Disease Team Therapy Development - Research
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 cells' 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 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 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 most of the previous stem cell gene therapy clinical trials for HIV, only one anti-HIV gene was 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 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 gene containing 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. In this case, we have not only cured the patient's leukemia but have also given the patient an HIV resistant immune system which will be able to fight HIV.
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 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. 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 assistant 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 (at a cost of $100,000) 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.
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/refractory 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 product profile is reasonable. However, similar protocols for HIV patients have been implemented previously with modest success. The competitiveness of the present approach hinges on achieving better gene transfer and better protection against HIV. - If successful, the clinical impact of the approach could be significant; however, the overall impact of this approach on HIV standard-of-care is uncertain. Autologous cell-based approaches face many impediments that make this approach unlikely to benefit patients in less developed parts of the world. - In the Target Product Profile, reviewers did not think that the proposed minimum acceptance criteria set for anti-HIV gene expression in immune system cells in vivo will be sufficient to provide clinical efficacy. Rationale - The biologic rationale to genetically induce HIV-resistant hematopoietic stem cells and the clinical rationale to take advantage of the autologous bone marrow transplantation to treat lymphoma are sound and based on data from a recent case study demonstrating a functional cure in a single HIV+ patient. - The reviewers acknowledged that the proposed project offers a compelling opportunity to help HIV+ patients develop immunity to HIV infection, as well as to cure their lymphoma. However, they caution that treatment effectiveness faces many unsolved technical hurdles. This proposal does not plan to address those bottlenecks. Therapeutic Development Readiness - Some reviewers indicated that although this is a sound idea that should be brought to the clinic, additional preclinical work is required to demonstrate that proposed transduction, expression, and engraftment efficiencies will be sufficient to reduce viral load and provide the described clinical benefit. It was suggested that this project is not ready for the clinic and would be better funded as a preclinical rather than clinical project. - Reviewers were impressed with the presented preclinical studies but were unconvinced that all the necessary proof-of-concept, safety, and product development studies have been or would be completed to allow initiation and completion of the proposed clinical studies. - The team has proposed unrealistic timelines to produce cGMP grade reagents and to perform product qualification studies before initiating the proposed clinical studies. - The team has underestimated the importance, challenges, and time to complete the toxicology studies required for the proposed gene modified stem cell therapeutic candidate. Feasibility of the Project Plan - Feasibility of the project plan was considered to be the major weakness of this proposal. The project plan has not taken into consideration a number of preclinical studies including optimization of vector transduction efficiency across multiple batches of HSC, stability of transgene expression, potential selection of resistant virus, and inclusion of tumorigenicity studies. - Reviewers commented that the study design was not yet sufficiently evaluated and not well thought out. It is unlikely that the time for treatment interruption proposed in the study will be sufficient to evaluate the efficacy of the therapeutic candidate. Reviewers were also not convinced that the proposed clinical sites would be able to enroll the number of patients with intended clinical indication in the proposed time frame. - Reviewers would have liked to see additional information indicating expected engraftment and demonstrating that engraftment level will be sufficient to confer clinical benefit. Principal Investigator (PI) and Development Team - While the PI and Co-PI have considerable experience in bone marrow transplantation and HIV research, reviewers were concerned by their lack of suitable experience in cell therapy product development. - A reviewer commented on the lack of prior experience of the team in the manufacture of clinical grade lentiviral vector, a process that is known to be technically challenging. Collaborations, Resources and Environment - There is limited experience in transplanting HIV-infected patients at the applicant institution. The secondary institution is outstanding with a large HIV population but their participation in transplant-related HIV trials is also limited. Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding. ) - Cost estimates for the manufacture of the clinical grade lentivirus were considered to be low. - Transplantation costs for HIV patient was considered to be excessive.
- David Pepperl
- Darin Weber
- Boro Dropulic