The Human Immunodeficiency Virus (HIV) is still a major health problem. In both developed and underdeveloped nations, millions of people are infected with this virus. HIV infects cells of the immune system, becomes part of the cell’s genetic information, stays there for the rest of the life of these cells, and uses these cells as a factory to make more HIV. In this process, the immune cells get destroyed. Soon a condition called AIDS, the Acquired Immunodeficiency Syndrome sets in where the immune system cannot fight common infections. If left untreated, death from severe infections occurs within 8 to 10 years. Although advances in treatment using small molecule drugs have extended the life span of HIV infected individuals, neither a cure for HIV infection nor a well working vaccine could be developed. Drug treatment is currently the only option to keep HIV infected individuals alive. Patients have to take a combination of drugs daily and reliably for the rest of their lives. If not taken regularly, HIV becomes resistant to the drugs and continues to destroy immune cells. What makes this situation even more complicated is the fact that many patients cannot take these drugs due to severe side effects.
Stem cell gene therapy for HIV may offer an alternative treatment. Blood forming stem cells, also called bone marrow stem cells make all blood cells of the body, including immune system cells such as T cells and macrophages that HIV destroys. If “anti-HIV genes” were inserted into the genetic information of bone marrow stem cells, these genes would be passed on to all new immune cells and make them resistant to HIV. Anti-HIV gene containing immune cells can now multiply in the presence of HIV and fight the virus. In previous and current stem cell gene therapy clinical trials for HIV, only one anti-HIV gene has been used. Our approach, however, will use a combination of three anti-HIV genes which are much more potent. They will not only prevent HIV from entering an immune cell but will also prevent HIV from mutating, since it would have to escape the anti-HIV effect of three genes, similar to triple combination anti-HIV drug therapy. To demonstrate safety and effectiveness of our treatment, we will perform a clinical trial in HIV lymphoma patients. In such patients, the destruction of the immune system by HIV led to the development of a cancer of the lymph nodes called B cell lymphoma. High dose chemotherapy together with the transplantation of the patient’s own bone marrow stem cells cures B cell lymphoma. We will insert anti-HIV genes in the patient’s bone marrow stem cells and then transplant these gene containing cells into the HIV infected lymphoma patient. The gene containing bone marrow stem cells will produce a new immune system and newly arising immune cells will be resistant to HIV. In this case, we have not only cured the patient's cancer but have also given the patient an HIV resistant immune system which will be able to fight HIV.
As of September 30, 2010, over 198,883 cumulative HIV/AIDS cases were reported in California. Another 40,000 un-named cases of HIV were also reported before 2006 although some of them may be duplicates of the named HIV cases. Patients living with HIV/AIDS totaled 108,986 at the end of September 2010. These numbers continue to grow since new cases of HIV and AIDS are being reported on a daily basis and patients now live much longer. In fact, after New York, California has the second highest number of HIV cases in the nation. Although the current and improved anti-retroviral small molecule drugs have prolonged the life of these patients, they still have to deal with the emotional, financial, and medical consequences of this disease. The fear of side effects and the potential generation of drug resistant strains of HIV is a constant struggle that these patients have to live with for the rest of their lives. Furthermore, not every patient with HIV responds to treatment and not every complication of HIV dissipates upon starting a drug regimen. In fact, the risk of some AIDS-related cancers still remains high despite the ongoing drug therapy. Additionally, in the current economic crisis, the financial burden of the long term treatment of these patients on California taxpayers is even more obvious. In 2006, the lifetime cost of taking care of an HIV patient was calculated to be about $618,900. Most of this was related to the medication cost. With the introduction of new HIV medications that have a substantially higher price and with the increase in the survival of HIV/AIDS patients, the cost of taking care of these patients can be estimated to be very high.
The proposed budget cuts and projected shortfall in the California AIDS assistant programs such as ADAP will make the situation worse and could result in catastrophic consequences for patients who desperately need this of kind of support. Consequently, improved therapeutic approaches and the focus on developing a cure for HIV infected patients are issues of great importance to the people of California.
Our proposed anti-HIV stem cell gene therapy strategy comprises the modification of autologous hematopoietic blood forming stem cells with a triple combination of potent anti-HIV genes delivered by a single lentiviral vector construct. This approach would engineer a patient’s immune cells in a way to make them completely resistant to HIV infection. By transplanting these anti-HIV gene expressing stem cells back into an HIV infected patient, the ability of HIV to further replicate and ravage the patient’s immune system would be diminished. The prospect of such a stem cell based therapy which may require only a single treatment to cure an HIV infected patient and which would last for the life of the individual would be especially compelling to the HIV community and the people of California.
The goal of this proposal is to demonstrate safety and effectiveness of a novel therapeutic against human immunodeficiency virus (HIV) infection in patients with relapsed B cell lymphoma. The treatment will consist of autologous bone marrow transplantation using a patient’s own hematopoietic stem cells (HSC) that have been genetically modified to express three independent anti-HIV genes. The applicants hypothesize that since HSC have the ability to self-renew, these cells will allow subsequent repopulation of the patient’s immune system with derivatives that are resistant to HIV. Proposed activities include completion of investigational new drug (IND)-enabling studies, filing of an IND and appropriate regulatory approvals, and initiation and completion of a Phase I/II clinical trial.
Significance and Impact
- The proposed target profile is reasonable and appropriate, and the intended patient population is well delineated.
- Although patients with relapsed B cell lymphoma comprise a very small subset of the HIV+ population, the proposed studies could yield proof of concept that would inform the development of other HIV treatments.
- While modern retroviral therapy has been extremely effective in the vast majority of HIV+ patients, these medications can be costly, must be taken for life, and can be associated with toxicity and other complications. If successful, the proposed strategy may enable a one-time functional cure for HIV infection, or at least reduce the number of daily medications that are needed to control the disease.
- The impact of this approach on HIV standard of care is uncertain, as autologous bone marrow transplantation is a risky procedure that is not likely to be offered to patients other than those requiring one for another indication, such as cancer. If a safe conditioning regimen were to be devised, however, it is possible that this approach could be more widely implemented.
- Reviewers cautioned that the effectiveness of the proposed therapeutic could potentially be limited by the need for ongoing expression of the anti-HIV genes and/or unexpected negative effects of their long term expression on HSC-derived lineages.
-The proposed therapy could be quite expensive, and it is questionable whether it would be feasible in patients from underdeveloped countries in near future.
- The applicant describes a single development candidate and proposes activities that are fully within scope of this RFA. It is likely that that one or more project objectives will be readily achieved within four years.
Project Rationale and Feasibility
- The rationale for targeting three distinct genes is excellent, as it reduces the risk of losing all anti-HIV activity by gene silencing as well as development of viral resistance. This approach also has the advantage of being active against CXCR4- as well as CCR5-specific HIV variants.
- A major concern is the potential difficulty in recruiting sufficient patients to complete the clinical trial in the project period. The proposal did not describe the applicant institution’s ability to identify HIV+ patients with relapsed B cell lymphoma who require an autologous transplant, a challenging scenario even at the largest transplant hospitals. Reviewers suggested that a multi-center trial might be in order.
- The draft project plan is feasible and should provide useful data for informing go/no go decisions. The milestones are clearly outlined, and the project activities are sufficiently focused to advance knowledge on safety and/or efficacy. The timelines are reasonable but ambitious, given the need to complete manufacture and testing of the gene modification vector under good manufacturing practices (GMP).
- Reviewers discussed a number of weaknesses in the preliminary data, which is not published, and questioned the predictive value of those studies. For example, some experiments utilized different starting material than that which is proposed for the clinical trial. Moreover, the order in which cells were modified and infected with HIV does not mimic the clinical situation, where patient cells would be infected prior to genetic modification.
- The proposed two-part clinical trial design is very good and mitigates risk.
- Reviewers found the strength of the preclinical work difficult to judge and therefore suggested that the applicant include data or discussion of the long-term durability of engraftment in the mouse model, as well as studies to compare the engraftment efficiency of anti-HIV transduced cells to un-manipulated cells. They further recommended that error bars/statistics be included on data so that reviewers can assess variability.
- Reviewers suggested that the applicant address the following questions in the full proposal: 1) Do anti-HIV gene expression levels change over time? 2) What is the period for follow-up tumorigenicity studies? 3) In patients, antiretroviral therapy will be suspended upon engraftment; how will this therapy affect engraftment if administered at the time of stem cell infusion? How will this therapy be managed subsequent to treatment and what risks will that present?
- Reviewers suggested that it would be useful if preclinical studies included benchmarks and internal controls, for example to compare the proposed vector system to one that has already gone into patients. Actual data showing strong suppression of viremia in the animal model would also strengthen the proposal.
- Reviewers recommended inclusion of a pre-pre-IND meeting in the early stages of this project.
Principal Investigator (PI) and Planning Leader
- The PI is highly experienced with bone marrow transplantation, including the use of gene-modified cells for treating cancer. He/she has been actively involved in multiple clinical trials and is well qualified to lead this effort.
- The Planning Leader has extensive experience with stem cell gene therapy trials for HIV. He/she has significant expertise on the technical aspects of cellular development and gene therapy, including GMP production of lentiviral vector and clinical grade transduced stem cells.
- Andrew Balber