Targeting high-risk multiple myeloma genotypes with optimized anti-CD70 CAR T cells
Abstract
Abstract Despite the success of B-cell maturation antigen (BCMA)–targeting chimeric antigen receptor (CAR) T cells (CAR-Ts) in multiple myeloma, patients with high-risk cytogenetic features continue to relapse most quickly and are in urgent need of additional therapeutic options. Here, we identify CD70, widely recognized as a favorable immunotherapy target in other cancers, as a specifically upregulated cell surface antigen in high-risk myeloma tumors. We use a structure-guided design to define a CD27-based anti-CD70 CAR-T design that outperforms all tested single-chain variable fragment–based CARs, leading to >80-fold improved CAR-T expansion in vivo. Epigenetic analysis via machine learning predicts key transcription factors and transcriptional networks driving CD70 upregulation in high-risk myeloma. Dual-targeting CAR-Ts against either CD70 or BCMA demonstrate a potential strategy to avoid antigen escape–mediated resistance. Together, these findings support the promise of targeting CD70 with optimized CAR-Ts in myeloma as well as future clinical translation of this approach.
Article Details
Authors (45)
Corynn Kasap
Adila Izgutdina
Bonell Patiño-Escobar
Amrik S. Kang
2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
Nikhil Chilakapati
2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
Naomi Akagi
2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
Ananya Manoj
2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
Haley Johnson
2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
Tasfia Rashid
2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
Juwita Werner
Abhilash Barpanda
Huimin Geng
Yu-Hsiu T. Lin
2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
Sham Rampersaud
1University of California, San Francisco, Laboratory Medicine, San Francisco, United States
Daniel Gil-Alós
2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
Amin Sobh
Daphne Dupere-Richer
Adolfo Aleman
Icahn School of Medicine at Mount Sinai, New York
Gianina Wicaksono
2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
K. M. Kawehi Kelii
2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
Radhika Dalal
1University of California, San Francisco, San Francisco, United States
Emilio Ramos
Anjanaa Vijayanarayanan
2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
Kiran Lakhani
1Emory University, Hematology and Medical Oncology, Atlanta, United States
Fernando Salangsang
7University of California, San Francisco, Preclinical Therapeutics Core, Helen Diller Family Comprehensive Cancer Center, San Francisco, United States
Paul Phojanakong
7University of California, San Francisco, Preclinical Therapeutics Core, Helen Diller Family Comprehensive Cancer Center, San Francisco, United States
Juan Antonio Camara Serrano
12Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Ons Zakraoui
12Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Isa Tariq
12Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Ajai Chari
University of California San Francisco, San Francisco, California, United States
Alfred Chung
6University of California San Francisco, San Francisco, United States
Anupama D. Kumar
1Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA
Thomas G. Martin
Jeffrey Wolf
1Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA
Sandy W. Wong
1Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA
Veronica Steri
Mala Shanmugam
1Emory University, Hematology and Medical Oncology, Atlanta, United States
Lawrence H. Boise
3Department of Hematology and Medical Oncology, Emory University, Atlanta, GA
Tanja Kortemme
Samir Parekh
Icahn School of Medicine at Mount Sinai, New York
Elliot Stieglitz
Jonathan D. Licht
8Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, FL
William J. Karlon
2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
Benjamin G. Barwick
Emory University
Arun P. Wiita