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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Comprehensive Single-Cell Immune Profiling Defines the Patient Multiple Myeloma Microenvironment Following Oncolytic
Steffan T Nawrocki1, Julian Olea2, Claudia Villa Celi2
1Division of Hematology and Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, Arizona.
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.
Insights
Pelareorep (PELA) combined with bortezomib and dexamethasone showed anti-myeloma activity and modulated the tumor immune microenvironment in patients with multiple myeloma.
Area of Science:
- Oncology
- Immunology
- Virology
Background:
- Preclinical studies indicated that pelareorep (PELA), an oncolytic reovirus formulation, possesses significant immunomodulatory and anti-myeloma properties.
- Multiple myeloma is a hematologic malignancy characterized by uncontrolled proliferation of plasma cells.
Purpose of the Study:
- To evaluate the safety and efficacy of PELA in combination with dexamethasone (Dex) and bortezomib (BZ) in patients with relapsed/refractory multiple myeloma.
- To characterize the changes in the tumor immune microenvironment (TiME) following treatment with PELA/Dex/BZ.
Main Methods:
- A Phase Ib clinical trial enrolled 14 patients with relapsed/refractory multiple myeloma.
- Patients received escalating doses of PELA combined with standard doses of Dex and BZ, with treatment cycles repeated every 28 days.
- Bone marrow and peripheral blood samples were collected pre- and post-treatment for comprehensive immunophenotyping and molecular analyses.
Main Results:
- The PELA/BZ/Dex regimen was well-tolerated, with transient toxicities and no dose-limiting toxicities observed.
- Of 11 response-evaluable patients, 6 (55%) demonstrated a decrease in paraprotein levels.
- Treatment led to increased T-cell and natural killer cell activation, elevated inflammatory cytokine release, and enhanced PD-L1 expression in the bone marrow.
Conclusions:
- PELA/Dex/BZ is a tolerable combination therapy demonstrating anti-myeloma activity in a subset of patients.
- Treatment induced significant immune reprogramming and alterations in the TiME.
- These findings support further investigation of PELA as an immunomodulatory agent for multiple myeloma.
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