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Modeling the Molecular Determinants of Induced Anti-Tumor Immune Responses in Mantle Cell Lymphoma

Arash Ash Alizadeh

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National Institutes of Health (NIH)
Adaptive anti-tumor immune responses are important determinants of clinical outcomes in patients with diverse cancer types, and increasingly a target of emerging cancer therapies. A central unmet need is a better understanding of the targets of anti-tumor immune responses necessary for effective active immunotherapies and vaccination strategies. We are currently conducting a clinical trial of therapeutic vaccination forpatients with Mantle Cell Lymphoma (NCT00490529), a heretofore incurable hematologic malignancy. In this application we will use a combination of novel technologies and bioinformatics platforms to discover the genetic and immunological determinants of the immune responses that we have induced. Our central hypothesis is that clinical and immunological responses in patients with this disease after their therapeutic vaccination are determined by the somatic mutations encoded in their tumor genomes. Alterations in the tumor proteome, such as novel (neo-) antigenic peptides generated in the process of somatic mutation, can serve as potent substrates for specific anti-tumor immune responses when appropriately presented in the context of major histocompatibility complex (MHC) to effector T-cells, and in turn recognized by their antigen receptors. We will test these hypotheses in close collaboration with ICBP@Stanford, first taking advantage of systematic methodologies for interrogation of the tumor coding genome, transcriptome, and MHC-peptidome to discover somatic mutations that are predicted (Aim 1) and/or observed (Aim 2) to bind cognate MHC. We will synthesize and assemble synthetic versions of these candidate peptide neoantigens with corresponding MHC molecules, and use them in large peptide-MHC `tetramer' panels to interrogate the T lymphocyte responses induced by tumor vaccination in the patients (Aim 3). In molecularly profiling, and functionally tracking these dynamic responses in serial blood specimens from patients before and after immunization, we aim to differentiate patients with or without clinical responses to this therapy, and to better predict their distinct outcomes. We anticipate that this integrated approach will reveal the interplay between nascent and induced immune responses and genetic factors in control of disease progression in MCL and inform new ways of battling this deadly disease. This approach should also have relevance to other cancers.

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