Mobilization of pre-existing polyclonal T cells specific to neoantigens but not self-antigens during treatment of a patient with melanoma with bempegaldesleukin and nivolumab

Abstract

T cells that recognize self-antigens and mutated neoantigens are thought to mediate antitumor activity of immune checkpoint blockade (ICB) in melanoma. Few studies have analyzed self and neoantigen-specific T cell responses in patients responding to ICB. Here, we report a patient with metastatic melanoma who had a durable clinical response after treatment with the programmed cell death protein 1 inhibitor, nivolumab, combined with the first-in-class CD122-preferential interleukin-2 pathway agonist, bempegaldesleukin (BEMPEG, NKTR-214). We used a combination of antigen-specific T cell expansion and measurement of interferon-γ secretion to identify multiple CD4⁺ and CD8⁺ T cell clones specific for neoantigens, lineage-specific antigens and cancer testis antigens in blood and tumor from this patient prior to and after therapy. Polyclonal CD4⁺ and CD8⁺ T cells specific to multiple neoantigens but not self-antigens were highly enriched in pretreatment tumor compared with peripheral blood. Neoantigen, but not self-antigen-specific T cell clones expanded in frequency in the blood during successful treatment. There was evidence of dramatic immune infiltration into the tumor on treatment, and a modest increase in the relative frequency of intratumoral neoantigen-specific T cells. These observations suggest that diverse CD8⁺ and CD4⁺ T cell clones specific for neoantigens present in tumor before treatment had a greater role in immune tumor rejection as compared with self-antigen-specific T cells in this patient. Trial registration number: NCT02983045.

Keywords: T-lymphocytes; antigens; melanoma; neoplasm.