Abstract 528: MDSC suppress the T cell repertoire and contribute to a pathologic cytokine milieu in cancer patients

Abstract

Abstract Myeloid derived suppressor cells (MDSC) are elevated in tumors and draining lymph nodes of cancer patients and produce a variety of immune suppressive factors that impair T cell activation and anti-tumor immunity. MDSC are also recruited from the bone marrow in response to T cell activation, including in response to immunotherapies that activate T cells. As MDSC and immune suppressive monocytes are significant producers of IL6, IL1β and TNFα, their elevation and activation in response to T cell activation can promote pathologic levels of these cytokines leading to potentially serious conditions such as cytokine release syndrome. Furthermore, patients deficient in functional antigen-specific T cells have elevated MDSC, consistent with their described suppression of antigen presentation and T cell activation. Therapeutic agents that deplete MDSC may offer both an improved therapeutic index for maintenance of T cell activation while promoting expansion of anti-tumor T cells. AMV564, a bivalent T cell engager that selectively depletes MDSC, is in clinical development in solid tumor patients. The cytokine profiles of patients treated with AMV564 as monotherapy or in combination with pembrolizumab were assessed using multiplex immunoassays, and the peripheral T cell repertoire was assessed by deep sequencing of the TCRβ locus. While CD33 has no apparent functional role on differentiated myeloid cells, on MDSC and immature monocytes, CD33 signaling promotes the production of immune-suppressive factors. Avid binding of clustered CD33 in this active signaling configuration drives the selectivity of AMV564 for these cell types. Analysis of patient samples demonstrates that AMV564 selectively depletes MDSC and promotes T cell activation and increases in effector CD8 and CD4 populations1. AMV564 promotes strong induction of IFNγ and other proinflammatory cytokines and chemokines, but with comparatively limited induction of IL6, IL1β and TNFα, consistent with the role of MDSC in producing these factors. This cytokine profile was maintained in combination with pembrolizumab. Dynamic changes in the peripheral T cell repertoire were apparent for patients treated with AMV564 monotherapy or in combination with pembrolizumab. Observations include significant expansion after one cycle of therapy (p = 0.008) including T cell clones not detectable at baseline, changes in diversity that reflect increases in middle-frequency clones, and oscillation in the peripheral T cell fraction consistent with T cell trafficking to tissues and tumors. Repertoire expansion correlated with increases in effector memory CD8 T cells. These findings in patients treated with AMV564 support the role of MDSC in both limiting the priming and activation of anti-tumor T cells as well as contributing to an immune suppressive and pathologic cytokine response to T cell activation. 1. Smith, V et. al. Cancer Res. 2020;80(16):5699 Citation Format: Sterling Eckard, Aurelien Sarde, Li Mei, Curtis Ruegg, Patrick Chun, Victoria Smith. MDSC suppress the T cell repertoire and contribute to a pathologic cytokine milieu in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 528.