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Autologous Stem Cell Transplantation with Purified, anti HIV Gene Modified Stem Cells For Treatment of HIV Related Malignancies.

Funding Type: 
Disease Team Therapy Development III
Grant Number: 
Funds requested: 
$10 982 932
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
The Human Immunodeficiency Virus (HIV) is still a major health problem. In both developed and underdeveloped nations, millions of people are infected with it. HIV enters cells of the immune system, becomes part of the cells' genetic information, stays there for the rest of the life of these cells and uses these cells 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 has as yet been 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 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 could then multiply in the presence of HIV and fight the virus. In most of the previous stem cell gene therapy clinical trials for HIV, only one anti-HIV gene was used. Our approach 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 drug therapy. To demonstrate safety and effectiveness of our treatment, we will perform a clinical trial in HIV lymphoma patients. In these patients, the destruction of the immune system by HIV led to the development of a type of leukemia 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 cells into the HIV infected lymphoma patient. The gene containing bone marrow stem cells will produce a new immune system and the newly arising immune cells will be resistant to HIV. Upon successful completion of this therapy, we will have not only cured the patient's leukemia but will have also have given the patient an HIV resistant immune system which will be able to fight HIV, preventing infection.
Statement of Benefit to California: 
As of September 30, 2010, over 198,883 cumulative HIV/AIDS cases were reported in California. Before 2006, another 40,000 un-named cases of HIV were also reported, 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 HIV infected individuals, these patients, their partners, friends and relatives still have to deal with the emotional, financial, and medical consequences of the disease. The fear of side effects and the potential generation of drug resistant strains of HIV are constant struggles 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 HIV-related cancers still remains high despite the ongoing drug therapy. Additionally, in the current economic crisis, the financial impact of the long term treatment of these patients on California taxpayers is even more obvious. Recently, the lifetime cost of taking care of an HIV patient was calculated to be about $1.5 million. 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 assistance programs such as ADAP will make the situation worse and could result in catastrophic consequences for patients who desperately need this 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 to become 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 destroy 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 functionally cure an HIV infected patient, lasting for the life of the individual, without having to take drugs would be especially compelling to the HIV community and the people of California.
Review Summary: 
EXECUTIVE SUMMARY This application is focused on the development of a gene-modified, autologous hematopoietic stem cell (HSC) therapy for HIV/AIDS. The scope of the project includes completion of preclinical animal studies, viral vector manufacturing, filing of an Investigational New Drug (IND) application to the Food & Drug Administration (FDA), and conduct of a Phase 1 clinical trial. The therapeutic candidate is autologous HSCs transduced with three anti-HIV genes and transplanted back into patients following high dose chemotherapy. The proposed patient population is HIV patients with B cell lymphoma, a type of leukemia associated with HIV infection. If safety and efficacy can be demonstrated in this patient population the applicants plan to move into cancer-free HIV/AIDS patients in later phase clinical trials. Significance and Impact - The Target Product Profile is unsatisfactory as it reflects short-term goals of the proposed Phase 1 trial rather than the aspirational goals of the entire development program. It also does not address the important challenge of HIV latency. - If the project is successful, the impact would be great. - There are competing, early stage, development programs in this space, but this proposal has unique aspects, including the use of three anti-HIV genes and a means to enrich gene-modified stem cells. Scientific Rationale and Risk/Benefit - Reviewers’ primary concern was that HIV lymphoma patients are not the appropriate population for the Phase 1 clinical trial. Frontline chemotherapy for this population of patients has improved to the extent that very few patients require full myeloablation and HSC transplant, as proposed in the applicants’ clinical trial, so the risk/benefit ratio is not favorable. - The approach proposed for HSC purification is innovative, but reviewers noted that transplanting only purified cells, as proposed in one cohort, might lead to higher rates of opportunistic infections in patients. - Reviewers were concerned that the planned treatment interruption during the clinical trial adds a risk of seeding sensitive elements of the remaining immune system with HIV. They were not convinced this interruption is necessary to determine the efficacy of the transduced cells. Therapeutic Development Readiness - The applicants present preclinical efficacy data in appropriate models and plan to obtain safety data in a separate preclinical model. Reviewers noted the separate safety data would be more valuable if it were obtained prior to submission of the IND. They have received a required approval from the National Institutes of Health Recombinant DNA Advisory Committee. Design and Feasibility - Reviewers were not convinced that a sufficient number of HIV lymphoma patients could be recruited for the Phase 1 trial, given the availability of other treatments. This was a major feasibility concern. - The activities leading up to the clinical trial generally appear reasonable and feasible. - Success criteria for Go/No Go milestones are not well defined. - Reviewers noted that given the proposed size of the Phase 1 trial, a relatively high rate of toxicity could go undetected. They recommended increasing the number of patients if possible. - The clinical protocol should specify stopping rules up front rather than leaving them to be determined by the Data Safety Monitoring Board. - Reviewers raised concerns about the feasibility of magnetic bead sorting at the proposed scale, which is significantly lower than the typical scale used in the system. Principal Investigator (PI), Development Team and Leadership Plan - The PI, Co-PI and team are well qualified to execute this project. The PI is experienced in the field of bone marrow transplantation, the Co-PI has expertise in gene therapy and a co-investigator has an extensive track record in immune-based therapies for HIV. Budget - Reviewers noted that the percent effort and salary proposed for the Co-PI seem excessive for the role described. - It was not clear why research studies are listed for Years 3 and 4 in the activity-based budget. Collaborations, Assets, Resources and Environment - Appropriate collaborations appear to be in place with an established and experienced group of collaborators. - The applicant institution is committed to supporting this type of research.
  • Andrew Balber

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