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Targeting high-risk multiple myeloma genotypes with optimized anti-CD70 CAR-T cells.
Kasap, Corynn; Izgutdina, Adila; Patiño-Escobar, Bonell; Kang, Amrik; Chilakapati, Nikhil; Akagi, Naomi; Johnson, Haley; Rashid, Tasfia; Werner, Juwita; Barpanda, Abhilash; Geng, Huimin; Lin, Yu-Hsiu T; Rampersaud, Sham; Gil-Alós, Daniel; Sobh, Amin; Dupéré-Richer, Daphné; Wicaksono, Gianina; Kawehi Kelii, K M; Dalal, Radhika; Ramos, Emilio; Vijayanarayanan, Anjanaa; Salangsang, Fernando; Phojanakong, Paul; Serrano, Juan Antonio Camara; Zakraoui, Ons; Tariq, Isa; Steri, Veronica; Shanmugam, Mala; Boise, Lawrence H; Kortemme, Tanja; Stieglitz, Elliot; Licht, Jonathan D; Karlon, William J; Barwick, Benjamin G; Wiita, Arun P.
Afiliação
  • Kasap C; Dept. of Medicine, Division of Hematology/Oncology, University of California, San Francisco, CA.
  • Izgutdina A; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Patiño-Escobar B; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Kang A; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Chilakapati N; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Akagi N; Medical Scientist Training Program, University of California, San Francisco, CA.
  • Johnson H; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Rashid T; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Werner J; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Barpanda A; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Geng H; Dept. of Pediatrics, Division of Oncology, University of California, San Francisco, CA.
  • Lin YT; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Rampersaud S; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Gil-Alós D; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Sobh A; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Dupéré-Richer D; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Wicaksono G; Dept of Hematology, Hospital 12 de Octubre, Madrid, Spain.
  • Kawehi Kelii KM; University of Florida Health Cancer Center, The University of Florida Cancer and Genetics Research Complex, Gainesville, Florida.
  • Dalal R; Division of Hematology/Oncology, The University of Florida College of Medicine, Gainesville, Florida.
  • Ramos E; University of Florida Health Cancer Center, The University of Florida Cancer and Genetics Research Complex, Gainesville, Florida.
  • Vijayanarayanan A; Division of Hematology/Oncology, The University of Florida College of Medicine, Gainesville, Florida.
  • Salangsang F; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Phojanakong P; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Serrano JAC; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA.
  • Zakraoui O; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Tariq I; Dept. of Laboratory Medicine, University of California, San Francisco, CA.
  • Steri V; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • Shanmugam M; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • Boise LH; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • Kortemme T; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • Stieglitz E; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • Licht JD; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • Karlon WJ; Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA.
  • Barwick BG; Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA.
  • Wiita AP; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA.
bioRxiv ; 2024 Feb 28.
Article em En | MEDLINE | ID: mdl-38463958
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2024 Tipo de documento: Article País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2024 Tipo de documento: Article País de publicação: Estados Unidos