TY - JOUR
T1 - Comprehensive Single-Cell Immune Profiling Defines the Patient Multiple Myeloma Microenvironment Following Oncolytic Virus Therapy in a Phase Ib Trial
AU - Nawrocki, Steffan T.
AU - Olea, Julian
AU - Celi, Claudia Villa
AU - Dadrastoussi, Homa
AU - Wu, Kaijin
AU - Tsao-Wei, Denice
AU - Colombo, Anthony
AU - Coffey, Matt
AU - Hernandez, Eduardo Fernandez
AU - Chen, Xuelian
AU - Nuovo, Gerard J.
AU - Carew, Jennifer S.
AU - Mohrbacher, Ann F.
AU - Fields, Paul
AU - Kuhn, Peter
AU - Siddiqi, Imran
AU - Merchant, Akil
AU - Kelly, Kevin R.
N1 - Publisher Copyright: c2023 The Authors; Published by the American Association for Cancer Research.
PY - 2023/12/15
Y1 - 2023/12/15
N2 - 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 ¼ 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 ¼ 9; imaging mass cytometry, n ¼ 6) and peripheral blood samples were collected for analysis (flow cytometry, n ¼ 5; T-cell receptor clonality, n ¼ 7; cytokine assay, n ¼ 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 (CD138þ IDO1þHLA-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.
AB - 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 ¼ 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 ¼ 9; imaging mass cytometry, n ¼ 6) and peripheral blood samples were collected for analysis (flow cytometry, n ¼ 5; T-cell receptor clonality, n ¼ 7; cytokine assay, n ¼ 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 (CD138þ IDO1þHLA-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.
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U2 - 10.1158/1078-0432.CCR-23-0229
DO - 10.1158/1078-0432.CCR-23-0229
M3 - Article
C2 - 37812476
SN - 1078-0432
VL - 29
SP - 5087
EP - 5103
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -