Journal
JOURNAL OF HEMATOLOGY & ONCOLOGY
Volume 14, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13045-021-01156-5
Keywords
Bispecific antibody; Dexamethasone; Disialogangliosides; Ex vivo bispecific antibody armed T-cells (EATs); Human epidermal growth factor receptor 2 (HER2); Immunotherapy; Myeloid-derived suppressor cell; T cell; Tumor infiltrating myeloid cell; Tumor microenvironment; Tumor-associated macrophage
Categories
Funding
- NCI Cancer Center Support Grant [P30 CA008748]
- Enid A. Haupt Endowed Chair, the Robert Steel Foundation, Kids Walk for Kids with Cancer
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Modulating tumor infiltrating myeloid cells (TIMs) can potentially improve the efficacy of bispecific antibodies (BsAbs) by enhancing T cell infiltration and persistence in tumors, thus improving the anti-tumor response.
Background Tumor microenvironment (TME) is a dynamic cellular milieu to promote tumor angiogenesis, growth, proliferation, and metastasis, while derailing the host anti-tumor response. TME impedes bispecific antibody (BsAb) or chimeric antigen receptor (CAR)-driven T cells infiltration, survival, and cytotoxic efficacy. Modulating tumor infiltrating myeloid cells (TIMs) could potentially improve the efficacy of BsAb. Methods We evaluated the effects of TIM modulation on BsAb-driven T cell infiltration into tumors, their persistence, and in vivo anti-tumor response. Anti-GD2 BsAb and anti-HER2 BsAb built on IgG-[L]-scFv platform were tested against human cancer xenografts in BALB-Rag2(-/-)IL-2R-gamma c-KO (BRG) mice. Depleting antibodies specific for polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC), monocytic MDSC (M-MDSC), and tumor associated macrophage (TAM) were used to study the role of each TIM component. Dexamethasone, an established anti-inflammatory agent, was tested for its effect on TIMs. Results BsAb-driven T cells recruited myeloid cells into human tumor xenografts. Each TIM targeting therapy depleted cells of interest in blood and in tumors. Depletion of PMN-MDSCs, M-MDSCs, and particularly TAMs was associated with enhanced T cell infiltration into tumors, significantly improving tumor control and survival in multiple cancer xenograft models. Dexamethasone premedication depleted monocytes in circulation and TAMs in tumors, enhanced BsAb-driven T cell infiltration, and anti-tumor response with survival benefit. Conclusion Reducing TIMs markedly enhanced anti-tumor effects of BsAb-based T cell immunotherapy by improving intratumoral T cell infiltration and persistence. TAM depletion was more effective than PMN- or M-MDSCs depletion at boosting the anti-tumor response of T cell engaging BsAb.
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