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.

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.
Competing Interests: Competing interests: JRV, BJ and SR have equity interest in Lyell Immunopharma, and JZ and EE are employees of Nektar therapeutics, and this paper discusses use of an investigational drug owned by Nektar therapeutics.
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