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

• DOI: 10.1182/blood.2024025536
• Publication Date: 2025-05-13T20:05:57Z
• Authors: Corynn Kasap; Adila Izgutdina; Bonell Patiño-Esc...; Amrik Singh Kang; Nikhil Chilakapati; Naomi Akagi; Ananya Mishu Manoj; Haley Johnson; Tasfia Rashid; Juwita Werner; Abhilash Barpanda; Huimin Geng; Yu-Hsiu Tony Lin; Sham Rampersaud; Daniel Gil-Alós; Amin Sobh; Daphné Dupéré-Richer; Adolfo Aleman; Gianina Wicaksono; K.M. Kawehi Kelii; Radhika Dalal; Emilio Ramos; Anjanaa Vijayanar...; Kiran Lakhani; Fernando Salangsang; Paul Phojanakong; Juan Antonio Cama...; ons Zakraoui; Isa Tariq; Ajai Chari; Alfred Chung; Anupama Deepa Kumar; Thomas Martin; Jeffrey Lee Wolf; Sandy Wong; Veronica Steri; Mala Shanmugam; Lawrence H Boise; Tanja Kortemme; Samir Parekh; Elliot Stieglitz; Jonathan D Licht; William Karlon; Benjamin G Barwick; Arun Wiita

Despite the success of BCMA-targeting CAR-Ts in multiple myeloma, patients with high-risk cytogenetic features still relapse most quickly and are urgent need additional therapeutic options. Here, we identify CD70, widely recognized as a favorable immunotherapy target other cancers, specifically upregulated cell surface antigen myeloma tumors. We use structure-guided design to define CD27-based anti-CD70 CAR-T that outperforms all tested scFv-based CARs, leading >80-fold improved expansion vivo. Epigenetic analysis via machine learning predicts key transcription factors transcriptional networks driving CD70 upregulation myeloma. Dual-targeting against either or BCMA demonstrate potential strategy avoid escape-mediated resistance. Together, these findings support promise targeting optimized well future clinical translation this approach.