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F3 - Cancer - Targeted Gene and Cell Therapy

785: Loss of Heterozygosity is Low for Specific HLA Alleles in Cancer Patients with Driver Mutations

Type: Poster Session

Poster Board Number: 785
Presentation Details
Session Title: Wednesday Posters: Cancer - Targeted Gene and Cell Therapy

Immunotherapies have revolutionized cancer treatment, yet the limited predictability of response and/or resistance mechanisms continues to present novel therapeutic developmental challenges, especially for solid tumors. Many of these use a sensitive and specific T cell receptor (TCR)-HLA:peptide complex interaction as a mechanism of action and can be impacted by HLA loss of heterozygosity (LOH). Allele-agnostic HLA LOH analyses assessing loss of any MHC class I allele are relevant for HLA-agnostic approaches such as immune checkpoint inhibitors; however, studies in the context of specific HLA alleles, mutations, and indications remain limited. Such context-specific HLA LOH frequencies are especially relevant to adoptive T cell therapies engineered with TCRs and bispecific TCR T cell engagers targeting neoantigen peptides derived from oncogenic driver mutations, such as those of KRAS and TP53, which are presented by a specific HLA allele. Thus, existing allele-agnostic analyses may overestimate the frequency and relevance of HLA LOH for allele-specific modalities.
A comprehensive genomic profiling dataset consisting of 78,418 cancer patient samples (Montesion M. et al., PMID: 33127846), germline heterozygous for one or more HLA class I locus, was analyzed for HLA LOH in the context of frequent driver mutations (KRAS G12C, G12D, G12V and TP53 R175H), corresponding HLA alleles (HLA-A*02:01, HLA-A*03:01, and HLA-A*11:01) and within specific tumor subtypes.
Allele-agnostic HLA LOH was observed in 16.6% of all samples and varied between indications and HLA alleles (Montesion 2021). However, allele-specific loss of HLAs A*02:01, A*03:01, and A*11:01 across all samples was much lower than allele-agnostic loss (6.3%, 6.6%, and 6.3%, respectively). Although, a trend for increased allele-specific HLA LOH was observed when analyzed by driver mutation, the frequency remained low. Specifically, across all cases, A*02:01, A*03:01, and A*11:01 allele-specific LOH ranged between 5.9%-9.7% in relation to KRAS G12C, G12D, and G12V compared to 5.9%-6.2% for wild-type (WT). Moreover, it did not achieve statistical significance for any HLA-KRAS mutation pairs in colorectal (CRC), non-small cell lung (NSCLC), and pancreatic (PDAC) cancers, except for HLA-A*11:01 and KRAS G12C in NSCLC, which was lower in mutated cases (5.3% for G12C vs 10.1% for WT KRAS, p=0.045). Both allele-agnostic and A*02:01-specific HLA LOH in TP53 WT samples were lower than average which may be related to the role of TP53 in genomic stability. The TP53 R175H mutation was associated with limited increase in HLA-A*02:01 LOH (from 4.4% for WT to 8.1% for TP53 R175H) and varied between indications, e.g. no significant increase was observed in R175H-positive breast cancer and NSCLC cases contrary to CRC and PDAC.
Based on this real-world dataset, over 90% of cases retain the TCR-targeted allele and, therefore, preserve the molecular complex necessary for HLA/driver mutation-based therapies. Notably, the analyzed database is enriched for advanced cancer patients. Further studies are warranted to test the hypothesis whether tumors in earlier lines of treatment have an even lower rate of HLA LOH and if correlations with treatments change longitudinally.

Plain Language Summary
Cancer occurs due to DNA mutations. Some mutations are exposed by the cancer cells to our immune system. Immune cells from people with cancer can be isolated from blood, genetically engineered to recognize cancer cells, and put back into the patient. The engineered cells find and kill the cancer cells. For this to work, the cancer cells must also have certain immune-related genes. However, cancer cells are under pressure from the immune system to limit or even drop these other genes. Therefore, we looked in data from cancer patients and saw that this elimination does not happen often for the specific combination of genes needed by certain types of engineered immune cells. This means that most people with cancer could receive help from some engineered immune cell therapies.

Christian Roy1, Tomasz Sewastianik1, Patrick Halvey1, Meagan Montesion2, Aastha Jindal1, Markus Vallaster1, Hubert Lam1, Sean Garrity1, Gary Shapiro1, Christopher A. Klebanoff3, Loic Vincent1, Greg Opiteck1, Dirk Nagorsen1

1Affini-T Therapeutics, Watertown, MA,2Foundation Medicine, Cambridge, MA,3Memorial Sloan Kettering Cancer Center, New York, NY"

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