancers. If untreated HIV infection leads to death. Current therapies to stop virus replication in the body are expensive and can have side effects. They also do not eliminate the virus from the body. Our overall goal is to use a gene therapy approach to improve a patient’s own immune response against HIV, thus rendering them able to fight their own viral infection. We will test an approach designed to engineer a patient’s immune system so that it can directly kill cells infected by HIV, thereby preventing spread of the virus throughout the body. This would decrease virus replication, and perhaps eliminate HIV from the body. This should prevent the HIV-induced destruction of the immune system, and restore the body’s ability to mount immune responses against a variety of infectious agents and cancers, and may eliminate the need for the patient to take antiretroviral drugs. Successful completion of this project will yield an immunotherapeutic that is ready for preclinical development as a treatment for HIV-1 infection and AIDS.
California ranks second in the nation in cases of HIV/AIDS, with over 155,000 persons living with HIV infection currently. This is projected to increase steadily to over 172,000 persons in the next 5 years. Aside from the personal, social, and work productivity losses due to HIV infection and its treatment, the direct healthcare cost to California is thought to approach $1.8 billion annually (CDC).
A curative treatment is therefore a high priority, given the high costs of chronic treatment and the increasingly apparent long-term toxicities of the antiretroviral drugs. Stem cell therapy offers promise for this goal, by addressing two major immune mechanisms of failure to control HIV infection: 1) loss of both anti-HIV CD8+ T-cells and the CD4+ T-cells required for their maintenance and function, and 2) CD8+ T-cell targeting that is subject to HIV evasion through mutation and down-modulation of the class I Human Leukocyte Antigens that present HIV protein sequences to CD8+ T-cells.
In this project, we propose to develop a strategy to program stem cells to provide a self-renewing population of both CD8+ and CD4+ HIV-targeted T-cells that are resistant to direct HIV infection, and which bypass the mechanisms by which HIV usually evades the immune response. If successful, this approach would allow development of a one-time stem cell gene therapy treatment that yields long-term immune control of HIV infection.
The objective of this Development Candidate Award proposal is to select a gene therapy and stem cell candidate therapeutic for individuals infected with human immunodeficiency virus (HIV). The immune system is able to partially control HIV in infected individuals but fails over time due to a variety of limitations including exhaustion of the natural T cell immune response. Here, the investigator intends to overcome the limitation of the natural immune response to HIV by engineering hematopoietic stem cells (HSCs) and T memory stem cell (TSCMs) to express receptors that recognize and kill HIV in order to provide an inexhaustible source of immune cells capable of eliminating HIV-infected cells. The therapeutic is intended to be administered via a one-time stem cell transplantation procedure, provide long-term benefit to the patient, and act as a functional cure with minimal adverse effects. This would be an advance over current standard of care, as HIV is currently treated via pharmacologic intervention, and the drugs must be regularly administered, are expensive, have extensive side effects and are not curative.
Objective and Milestones
- The objective is clear and comprehensive, although the approach includes numerous elements and is highly complex.
- Milestones are well constructed and achievable, but defined specifications and hard go/no go criteria must be incorporated into the milestones. For example, it is unclear how will the product cell type(s) or the most promising gene target(s) will be selected. Given the highly complex nature of the candidate, it is critical for completion of the project in the proposed timeframe that the applicants have clear criteria for candidate selection.
- The project appears to feature two development candidates rather than a single candidate. While all the elements appear necessary for product activity, this lack of focus is a risk to the success of the project. Some reviewers recommended development of a single candidate, and all reviewers agreed it is necessary for the team to remain singularly focused on the project objective.
- The Target Product Profile (TPP) is well put together, and the intended product is clear. However, the description is written more as a narrative than a true TPP. For example, metrics are not described for the desired biologic activity nor for the minimum activity for efficacy. Safety concerns such as off targets effects or oncogenic potential are not fully described and do not include the minimal safety metrics that the product must meet.
Rationale and Significance
- The proposed therapeutic is potentially curative and targets an obvious unmet medical need. If successfully developed, the product would represent a major advance in the standard of care; therefore, the significance of the proposed research is high.
- The preliminary data (PD) support the hypothesis, the proposed approach, and strongly document the ability of the investigators to execute the research plan. The only weakness is a lack of PD providing information regarding the in vivo dose and the transduction efficiency that might be required for the proposed therapeutic to be clinically beneficial.
- There are several competitive approaches with curative intent in development by other groups, though this one does have some advantages.
- The rationale is logical and already proven in the oncology field. However, it is not clear that the viral load will be decreased or eliminated (the applicant provided a rationale as to why this may occur, but PD is lacking) nor is it clear how long-lived any beneficial effects might be. Important to the rationale is that the engineered cells do not become exhausted; the PD did not convince all reviewers that the engineered cells will avoid this fate.
Feasibility and Design
- Successful completion of the proposed plan should result in a development candidate at the cusp of entering preclinical IND-enabling research.
- Overall, the research plan is comprehensive, organized, and well designed.
- The research plan should include clear selection criteria for both the cell type and the gene targets. Additionally, there should be a definitive timeline indicating when the first phase of the program is complete and when activities will move forward with a candidate that meets the selection criteria.
- Reviewers suggested that a number of research details should be more thoroughly considered or addressed including the use of the target cell type (PBMCs) in testing, the isolation of the product using a clinically compatible method, performing HSC differentiation in vivo in the presence of HIV (since this will mimic the clinical setting) and timing of cell marker removal.
- Reviewers expressed concern that some safety elements were not well defined or adequately considered.
Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team
- The PI is outstanding, experienced, and has an excellent track record.
- The multidisciplinary team is strong, and reviewers had no doubt that the team is capable of executing the proposed research plan.
- There is an excellent communication plan, and the team is well coordinated and positioned to perform the described work.
- Most key team members committed only the minimal effort required. Given the ambitious nature of the proposal, this may make completion of the objective within the time period challenging.
-The budget is appropriate, though it is not clear that it is necessary to purchase additional cell sorting equipment given the resources at the institution.
Collaborations, Assets, Resources and Environment
- Collaborations are excellent and appropriate.
- The team has the necessary support, facilities, and collaborations.
- There was some concern regarding freedom to operate and intellectual property. The investigator should consider these issues in advance of the end of the award period.
Responsiveness to the RFA
- The proposal is responsive to the RFA.
- Though the concept and indication are not novel within the CIRM portfolio, the proposed approach is not currently represented.