Is HLA Allele Loss Overstated? Insights from 80k Patients

How frequent aremutations in the tumor that limit immunotherapy efficacy?
Immunotherapy in general and HLA-peptide targeted therapies in particular rely on tumor cells to present HLA complexes, which are the targets of an activated Tcell. During such therapies, the pressure is high for tumors to escape recognition by anti-tumor T cells through loss of HLAs. While a complete loss of HLA drives NK cell recognition, specific HLA alleles can be lost more readily. Studies in smaller patient populations indicated a significant, but variable frequency. Large scale studies of such HLA allele loss was yet missing in the literature. Now Memorial Sloan Kettering Cancer Center was investigating HLA loss in close to 80k patients and over 32 cancer types. While around 17% of patients over all tumor types showed some loss of HLA alleles, the frequency was dependent on the indication and the HLA allele. Less than 10% of cases had loss of A*02:01, the allele against which most current therapies are being developed.

While this finding supports the notion that loss of HLA alleles is not a significant threat to HLA-targeted therapy development, previous treatment with immunotherapy might significantly effect such observations. The ability of a given tumor to present a certain HLA-peptide target is definitely a major factor defining drug efficacy.
At Alithea Bio we believe that immunopeptidomic data can significantly improve our ability to predict response to immunotherapy treatment. Watch out for news in this space…

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