Isolation of T cell receptors targeting recurrent neoantigens in hematological malignancies

Journal for Immunotherapy of Cancer
Vanessa M TubbGavin M Bendle

Abstract

Mutation-derived neoantigens represent an important class of tumour-specific, tumour rejection antigens, and are attractive targets for TCR gene therapy of cancer. The majority of such mutations are patient-specific and targeting these requires a fully personalized approach. However, some mutations are found recurrently among cancer patients, and represent potential targets for neoantigen-specific TCR gene therapy that is more widely applicable. Therefore, we have investigated if some cancer mutations found recurrently in hematological malignancies encode immunogenic neoantigens presented by common European Caucasoid HLA class I alleles and can form targets for TCR gene therapy. We initially focused on identifying HLA class I neoepitopes derived from calreticulin (CALR) exon 9 mutations, found in ~ 80% of JAK2wt myeloproliferative neoplasms (MPN). Based on MHC class I peptide predictions, a number of peptides derived from mutant CALR (mCALR) were predicted to bind to HLA-A*03:01 and HLA-B*07:02. However, using mass spectrometry and ex vivo pMHC multimer staining of PBMC from MPN patients with CALR exon 9 mutations, we found no evidence that these peptides were naturally processed and presented on the surface of mCALR-expressing...Continue Reading

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Citations

Jul 23, 2020·Frontiers in Immunology·Valentina BianchiGeorge Coukos
Sep 29, 2019·Blood·Joan HowAnn Mullally
Jan 11, 2020·Frontiers in Immunology·Malte RoerdenJuliane S Walz
Mar 3, 2020·Frontiers in Immunology·Melinda A Biernacki, Marie Bleakley
Jan 28, 2020·The Journal of Clinical Investigation·Livius Penter, Catherine J Wu
Jul 12, 2019·Frontiers in Immunology·Andrea Garcia-GarijoAlena Gros
Jan 19, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Tiffany R MerlinskyElodie Pronier

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Methods Mentioned

BETA
immunoprecipitation
flow cytometry
Illumina sequencing
MDS
ubiquitination
peptide exchange

Software Mentioned

SPARPRTSC
FACSDiva
SCIEX
NetMHC

Related Concepts

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