학술논문
Targeting MCL-1 and BCL-2 with polatuzumab vedotin and venetoclax overcomes treatment resistance in R/R non-Hodgkin lymphoma: Results from preclinical models and a Phase Ib study.
Document Type
Academic Journal
Author
Lasater EA; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, USA.; Amin DN; Department of Discovery Oncology, Genentech, Inc., South San Francisco, California, USA.; Department of Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California, USA.; Bannerji R; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.; Mali RS; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, USA.; Barrett K; Department of Biomarker Development, Genentech, Inc., South San Francisco, California, USA.; Rys RN; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.; Department of Medicine, McGill University, Montreal, Quebec, Canada.; Oeh J; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, USA.; Lin E; Department of Discovery Oncology, Genentech, Inc., South San Francisco, California, USA.; Sterne-Weiler T; Department of Oncology Bioinformatics, Genentech, Inc., South San Francisco, California, USA.; Ingalla ER; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, USA.; Go M; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, USA.; Yu SF; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, USA.; Krem MM; Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA.; Arthur C; Royal North Shore Hospital (RNSH), Sydney, New South Wales, Australia.; Hahn U; The Queen Elizabeth Hospital (TQEH), Adelaide, South Australia, Australia.; Johnston A; Royal Hobart Hospital (RHH), Hobart, Tasmania, Australia.; Karur V; Baylor Scott & White Healthcare, Temple, Texas, USA.; Khan N; Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.; Marlton P; Princess Alexandra Hospital, and University of Queensland, Brisbane, Queensland, Australia.; Phillips T; University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA.; Gritti G; Hematology and Bone Marrow Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy.; Seymour JF; Peter MacCallum Cancer Centre, Royal Melbourne Hospital, and University of Melbourne, Melbourne, Victoria, Australia.; Tani M; Ospedale S. Maria delle Croci, Ravenna, Italy.; Yuen S; Calvary Mater Newcastle, Waratah, New South Wales, Australia.; Martin S; Department of Discovery Oncology, Genentech, Inc., South San Francisco, California, USA.; Chang MT; Department of Oncology Bioinformatics, Genentech, Inc., South San Francisco, California, USA.; Rose CM; Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, California, USA.; Pham VC; Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, California, USA.; Polson AG; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, USA.; Chang Y; Hoffmann-La Roche Ltd, Mississauga, Ontario, Canada.; Wever C; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.; Department of Medicine, McGill University, Montreal, Quebec, Canada.; Johnson NA; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.; Department of Medicine, McGill University, Montreal, Quebec, Canada.; Jiang Y; Department of Biomarker Development, Genentech, Inc., South San Francisco, California, USA.; Hirata J; Product Development Oncology, Genentech, Inc., South San Francisco, California, USA.; Sampath D; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, USA.; Musick L; Product Development Oncology, Genentech, Inc., South San Francisco, California, USA.; Flowers CR; Department of Lymphoma and Myeloma, UT MD Anderson Cancer Center, Houston, Texas, USA.; Wertz IE; Department of Discovery Oncology, Genentech, Inc., South San Francisco, California, USA.; Department of Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California, USA.
Source
Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 7610369 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-8652 (Electronic) Linking ISSN: 03618609 NLM ISO Abbreviation: Am J Hematol Subsets: MEDLINE
Subject
Language
English
Abstract
The treatment of patients with relapsed or refractory lymphoid neoplasms represents a significant clinical challenge. Here, we identify the pro-survival BCL-2 protein family member MCL-1 as a resistance factor for the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma (NHL) cell lines and primary NHL samples. Mechanistically, we show that the antibody-drug conjugate polatuzumab vedotin promotes MCL-1 degradation via the ubiquitin/proteasome system. This targeted MCL-1 antagonism, when combined with venetoclax and the anti-CD20 antibodies obinutuzumab or rituximab, results in tumor regressions in preclinical NHL models, which are sustained even off-treatment. In a Phase Ib clinical trial (NCT02611323) of heavily pre-treated patients with relapsed or refractory NHL, 25/33 (76%) patients with follicular lymphoma and 5/17 (29%) patients with diffuse large B-cell lymphoma achieved complete or partial responses with an acceptable safety profile when treated with the recommended Phase II dose of polatuzumab vedotin in combination with venetoclax and an anti-CD20 antibody.
(© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)
(© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)