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

Journal: Blood
Published Date: May 13, 2025

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.

Authors

  • Corynn Kasap
    Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • Adila Izgutdina
    University of California San Francisco, San Francisco, California, United States.
  • Bonell Patiño-Escobar
    University of California San Francisco, San Francisco, California, United States.
  • Amrik Singh Kang
    University of California San Francisco, San Francisco, California, United States.
  • Nikhil Chilakapati
    University of California San Francisco, San Francisco, California, United States.
  • Naomi Akagi
    University of California San Francisco, San Francisco, California, United States.
  • Ananya Mishu Manoj
    University of California San Francisco, San Francisco, California, United States.
  • Haley Johnson
    University of California San Francisco, San Francisco, California, United States.
  • Tasfia Rashid
    University of California San Francisco, San Francisco, California, United States.
  • Juwita Werner
    University of California, San Francisco, San Francisco, California, United States.
  • Abhilash Barpanda
    University of California San Francisco, San Francisco, California, United States.
  • Huimin Geng
    University of California, San Francisco, San Francisoco, California, United States.
  • Yu-Hsiu Tony Lin
    University of California San Francisco, San Francisco, California, United States.
  • Sham Rampersaud
    University of California, San Francisco, San Francisco, California, United States.
  • Daniel Gil-Alós
    Hospital 12 de Octubre, Madrid, Spain.
  • Amin Sobh
    University of Florida, Gainesville, Florida, United States.
  • Daphné Dupéré-Richer
    University of Florida, Gainesville, Florida, United States.
  • Adolfo Aleman
    Icahn School of Medicine at Mount Sinai, NEW YORK, New York, United States.
  • Gianina Wicaksono
    University of California San Francisco, San Francisco, California, United States.
  • K M Kawehi Kelii
    University of California San Francisco, San Francisco, California, United States.
  • Radhika Dalal
    University of California San Francisco, San Francisco, California, United States.
  • Emilio Ramos
    University of California San Francisco, San Francisco, California, United States.
  • Anjanaa Vijayanarayanan
    University of California San Francisco Medical Center, San Fransisco, California, United States.
  • Kiran Lakhani
    Emory University School of Medicine, Atlanta, Georgia, United States.
  • Fernando Salangsang
    University of California San Francisco, San Francisco, California, United States.
  • Paul Phojanakong
    University of California San Francisco, San Francisco, California, United States.
  • Juan Antonio Camara Serrano
    University of California San Francisco, San Francisco, California, United States.
  • Ons Zakraoui
    University of California San Francisco, San Francisco, California, United States.
  • Isa Tariq
    University of California San Francisco, San Francisco, California, United States.
  • Ajai Chari
    Univeristy of California, San Francisco, San Francisco, California, United States.
  • Alfred Chung
    University of California San Francisco, San Francisco, California, United States.
  • Anupama Deepa Kumar
    University of California San Francisco, San Francisco, California, United States.
  • Thomas Martin
    UCSF, San Francisco, California, United States.
  • Jeffrey Lee Wolf
    UCSF, San Francisco, California, United States.
  • Sandy Wong
    University of California San Francisco, San Francisco, California, United States.
  • Veronica Steri
    University of California San Francisco, San Francisco, California, United States.
  • Mala Shanmugam
    Winship Cancer Institute, Emory University, Atlanta, Georgia, United States.
  • Lawrence H Boise
    Emory University School of Medicine, Atlanta, Georgia, United States.
  • Tanja Kortemme
    UC Berkeley-UCSF Graduate Program in Bioengineering, University of California, San Francisco, CA 94158.
  • Samir Parekh
    Icahn School of Medicine at Mount Sinai, NEW YORK, New York, United States.
  • Elliot Stieglitz
    Benioff Children's Hospital, University of California, San Francisco, San Francisco, California, United States.
  • Jonathan D Licht
    The University of Florida, Gainesville, Florida, United States.
  • William Karlon
    UCSF, San Francisco, California, United States.
  • Benjamin G Barwick
    Emory University, Atlanta, Georgia, United States.
  • Arun Wiita
    University of California San Francisco, San Francisco, California, United States.

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