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2010 Research Awards » Team Science Awards

The MRA awarded six teams pursing multidisciplinary translational research.

 

 

Development of targeted therapies for Gq/11 mutant melanomas

 

Principal Investigators:


Uveal melanoma is the most common intraocular malignancy in the United States and has a 10-year disease specific survival rate of 50%. No effective treatment options exist. We recently identified mutations in two novel cancer genes, GNAQ and GNA11, that are found in 82% of uveal melanomas. GNAQ and GNA11 mutations are found in a mutually exclusive and only occur in melanocytic tumors without BRAF, NRAS, or KIT mutations. The mutations are thought to arise early during tumor progression, as they can also be found in benign lesions. The nature of the additional genetic alterations required for full transformation is currently not known. Work to date has shown that mutations in GNAQ/GNA11 activate several signaling cascades, which are likely to harbor targets for therapy. We have assembled a team of investigators and clinicians at a major cancer center to identify predictive markers by using tumor tissue obtained from patients with uveal melanoma treated with AZD6244. This drug is a MEK inhibitor which was implicated by our cell-based studies. We will analyze patient tissues to identify genetic alterations that can help predict which patients will best respond to this drug.

 


Modulating anti-tumor immunity with dendritic cells

Henry Silverman – MRA Team Science Award

 

Principal Investigators:

 

This research project aims to improve dendritic cell (DC) vaccines that stimulate effective immune responses against melanoma. Small clinical trials have demonstrated that DC vaccines are safe and can lead to improved immune responses; however, the two large clinical trials had mixed results. This is probably because there is not enough known about how to make the best DCs that will be most effective against cancer. A promising new strategy to help DCs is by activating specialized proteins found on DCs called Toll-like receptors (TLR). Activation of TLRs on DC leads to enhancement of the ability of DCs to stimulate effective immune responses. Our own studies showed that activation of TLRs stimulate immune responses in patients with melanoma. We believe that activating these TLRs on DCs will be an important step in generating the best DCs to stimulate immune responses against melanoma that is effective.We propose several projects with the goal of improving DC vaccines that stimulate effective immune responses against cancer. We will study the effects of activating TLRs in animal models of melanoma and will evaluate the effects of activating different types of TLRs on DCs and also use different antibodies, known to enhance DC function, to assess if  immune responses can be improved. Finally, we propose a clinical trial based on this knowledge. Patients with melanoma in the clinical trial will receive a DC vaccine injection that is activated using TLRs followed by another injection of proteins that activates TLRs on DCs and other immune cells in the body. If successful, this will meet the ultimate goal of improving DC vaccines to benefit patients with melanoma.

 

 

The isolation of human anti-MICA monoclonal antibodies

 

Principal Investigators:

 

This project is aimed at isolating specific antibodies from the blood of melanoma patients who have derived durable clinical benefits from experimental immunotherapies. Our studies have indicated that antibodies directed to a target expressed on melanoma cells (called MICA) may be involved in the therapeutic benefits of melanoma vaccines and blockade of CTLA-4. We have developed a novel approach to identify the blood cells that produce the antibodies to MICA. We will use this approach to isolate a panel of the anti-MICA antibodies from long-term responding melanoma patients. These antibodies will then be evaluated for functional activity in a variety of model systems. The most potent antibody could be considered for future clinical development, so as to allow testing for therapeutic benefits in patients with advanced melanoma.      

 

 

Advanced immune monitoring and TCR cloning in clinical trials of T cell receptor (TCR) engineered adoptive cell transfer therapy

 

Principal Investigators:

 

We propose a patient-oriented research to improve the performance of adoptive cell transfer (ACT) therapy using T cell receptor (TCR) engineered lymphocytes by incorporating new generation immune monitoring assays and molecular cloning of TCRs for future clinical use. This project proposes to accelerate the assessment of the results of genetic engineering of the human immune system tested in clinical trials leading to the development of new therapeutic reagents in order to aid in the formulation of new clinical protocols. It capitalizes on existing efforts to develop miniaturized and multiplexed diagnostic platforms for immune monitoring coupled with advanced molecular cloning to efficiently analyze immune responses to cancer and isolate the minimal components providing the cancer specificity to killer immune cells.

 

 

Studies on the mechanism(s) of de novo and acquired resistance to selective RAF inhibition:

 

Principal Investigators:

 

Approximately half of melanomas have an activating mutation of the BRAF gene. PLX4032 (also called RG7204) is a potent and selective inhibitor of the most common mutant form of BRAF. In a Phase I trial of PLX4032, approximately 80% of patients with melanoma whose tumors express the BRAF mutation experienced significant tumor shrinkage with minimal side effects. In contrast, none of the patients with melanomas without a BRAF mutation responded to the drug. These promising results demonstrate what can be achieved with personalized, molecularly targeted therapy for melanoma. However, the degree of tumor shrinkage varied greatly among patients and many of the patients who initially responded to PLX4032 subsequently developed resistance. The experience with targeted therapies in other diseases suggests that understanding the causes of resistance can lead to improved patient selection for treatments like PLX4032 and the development of more effective drug combinations. A number of laboratories including those directed by the investigators leading this proposal have conducted research that suggests possible mechanisms of resistance to PLX4032. However, none of these mechanisms have been definitively confirmed as clinical relevant in patients treated with PLX4032. We believe that identifying the mechanisms of resistance to PLX4032 and demonstrating their clinical significance is one of the highest priorities in the melanoma community.  We will establish a consortium of the academic melanoma centers that have led the clinical trials with PLX4032 to work together to share their patient specimens and expertise to systematically evaluate possible mechanisms of resistance to PLX4032 and other highly selective BRAF inhibitors. The effort will include laboratory studies to further elucidate potential mechanisms of resistance, development of a multi-institutional database to track the acquisition and analysis of clinical specimens, standardization of molecular testing procedures, and analysis of biopsies obtained from patients who were treated with highly selective BRAF inhibitors. This project will address not only the critical challenge of overcoming resistance to selective BRAF inhibition, but it will set the stage for the efficient development and improvement of other new, promising therapies for this highly aggressive disease.

 

Publications:

 

 

Strategies to enhance the efficacy of adoptive T cell therapy

Principal Investigators:

 

A number of studies performed by our labs and others using adoptive T cell therapy have been successful in treating patients with melanoma in its advanced stages. However, only a limited number of patients respond completely to treatment; many patients respond incompletely, or relapse at a later date after an initial response. An important factor contributing to an effective and long-lasting response to adoptive T cell therapy is the capacity of the T cell to survive, persist and expand, in the body after it has been infused. We have explored different strategies to extend the persistence of T cells in patients. One of these approaches involves combining a vaccine with the T cells. A vaccine that is given after T cell infusion allows the vaccine to stimulate the infused T cells and enhance their survival by driving them to expand in the patient. To test this idea, we are proposing a clinical trial that involves two T cell infusions: first, an infusion of antigen-specific T cells given without the vaccine and then, a second infusion given with the vaccine. By comparing the survival of the T cells from the first infusion with that from the second infusion, we can determine if the vaccine was effective in expanding the infused T cells in the patient. Because we have developed tools in the lab that can track and analyze the infused T cells, even at the single cell level, we can begin to understand the requirements for effective T cell therapy. We believe that the results of this study may benefit not only adoptive T cell therapy of melanoma but other cancers and make it possible in the future to treat patients in a manner that is safe, effective and long-lasting.


 
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