Abstract
BackgroundCancer vaccines can effectively establish clinically relevant tumor immunity. Novel sequencing approaches rapidly identify the mutational fingerprint of tumors, thus allowing to generate personalized tumor vaccines within a few weeks from diagnosis. Here, we report the case of a 62-year-old patient receiving a four-peptide-vaccine targeting the two sole mutations of his pancreatic tumor, identified via exome sequencing.MethodsVaccination started during chemotherapy in second complete remission and continued monthly thereafter. We tracked IFN-γ+ T cell responses against vaccine peptides in peripheral blood after 12, 17 and 34 vaccinations by analyzing T-cell receptor (TCR) repertoire diversity and epitope-binding regions of peptide-reactive T-cell lines and clones. By restricting analysis to sorted IFN-γ-producing T cells we could assure epitope-specificity, functionality, and TH1 polarization.ResultsA peptide-specific T-cell response against three of the four vaccine peptides could be detected sequentially. Molecular TCR analysis revealed a broad vaccine-reactive TCR repertoire with clones of discernible specificity. Four identical or convergent TCR sequences could be identified at more than one time-point, indicating timely persistence of vaccine-reactive T cells. One dominant TCR expressing a dual TCRVα chain could be found in three T-cell clones. The observed T-cell responses possibly contributed to clinical outcome: The patient is alive 6 years after initial diagnosis and in complete remission for 4 years now.ConclusionsTherapeutic vaccination with a neoantigen-derived four-peptide vaccine resulted in a diverse and long-lasting immune response against these targets which was associated with prolonged clinical remission. These data warrant confirmation in a larger proof-of concept clinical trial.
Highlights
Cancer vaccines can effectively establish clinically relevant tumor immunity
Preliminary studies yielded promising results, yet could not demonstrate significant improvement of patient survival. They emphasized several critical aspects for the design of successful nextgeneration cancer vaccines, namely: (i) cancer vaccines should target tumor-specific antigens not expressed on healthy tissue, (ii) the applied adjuvant should potently activate antigen-presenting cells (APCs) which in turn stimulate antigen-specific cytotoxic T lymphocytes (CTLs) [15], and (iii) vaccine schedules should include strategies for breaking immunological tolerance
Vaccine application and clinical outcome After receiving state-of-the-art oncological treatment for primary and relapsed pancreatic carcinoma, immunotherapeutic interventions were initiated in July 2013 when routine staging did not show any residual tumor, neither at the primary nor at the metastatic site
Summary
Cancer vaccines can effectively establish clinically relevant tumor immunity. Novel sequencing approaches rapidly identify the mutational fingerprint of tumors, allowing to generate personalized tumor vaccines within a few weeks from diagnosis. Data collected so far document that a variety of anticancer vaccines including cell-, DNA-, and purified component-based vaccines are capable of circumventing the poorly immunogenic and highly immunosuppressive nature of most tumors and eliciting therapeutically relevant immune responses [5, 6]. Preliminary studies yielded promising results, yet could not demonstrate significant improvement of patient survival. They emphasized several critical aspects for the design of successful nextgeneration cancer vaccines, namely: (i) cancer vaccines should target tumor-specific antigens not expressed on healthy tissue, (ii) the applied adjuvant should potently activate antigen-presenting cells (APCs) which in turn stimulate antigen-specific cytotoxic T lymphocytes (CTLs) [15], and (iii) vaccine schedules should include strategies for breaking immunological tolerance
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