Targeting high-risk multiple myeloma genotypes with optimized anti-CD70 CAR T cells
Corynn Kasap, Adila Izgutdina, Bonell Patiño-Escobar, Amrik S. Kang, Nikhil Chilakapati, Naomi Akagi, Ananya Manoj, H. A. Johnson, Tasfia Rashid, Juwita Werner, Abhilash Barpanda, Huimin Geng, Yu-Hsiu T. Lin, Sham Rampersaud, Daniel Gil-Alós, Amin Sobh, Daphné Dupéré-Richer, Adolfo Aleman, Gianina Wicaksono, K.M. Kawehi Kelii, Radhika Dalal, Emilio Ramos, Anjanaa Vijayanarayanan, Kiran Lakhani, Fernando Salangsang, Paul Phojanakong, Juan A. Cámara, Ons Zakraoui, Isa Tariq, Ajai Chari, Alfred Chung, Anupama Kumar, Thomas G. Martin, Jeffrey L. Wolf, Sandy W. Wong, Veronica Steri, Mala Shanmugam, Lawrence Boise, Tanja Kortemme, Samir Parekh, Elliot Stieglitz, Jonathan D. Licht, William Karlon, Benjamin G. Barwick, Arun P. Wiita
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.