Kasap Corynn, Izgutdina Adila, Patiño-Escobar Bonell, Kang Amrik Singh, Chilakapati Nikhil, Akagi Naomi, Manoj Ananya Mishu, Johnson Haley, Rashid Tasfia, Werner Juwita, Barpanda Abhilash, Geng Huimin, Lin Yu-Hsiu Tony, Rampersaud Sham, Gil-Alós Daniel, Sobh Amin, Dupéré-Richer Daphné, Aleman Adolfo, Wicaksono Gianina, Kelii K M Kawehi, Dalal Radhika, Ramos Emilio, Vijayanarayanan Anjanaa, Lakhani Kiran, Salangsang Fernando, Phojanakong Paul, Camara Serrano Juan Antonio, Zakraoui Ons, Tariq Isa, Chari Ajai, Chung Alfred, Kumar Anupama Deepa, Martin Thomas, Wolf Jeffrey Lee, Wong Sandy, Steri Veronica, Shanmugam Mala, Boise Lawrence H, Kortemme Tanja, Parekh Samir, Stieglitz Elliot, Licht Jonathan D, Karlon William, Barwick Benjamin G, Wiita Arun
University of California San Francisco, San Francisco, California, United States.
University of California, San Francisco, San Francisco, California, United States.
Blood. 2025 May 13. doi: 10.1182/blood.2024025536.
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.
尽管靶向BCMA的嵌合抗原受体T细胞（CAR-T）在多发性骨髓瘤治疗中取得了成功，但具有高危细胞遗传学特征的患者复发最快，迫切需要更多治疗选择。在此，我们确定CD70（在其他癌症中被广泛认为是一种理想的免疫治疗靶点）为高危骨髓瘤肿瘤中特异性上调的细胞表面抗原。我们采用结构导向设计来定义一种基于CD27的抗CD70 CAR-T设计，该设计优于所有测试的基于单链抗体片段（scFv）的CAR，使体内CAR-T扩增提高了80倍以上。通过机器学习进行的表观遗传学分析预测了驱动高危骨髓瘤中CD70上调的关键转录因子和转录网络。针对CD70或BCMA的双靶点CAR-T展示了一种避免抗原逃逸介导的耐药性的潜在策略。总之，这些发现支持了在骨髓瘤中用优化的CAR-T靶向CD70的前景以及该方法未来的临床转化。
