Molecular and Clinical Determinants of CAR-T Therapy Response in DLBCL

作者：Devang Thakkar, Brian T. Hill, Rachel Kositsky, Shari Tian, Leonardo P. A. Biral, Veronica Russell, Tushar Dave, Cassandra Love, Caroline Roth, Matthew McKinney, Ahmed Galal, Jadee Neff, Agrima Mian, Ellen K. Kendall, Sarah L. Ondrejka, Matthew Chiaramonte, Govind Bhagat, Kenneth Ofori, Ran Reshef, Alexandra E. Kovach, Tarsheen Sethi, Emily F. Mason, Shakthi Bhaskar, Olalekan O. Oluwole, Chad M. McCall, Christopher R. Pallas, Nilanjan Ghosh, Robert Ferdman, George Chen, Francisco J. Hernandez‐Ilizaliturri, Joanna Zurko, Ashley M. Cunningham, Nirav N. Shah, Boyu Hu, Deborah M. Stephens, Monalisa Ghosh, Neil A. Bailey, Krish Patel, John M. Pagel, Kavya Kannan, Eric D. Hsi, Rakhee Vaidya, Andrew Ip, André Goy, Swetha Kambhampati, Robert S. Ohgami, Charalambos Andreadis, Christian Gordillo, Brianna Just, Jonathon B. Cohen, Arielle Baim, Julie Barbello, Erika Cavallone, Veronika Bachanová, Maureen Laschen, Andinet Teferra, Frédérique Lorcy, Sylvain Lamure, Guillaume Cartron, Valérie Dardalhon, Kikkeri N. Naresh, Magdalena Czader, Anupama Reddy, Elizabeth Thacker, Clayton Parker, Lanie E. Happ, Sandeep S. Davé · 发表于：Blood · 年份：2024 · DOI：10.1182/blood-2024-199758 · 被引用次数：1 · 研究领域：CAR-T cell therapy research、Biosimilars and Bioanalytical Methods

Introduction: Diffuse large B-cell lymphoma (DLBCL) is one of the most common forms of blood cancer worldwide. Outcomes for patients with relapsed or refractory (r/r) DLBCL have remained dismal. Chimeric antigen receptor (CAR) T-cell therapy targeting the B-cell surface marker CD19 has recently emerged as a novel, effective approach capable of producing durable responses in r/r DLBCL patients. Indeed, nearly all r/r DLBCL patients in the United States are considered candidates for FDA-approved CAR-T therapy. However, CAR-T therapy has a number of major shortcomings. First, it has limited efficacy. The median progression-free survival (PFS) of r/r DLBCL patients treated with CAR-T therapy is roughly six months. Second, it has major toxicities. CAR-T therapy is associated with risk of life-threatening side effects such as cytokine release syndrome (CRS) and CAR-T cell-related encephalopathy syndrome (CRES). Third, it is highly expensive. Strategies for identifying, a priori, those patients likely to respond to this therapy could provide an important tool for clinical decision-making and improving outcomes in patients with r/r DLBCL. Methods & Results: We enrolled a real-world cohort of 161 r/r DLBCL patients treated with CD19-directed CAR-T therapy and applied whole exome and transcriptome sequencing on their pre-treatment biopsies to identify predictors of outcome. A number of clinical variables were associated with worse PFS or overall survival (OS) including a higher Int...