Journal Article

Targeting high-risk multiple myeloma genotypes with optimized anti-CD70 CAR-T cells

Kortemme, Tanja, Lin, Yu-Hsiu T, Akagi, Naomi, Gil-Alós, Daniel, Sobh, Amin, Phojanakong, Paul, Kang, Amrik, Ramos, Emilio, Chilakapati, Nikhil, Dupéré-Richer, Daphné, Johnson, Haley, Wicaksono, Gianina, Karlon, William J, Patiño-Escobar, Bonell, Tariq, Isa, Rampersaud, Sham, Shanmugam, Mala, Kawehi Kelii, K M, Kasap, Corynn, Vijayanarayanan, Anjanaa, Steri, Veronica, Stieglitz, Elliot, Zakraoui, Ons, Geng, Huimin, Barwick, Benjamin G, Licht, Jonathan D, Rashid, Tasfia, Salangsang, Fernando, Wiita, Arun P, Barpanda, Abhilash, Dalal, Radhika, Werner, Juwita, Boise, Lawrence H, Serrano, Juan Antonio Camara, Izgutdina, Adila

2024

Overview

Despite the success of BCMA-targeting CAR-Ts in multiple myeloma, patients with high-risk cytogenetic features still 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 scFv-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.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Antigens / Cancer Biology / CD27 antigen / CD70 antigen / Cell surface / Cytogenetics / Epigenetics / Genotypes / Immunotherapy / Lymphocytes T / Multiple myeloma / Patent applications / Transcription factors