01 Dec Similar Frameshift Mutations Identified in Variety of Tumors

MedicalResearch.com Interview with:

Dr. Bhardwaj

Nina Bhardwaj MD PhD
Director of Immunotherapy
Tisch Cancer Institute
Icahn School of Medicine at Mt Sinai
Ward-Coleman Chair in Cancer Research
Professor of Hematology and Oncology

MedicalResearch.com: What is the background for this study?

Response: Neoantigens are novel antigens expressed by tumors as a result of somatic mutations or frame shift mutations. They can be very immunogenic and consequently they are being incorporated into cancer vaccine platforms. In most cases it is necessary to determine each patient’s individual mutations and customize their vaccine antigens accordingly. We sought to identify shared mutations in cancer antigens which are deficient in DNA repair mechanisms namely microsatellite unstable tumors. These tumors have mutations in genes that normally are responsible for ensuring that DNA is properly replicated. Because these genes encode proteins that ensure proper repair around micro-satellite areas (which contain short repeated sequences of DNA and are present in similar regions from one person’s genome to the next), when they are mutated, these regions may not be repaired. Consequently due to nucleotide deletions and insertions one gets frame shift mutations which result in new protein expression which can be shared across tumors, as has been observed for a few regions. We therefore did a comprehensive study of a subset of tumors to determine the breadth of shared frame shift mutations.

MedicalResearch.com: What are the main findings? Would you give some examples of Microsatellite instability-high (MSI-H) tumors?

Response: We identified tumor-specific frameshifts encoding multiple epitopes that originated from indel mutations shared among patients with MSI-H endometrial, colorectal and stomach cancers. Epitopes derived from these shared frameshifts have high population occurrence rates, wide presence in many tumor subclones and are predicted to bind to the most frequent MHC alleles in TCGA MSI-H patient cohorts. Neoantigens arising from these mutations are distinctly unlike self and viral antigens, signifying novel groups of potentially highly immunogenic tumor antigens. We further confirmed that these mutated antigens were highly stimulatory  stimulating T cells from MSI-H cancer patients. Our study uncovers the widespread occurrence and strong immunogenicity of tumor-specific antigens derived from shared frameshift mutations in MSI-H cancer and Lynch Syndrome patients.

MedicalResearch.com: What should readers take away from your report?

Response: That these classes of antigens are very immunogenic, can be used potentially for the design of common “off-the-shelf” cancer vaccines and eventually for T cell therapy.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: We need to determine in larger cohorts whether these antigens are broadly recognized, if T cells that are specific for them gain entry into the tumor site, whether they are responsible for controlling tumor growth and whether they can be combined with standard of care checkpoint blockade to further induce long term tumor control.

Any disclosures?

Response: My disclosures: N.B. receives research support or reagents from Roche, Avidea,  Genentech, Regeneron Pharmaceuticals, Dragonfly Therapeutics. N.B. receives grant support from the NIH, the NCI,  Ludwig Institute for Cancer Research, Melanoma Research Alliance, Leukemia & Lymphoma Society, The Pershing Square Foundation and the Parker Institute for Cancer Immunotherapy. NB serves on  advisory board for  the  Roswell Park Cancer Center, Rome Therapeutics, BreakBio, Carisma Therapeutisc and CureVac.

Citation:

CELL publication:
Vladimir Roudko, Cansu Cimen Bozkus, Theofano Orfanelli, Christopher B. McClain, Caitlin Carr, Timothy O’Donnell, Lauren Chakraborty, Robert Samstein, Kuan-lin Huang, Stephanie V. Blank, Benjamin Greenbaum, Nina Bhardwaj,
Shared Immunogenic Poly-Epitope Frameshift Mutations in Microsatellite Unstable Tumors,
Cell,
2020, ISSN 0092-8674,
https://doi.org/10.1016/j.cell.2020.11.004.

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Last Updated on December 1, 2020 by Marie Benz MD FAAD