Comprehensive Single-Cell Immune Profiling Defines the Patient Multiple Myeloma Microenvironment Following Oncolytic Virus Therapy in a Phase Ib Trial.

Autor:	Nawrocki ST; Division of Hematology and Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, Arizona., Olea J; Division of Hematology, Health Sciences Campus, University of Southern California, Los Angeles, California., Villa Celi C; Division of Hematology, Health Sciences Campus, University of Southern California, Los Angeles, California., Dadrastoussi H; Division of Hematology, Health Sciences Campus, University of Southern California, Los Angeles, California., Wu K; Division of Hematology, Health Sciences Campus, University of Southern California, Los Angeles, California., Tsao-Wei D; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California., Colombo A; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California., Coffey M; Oncolytics Biotech, Inc, Calgary, Alberta, Canada., Fernandez Hernandez E; Division of Hematology, Health Sciences Campus, University of Southern California, Los Angeles, California., Chen X; Division of Hematology, Health Sciences Campus, University of Southern California, Los Angeles, California., Nuovo GJ; The Ohio State University Comprehensive Cancer Center Columbus, Columbus, Ohio., Carew JS; Division of Hematology and Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, Arizona., Mohrbacher AF; Division of Hematology, Health Sciences Campus, University of Southern California, Los Angeles, California., Fields P; Formerly, Adaptive Biotechnologies, Seattle, Washington; currently, Tempus Labs, Seattle, Washington., Kuhn P; USC Michelson Center for Convergent Biosciences and Department of Biological Sciences, University of Southern California, Los Angeles., Siddiqi I; Department of Pathology, University of Southern California, Los Angeles, California., Merchant A; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California., Kelly KR; Division of Hematology, Health Sciences Campus, University of Southern California, Los Angeles, California.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Dec 15; Vol. 29 (24), pp. 5087-5103.
DOI:	10.1158/1078-0432.CCR-23-0229
Abstrakt:	Purpose: Our preclinical studies showed that the oncolytic reovirus formulation pelareorep (PELA) has significant immunomodulatory anti-myeloma activity. We conducted an investigator-initiated clinical trial to evaluate PELA in combination with dexamethasone (Dex) and bortezomib (BZ) and define the tumor immune microenvironment (TiME) in patients with multiple myeloma treated with this regimen. Patients and Methods: Patients with relapsed/refractory multiple myeloma (n = 14) were enrolled in a phase Ib clinical trial (ClinicalTrials.gov: NCT02514382) of three escalating PELA doses administered on Days 1, 2, 8, 9, 15, and 16. Patients received 40 mg Dex and 1.5 mg/m2 BZ on Days 1, 8, and 15. Cycles were repeated every 28 days. Pre- and posttreatment bone marrow specimens (IHC, n = 9; imaging mass cytometry, n = 6) and peripheral blood samples were collected for analysis (flow cytometry, n = 5; T-cell receptor clonality, n = 7; cytokine assay, n = 7). Results: PELA/BZ/Dex was well-tolerated in all patients. Treatment-emergent toxicities were transient, and no dose-limiting toxicities occurred. Six (55%) of 11 response-evaluable patients showed decreased paraprotein. Treatment increased T and natural killer cell activation, inflammatory cytokine release, and programmed death-ligand 1 expression in bone marrow. Compared with nonresponders, responders had higher reovirus protein levels, increased cytotoxic T-cell infiltration posttreatment, cytotoxic T cells in significantly closer proximity to multiple myeloma cells, and larger populations of a novel immune-primed multiple myeloma phenotype (CD138+ IDO1+HLA-ABCHigh), indicating immunomodulation. Conclusions: PELA/BZ/Dex is well-tolerated and associated with anti-multiple myeloma activity in a subset of responding patients, characterized by immune reprogramming and TiME changes, warranting further investigation of PELA as an immunomodulator. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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