In 2012, we described one of the first uses of next-generation sequencing and bioinformatics approaches to rapidly and accurately identify a tumor-specific mutant protein that functioned as a major rejection antigen in a highly immunogenic (unedited), chemically induced mouse tumor line that was rejected when transplanted into nave syngeneic wild type mice. Since publishing this work, we have generated compelling preliminary data leading us to form the hypothesis that the antigens in clinically apparent (edited) tumor cells that are recognized by CD8+ T cells stimulated during successful checkpoint blockade cancer immunotherapy may also be tumor-specific mutant proteins and that they too can be rapidly identified using our genomics approach. In this proposal, we wish to formally test this hypothesis to provide a foundation for the eventual translation of our method to human cancer patients so as to facilitate personalization of cancer immunotherapies. To achieve this goal we will pursue three specific aims.
Specific Aim I : Identify Tumor-specific Mutational Antigens Eliciting CD8+ T Cell Responses to MCA Sarcomas and B16-F10 Melanoma With Differential Sensitivities to Checkpoint Blockade Therapy. Here we will focus our efforts on further validating and perhaps even improving our capacity to identify those antigens derived from tumor-specific mutant proteins that have potential therapeutic utility in cancer. We will ask whether tumor-specific mutant proteins are the favored targets of checkpoint blockade therapy and whether checkpoint blockade selects only the most antigenic of these mutations.
Specific Aim II. Determine Whether Vaccines Targeting Tumor-Specific Mutational Antigens, Either Alone or in Combination with Checkpoint Blockade, Can Therapeutically Control Growth of MCA Sarcomas or B16-F10 Melanoma. Here we will explore whether the tumor-specific mutant antigens we identify in Aim I can be used as a basis for therapeutic tumor-specific cancer vaccines. We will investigate the following three questions: Can personalized vaccines: (a) be used instead of checkpoint blockade? (b) improve checkpoint blockade in sensitive tumors? (c) evoke checkpoint blockade effectiveness in insensitive tumors? Specific Aim III. Define the Characteristics of Tumor-specific CD8+ T Cells that Specify Their Therapeutic Effectiveness. These experiments will seek to define the characteristics of activated tumor antigen-specific CD8+ T cells that result in successful cancer immunotherapy. We want to test the hypothesis that CyTOF and RNA-Seq analyses will facilitate identification of tumor-specific CD8+ T cells expressing specific phenotypic markers that can predict a favorable clinical outcome.
Cancer Immunotherapy has made great strides in the past few years and was designated as 'The Breakthrough of the Year 2013' by Science Magazine. Although the specificity and destructive power of the immune system has, at last, begun to be harnessed for use in cancer, it remains unclear how the serious side- effects of this therapy can be reduced and why only a portion of cancer patients receiving cancer immunotherapy respond to it. We have developed a genomics and bioinformatics based approach that appears to be capable of identifying abnormal mutant proteins that are specifically expressed in cancer cells from each cancer patient and that can function as tumor specific antigenic targets for immunotherapy. The work proposed in this application seeks to use a preclinical mouse model of cancer to critically test (a) the ability of our method to identify antigenic mutant proteins in cancer cells; (b) whether our method can distinguish between cancers that express strong versus weak mutant antigens thus making individuals carrying those cancers good- versus bad-candidates for cancer immunotherapy, respectively; and (c) whether we can generate cancer vaccines based on an individual's tumor specific mutant antigenic proteins to enhance the success rates of current cancer immunotherapies. This work, if successful, could be rapidly translated to human cancer patients and underpin the development of personalized cancer immunotherapies that are safer and more effective than those currently available.
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