In:
Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 7, No. 2_Supplement ( 2019-02-01), p. A005-A005
Abstract:
Introduction: Mutation-derived tumor antigens (MTAs) arise as a direct result of somatic variations, including nucleotide substitutions, insertions, and deletions that occur during carcinogenesis. These somatic variations can be characterized via genetic sequencing and used to identify MTAs. We developed a platform for a fully-personalized MTA-based vaccine in the adjuvant treatment of solid and hematologic malignanicies. Methods: This is a single-arm, open label, proof-of-concept phase I study designed to test the safety and immunogenicity of Personalized Genomic Vaccine 001 (PGV001) that targets up to 10 predicted personal tumor neoantigens. The single-center study will enroll 20 eligible subjects with histologic diagnosis of solid and hematologic malignancies. Subjects must have no measurable disease at time of first vaccine administration, and 5-year disease recurrence risk of & gt; 30%. Toxicity will be defined by CTCAE v5.0. Blood samples will be collected at various time points for immune response monitoring. Each patient’s vaccine peptides are selected by identifying somatic mutations from comparison of tumor and normal exome sequencing data, phasing somatic variants with co-occurring germline variants using tumor RNA sequencing data, and ranking mutated peptide sequences ”Openvax pipeline.” The process for determining somatic variants hews closely to the Broad Institute’s “Best Practices” for cancer SNVs and indels. The phasing of somatic and germline variants is implemented in a custom bioinformatics tool called Isovar. Mutated protein sequences containing phased variants are ranked according to two criteria: expression of the mutant allele in tumor RNA and aggregated predicted affinity to the patient’s Class I MHCs. Both quantities are normalized and multiplied together to create single ranked ordering of the candidate mutant sequences. Results: PGV001_002 (head and neck squamous cell cancer), who has completed vaccination, received 10 doses of vaccine comprising 10 long peptides (25 amino acid length) combined with poly-ICLC (toll-like receptor-3 agonist) intradermally. Vaccine-induced blood T-cell responses were determined, at weeks 0 (before-treatment) and 27 (after-treatment), ex vivo by interferon (IFN)-g enzyme-linked immunospot (ELISPOT) assay and after in vitro expansion by intracellular cytokine staining (ICS). Overlapping 15-16-mer assays peptides (OLPs) spanning the entirety of each ILP and 9-10-mer peptides corresponding to each predicted class I epitope (Min) were pooled and used to monitor immunogenicity. Ex vivo responses to these peptide pools were undetectable at week 0 but were evident at week 27 against 2 OLPs out of 10 (20%) and in 5 Min out of 10 (50%). After in vitro expansion, neoantigen-specific CD4+ and CD8+ T-cell responses were found in 5 out of 10 pooled peptides (50%). 7 out of 10 (70%) epitopes elicited polyfunctional T-cell responses (secretion of INF-α, TNF-α, and/or IL-2) from either CD4+ or CD8+ T-cells. Conclusion: To identify which predicted epitopes within the peptides pools stimulated the T-cell responses, we deconvoluted all the pools by either ex vivo and in vitro expansion. Ex vivo IFN-α production was detected in 1 (15-mer) peptide out of 15 (6.7%) and in 4 (9-10-mer) peptides out of 22 (18.2%). After expansion with single peptides, of 22 (9-10-mer) peptides tested, CD8+ T-cells were reactive against 13 peptides (59%), while CD4+ responses were seen in response to 11 of 15 (15-16-mer) peptides tested. Both CD4+ and CD8+ T-cell responses were polyfunctional. The PGV001 vaccine in our first patient showed both safety and immunogenicity, eliciting both CD4+ and CD8+ responses to the vaccine peptides. As we are enrolling additional patients, the information learned from this clinical trial will instruct the next generation of MTA-based vaccines, future development of immunotherapeutic approaches and rational combinations. Citation Format: Ana B. Blazquez, Alex Rubinsteyn, Julia Kodysh, John P. Finnigan, Thomas Marron, Rachel L. Sabado, Marcia Meseck, Timothy J. O'Donnell, Jeffrey Hammerbacher, Michael Donovan, John Holt, Milind Mahajan, John Mandeli, Krysztof Misiukiewicz, Eric M. Genden, Brett A. Milles, Hooman Khorasani, Peter R. Dottino, Hanna Irie, Amy B. Tiersten, Elisa R. Port, Andrea S. Wolf, Hern J. Cho, Ashutosh Tewari, Samir S. Parekh, Sujit Nair, Matthew D. Galsky, William K. Oh, Sacha Gnjatic, Eric E. Schadt, Phillip A. Friedlander, Nina Bhardwaj. A phase I study of the safety and immunogenicity of a multipeptide personalized genomic vaccine in the adjuvant treatment of solid cancers [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A005.
Type of Medium:
Online Resource
ISSN:
2326-6066
,
2326-6074
DOI:
10.1158/2326-6074.CRICIMTEATIAACR18-A005
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
detail.hit.zdb_id:
2732517-9
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