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Publications

Journal Article Preprint Epublish 9 citations

PubMed: 38463958 DOI: 10.1101/2024.02.24.581875

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

bioRxiv

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

Affiliations

  • Dept. of Medicine, Division of Hematology/Oncology, University of California, San Francisco, CA.
  • Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Medical Scientist Training Program, University of California, San Francisco, CA.
  • Dept. of Pediatrics, Division of Oncology, University of California, San Francisco, CA.
  • Dept of Hematology, Hospital 12 de Octubre, Madrid, Spain.
  • University of Florida Health Cancer Center, The University of Florida Cancer and Genetics Research Complex, Gainesville, Florida.
  • Division of Hematology/Oncology, The University of Florida College of Medicine, Gainesville, Florida.
  • Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA.
  • Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA.
  • Chan Zuckerberg Biohub San Francisco, San Francisco, CA.

Abstract

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.

MeSH

Cells, Antigens, Surface, Neoplasms, Multiple Myeloma, Genotype, Car-T Cell