Generation of Cytotoxic T Lymphocytes (CTL) Against the Cisplatin Resistant Phenotype Displayed by Non Small Cell Lung Cancer

  • Yannelli, John (PI)

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Description

Lung cancer is the leading killer due to cancer of men and women in the United States. Conventional therapies are limited in their ability to impact the disease. Patients treated with the chemotherapeutic drug Cisplatin, often re-occur even following what appear to be significant durable responses. Cisplatin binds to DNA and forms adducts, thus preventing DNA synthesis, transcription and eventual translation of critical cellular proteins associated with the neoplastic state. Resistant tumor cells, however, evolve mechanisms to: 1) prevent drug uptake into the cytoplasm, 2) increase drug efflux fTomthe cytoplasm out of the cell, 3) immobilize drug in the cytoplasm, and 4) repair damage done by DNA adducts formed as a result of drug binding to the DNA. The current proposal suggests that the proteins that the tumor cells express to maintain the chemo-resistant phenotype can serve as targets for the immune system, specifically cytotoxic T lymphocytes (CTL). The PI has developed a unique model system ofNSCLC tumor cell lines and associated clones which express both Cisplatin sensitive and resistant phenotype. The proposal will utilize the Cisplatin resistant tumor cell clones to generate CTL which can recognize and kill resistant tumor cells. The PI suggests a future immunotherapy strategy where-by patients are immunized using DC vaccines which express proteins associated with the chemo-resistant state. Following chemotherapy with the specific agent, the patients will be boosted with DC vaccines, thus increasing the CTL precursor frequency against those tumor cells which will eventually develop Cisplatin resistance. The current study is for 2 years and will provide the PI with critical "Proof of Principal" data that the hypothesis is well founded and feasible. The data generated will be used to submit an RO-l and eventually utilized to develop new and innovative immunotherapies for patients with this deadly disease.
StatusFinished
Effective start/end date9/1/078/31/09

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