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Individualized in situ vaccination by radiation and immunotherapy

通过放射和免疫治疗进行个体化原位疫苗接种

基本信息

批准号：
9127533
负责人：
Sandra Demaria
金额：
$ 40.51万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-09 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127533
关键词：
4T1 Aftercare Algorithms Antigens Bioinformatics Biological Assay Biotechnology Blocking Antibodies Blood CD4 Positive T Lymphocytes CD8B1 gene CT26 Cancer Patient Cancer Vaccines Carcinoma Cessation of life Clinical Research Clinical Trials Clinical Trials Design Computer software Cross Presentation Cytotoxic T-Lymphocyte-Associated Protein 4 DNA Data Dendritic Cells Disease Enrollment Evaluation Frequencies Genomics Human Immune Immune response Immune system Immunotherapy In Situ In complete remission Individual Irradiated tumor Malignant neoplasm of lung Mediating Metastatic Neoplasm to the Lung Mus Mutate Mutation Neoplasm Metastasis Normal Cell Outcome Patients Peptides Process Proteins Publishing Radiation Radiation therapy Regimen Sampling Site Somatic Mutation Source Specificity Spleen Staining method Stains T cell response T-Cell Immunologic Specificity T-Cell Receptor T-Lymphocyte TRB@ gene cluster Testing Transforming Growth Factor beta Tumor Antigens Tumor Immunity Tumor-Derived Vaccinated Vaccination Vaccines base cancer cell cancer immunotherapy cancer therapy complementarity-determining region 3 deep sequencing exome sequencing immunogenic improved in vivo inhibitor/antagonist mouse model neoplastic cell novel strategies partial response peripheral blood prospective public health relevance selective expression success transcriptome tumor

项目摘要

DESCRIPTION (provided by applicant): Recent successes of immunotherapy have demonstrated the power of T cells to reject tumors. Two key observations have emerged from clinical studies. First, some patients with metastatic disease have a sufficient number and repertoire of tumor-reactive T cells that can be unleashed by immune checkpoint inhibitors to cause tumor regression. Second, unique mutated proteins expressed by an individual tumor are an untapped source of powerful tumor-specific T cell antigens. Because most cancer patients lack significant anti-tumor immune responses and do not respond to currently available immunotherapies, there is an urgent need to devise novel strategies to vaccinate these patients against their own individual tumor. We have pioneered studies to explore the use of local tumor radiotherapy (RT) as a means to release tumor antigens in an immunogenic context. We were the first to demonstrate that RT converted an insensitive mouse carcinoma into one responsive to CTLA-4 blockade, and have recently completed a prospective clinical trial testing this combination in lung cancer, a tumor type unresponsive to anti-CTLA-4 monotherapy. Interim analysis shows encouraging activity of the combination, with some complete and partial responses. Importantly, we have shown that priming of CD8 T cells specific for endogenous tumor antigens by RT requires immune checkpoint blockade. Our preliminary data also indicate that unique changes in T cell receptor (TCR) repertoire of intra-tumoral CD8 T cells are induced by RT + CTLA-4 blockade. Significant changes in TCR repertoire were also seen in peripheral blood of responding patients. Thus, our published and preliminary data strongly support the hypothesis that RT can generate an effective individualized in situ tumor vaccine. However, several unanswered questions hinder rapid progress in the use of RT as a widely available and relatively inexpensive strategy to target the patient-specific neoantigen repertoir. For instance, evidence that RT induces T cell responses to neoantigens is lacking, and it is not known if by changing the transcriptome of surviving irradiated cancer cells RT may expose unique neoantigens not expressed in untreated tumors. The influence of the RT regimen and of the immune checkpoint inhibitor used on this process remain poorly understood. Finally, while there is evidence that abscopal effects are mediated by T cells, the specificity of these T cell responses has not been characterized. Studies proposed are aimed at answering these questions in order to move the field forward and improve clinical trial design and the use of RT in combination with immunotherapy. A comprehensive evaluation of the specificity of T cells activated by RT combined with anti-CTLA-4 or anti-PD-1 will be performed. In addition, we will characterize the effects of RT on the tumor mutanome to identify potential immunogenic mutations exposed by RT. Analysis of samples from patients treated with RT+anti-CTLA-4 will provide preliminary evidence in humans.