Extensive stage small cell lung cancer (SCLC) is an incurable, aggressive form of lung cancer. SCLC is frequentlyassociated with mutations in the p53 gene that often result in p53 overexpression in tumor cells. This overexpressionproduces a variety of antigenic epitopes that form the basis for tumor specific cellular immunotherapy. Dependence oftumor cells on abnormal p53 for their survival makes this protein an 'ideal' candidate for cancer immunotherapy.Because of their unique features, dendritic cells (DC) are the best vehicles for delivery of tumor antigens (Ags). Wehave developed a new vaccine based on transduction of DC with wild-type p53 using an adenoviral construct. Thisvaccine demonstrated potency in pre-clinical experiments. Based on those observations we performed a phase l/llclinical trial designed to test the safety and efficacy of the Ad.p53-DC vaccine in patients who have extensive stageSCLC. The vaccine itself was safe, and produced major tumor responses in two patients. P53-specific T cell responseswere induced by the vaccine in half of the treated patients. . Our data demonstrated that for those patients who did notdevelop an immunological response to vaccination, the lack of immune response was closely associated withaccumulation of immature myeloid cells (ImC), previously shown to be immunosuppressive. However, the mainfindings from the trial were an unusually high frequency of major objective tumor regressions in patients treated withchemotherapy immediately after the vaccine. These observations were quite unexpected since the existing paradigmsuggests that chemotherapy is detrimental to the efficacy of an immune response. During last 8 months, four groupsincluding ours nearly simultaneously reported similar observations in different cohorts of patients treated with differentvaccines and chemotherapeutics. This suggests a possible new direction in cancer treatment where the combination ofimmunotherapy and chemotherapy in direct sequence may provide substantial clinical benefits. All previous trialsincluding ours were not designed to evaluate this paradigm. We believe that this issue is of paramount significance forthe entire field and deserves definitive testing. Therefore we propose to test the following hypotheses: (1) thecombination of the Ad.p53-DC vaccine and subsequent chemotherapy will result in a substantial improvement in theclinical response, and (2) the addition of all-trans-retinoic acid (ATRA) to the Ad.p53-DC vaccine may substantiallyimprove the p53-specific immune response and hence clinical response in SCLC patients. The proposed project hastwo specific aims.
Specific Aim 1. Determine the clinical response to the Adv-p53 DC vaccine in patients with extensive stageSCLC, whether chemotherapy given after the vaccine is more effective, and whether all-ATRA enhances thisresponse.
Specific Aim 2. Determine the immune modifying effect of immunization and chemotherapy on p53-specificimmunity.
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