Immunodepletion of MDSC by AMV564, a novel bivalent, bispecific CD33/CD3 T cell engager, ex vivo in MDS and melanoma.

Autor:	Cheng P; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Chen X; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Dalton R; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Calescibetta A; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., So T; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Gilvary D; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Ward G; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Smith V; Amphivena Therapeutics, Inc., South San Francisco, CA 94080, USA., Eckard S; Amphivena Therapeutics, Inc., South San Francisco, CA 94080, USA., Fox JA; Amphivena Therapeutics, Inc., South San Francisco, CA 94080, USA., Guenot J; Amphivena Therapeutics, Inc., South San Francisco, CA 94080, USA., Markowitz J; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Cleveland JL; Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Wright KL; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., List AF; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Precision BioSciences, Durham, NC 27701, USA., Wei S; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Eksioglu EA; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address: erika.eksioglu@moffitt.org.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2022 Jun 01; Vol. 30 (6), pp. 2315-2326. Date of Electronic Publication: 2022 Feb 09.
DOI:	10.1016/j.ymthe.2022.02.005
Abstrakt:	We have reported previously that CD33 hi myeloid-derived suppressor cells (MDSCs) play a direct role in the pathogenesis of myelodysplastic syndromes (MDSs) and that their sustained activation contributes to hematopoietic and immune impairment, including modulation of PD1/PDL1. MDSCs can also limit the clinical activity of immune checkpoint inhibition in solid malignancies. We hypothesized that depletion of MDSCs may ameliorate resistance to checkpoint inhibitors and, hence, targeted them with AMV564 combined with anti-PD1 in MDS bone marrow (BM) mononuclear cells (MNCs) enhanced activation of cytotoxic T cells. AMV564 was active in vivo in a leukemia xenograft model when co-administered with healthy donor peripheral blood MNCs (PBMCs). Our findings provide a strong rationale for clinical investigation of AMV564 as a single agent or in combination with an anti-PD1 antibody and in particular for treatment of cancers resistant to checkpoint inhibitors. Competing Interests: Declaration of interests S.E. and V.S. are employees of Amphivena Therapeutics, Inc. S.W. and A.L. are scientific/medical advisors for Amphivena Therapeutics, Inc. The S.W. and A.F.L. laboratories received unrelated support from Celgene and Genentech. A.F.L. has provided consulting services and has received research funding support from multiple other pharmaceutical and biotechnology companies that pursue cancer research, including Celgene, Precision BioSciences, Prelude Therapeutics, and CTI Biopharma, and serves on the scientific advisory boards of Aileron and CBMG. A.F.L. also has potential royalty income from IP he developed related to cancer treatment and is a member of the MDS Foundation board of directors. S.W. has received unrelated support from Blackbird BioFinance, LLC. J.A.F. is a consultant for and owns Amphivena stocks and is currently employed by Sunesis Pharmaceuticals. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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