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：
9904135
负责人：
Sandra Demaria
金额：
$ 38.77万
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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904135
关键词：
4T1 Abscopal effect Aftercare Algorithms Antigens Bioinformatics Biological Assay Biotechnology Blocking Antibodies Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CT26 CTLA4 blockade CTLA4 gene Cancer Patient Cancer Vaccines Carcinoma Cessation of life Clinical Research Clinical Trials Clinical Trials Design Clone Cells Computer software Cross Presentation DNA Data Dendritic Cells Disease Enrollment Evaluation Exposure to Frequencies Genomics Human Immune Immune checkpoint inhibitor Immune response Immune system Immunotherapeutic agent 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 Stains T cell response T-Cell Immunologic Specificity T-Cell Receptor T-Lymphocyte T-cell receptor repertoire TRB@ gene cluster Testing Transforming Growth Factor beta Tumor Antigens Tumor Immunity Tumor-Derived Vaccinated Vaccination Vaccines anti-CTLA4 anti-PD-1 anti-tumor immune response antigen-specific T cells base cancer cell cancer immunotherapy cancer therapy cancer vaccination complementarity-determining region 3 deep sequencing exome sequencing immune checkpoint blockade immunogenic improved in vivo mouse model neoantigens neoplastic cell novel strategies partial response peripheral blood programmed cell death protein 1 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.

描述（由适用提供）：免疫疗法的最新成功证明了T细胞拒绝肿瘤的能力。临床研究已经出现了两个关键观察。首先，一些转移性疾病的患者具有足够的肿瘤反应性T细胞的数量和曲目，可通过免疫切除剂抑制剂释放以引起肿瘤退化。其次，由单个肿瘤表达的独特突变蛋白是强大肿瘤特异性T细胞抗原的未开发的来源。由于大多数癌症患者缺乏明显的抗肿瘤免疫调查，并且对当前可用的免疫疗法没有反应，因此迫切需要制定新的策略来为这些患者接种自己的个体肿瘤。我们进行了开创性的研究，以探索使用局部肿瘤放疗（RT）作为在免疫原性中释放肿瘤抗原的一种手段。我们是第一个证明RT将不敏感的小鼠癌转化为对CTLA-4封锁有反应的一种，并且最近完成了一项前瞻性临床试验，该试验在肺癌中进行了这种组合，这是一种对抗CTLA-4单疗法的肿瘤类型。临时分析显示了组合的令人鼓舞的活动，并具有一些完整和部分响应。重要的是，我们已经表明，通过RT对内源性肿瘤抗原的CD8 T细胞启动需要免疫检查点阻滞。我们的初步数据还表明，肿瘤内CD8 T细胞的T细胞接收器（TCR）曲目的独特变化是由RT + CTLA-4阻断诱导的。在反应患者的外周血中也出现了TCR库的显着变化。这是我们发布和初步数据强烈支持RT可以产生有效个性化原位肿瘤疫苗的假设。但是，几个未解决的问题阻碍了RT用作广泛可用且相对便宜的策略的快速进步，以针对患者特异性的新抗原曲目。例如，缺乏RT诱导T细胞对新抗原的反应的证据，并且不知道通过更改生存辐照癌细胞的转录组RT的转录组RT可能会暴露于未经处理的肿瘤中未表达的独特新抗原。在此过程中使用的RT方案和免疫检查点抑制剂的影响仍然很少了解。最后，虽然有证据表明脱落作用是由T细胞介导的，但尚未表征这些T细胞反应的特异性。提出的研究旨在回答这些问题，以使该领域向前发展并改善临床试验设计以及将RT与免疫疗法结合使用。将对由RT激活的T细胞与抗CTLA-4或抗PD-1进行全面评估。此外，我们将表征RT对肿瘤杂种组的影响，以鉴定RT暴露的潜在免疫原性突变。分析用RT+抗CTLA-4治疗的患者的样本将提供人类初步证据。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Radiotherapy and CTLA-4 Blockade Shape the TCR Repertoire of Tumor-Infiltrating T Cells.

DOI：
10.1158/2326-6066.cir-17-0134
发表时间：
2018-03
期刊：
Cancer immunology research
影响因子：
10.1
作者：
Rudqvist NP;Pilones KA;Lhuillier C;Wennerberg E;Sidhom JW;Emerson RO;Robins HS;Schneck J;Formenti SC;Demaria S
通讯作者：
Demaria S

Expression of the mono-ADP-ribosyltransferase ART1 by tumor cells mediates immune resistance in non-small cell lung cancer.