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

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.

SUBMITTER: Kasap C

PROVIDER: S-EPMC10925123 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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

Kasap Corynn C Izgutdina Adila A Patiño-Escobar Bonell B Kang Amrik A Chilakapati Nikhil N Akagi Naomi N Johnson Haley H Rashid Tasfia T Werner Juwita J Barpanda Abhilash A Geng Huimin H Lin Yu-Hsiu T YT Rampersaud Sham S Gil-Alós Daniel D Sobh Amin A Dupéré-Richer Daphné D Wicaksono Gianina G Kawehi Kelii K M KM Dalal Radhika R Ramos Emilio E Vijayanarayanan Anjanaa A Salangsang Fernando F Phojanakong Paul P Serrano Juan Antonio Camara JAC Zakraoui Ons O Tariq Isa I Steri Veronica V Shanmugam Mala M Boise Lawrence H LH Kortemme Tanja T Stieglitz Elliot E Licht Jonathan D JD Karlon William J WJ Barwick Benjamin G BG Wiita Arun P AP

bioRxiv : the preprint server for biology 20240228

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, lead ...[more]

PMID: 38463958

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Project description:The present study aimed to study the efficacy and adverse effects of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in relapsed or refractory multiple myeloma. Patients were divided into three dose groups based on cell therapy concentration. After CAR-T cell therapy for 10 patients with recurrent or refractory multiple myeloma, the patients were monitored and evaluated regularly to observe the efficacy and adverse reactions of CAR-T cell therapy. At a median follow-up of 337 (253-504) days, one patient succumbed 24 days due to rapidly progressing disease. The overall response rate of nine patients was 88.9%, including 77.8% (7/9) with minimal residual disease negative complete remission (CR) and 11.1% (1/9) with partial remission. A total of three patients were maintained in remission state for more than a year and eight were maintained for more than six months. Among the three patients with extramedullary invasion, two extramedullary lesions disappeared and one was stable. The highest copy number of CAR-T cells in seven patients with CR was >1x105 copies/µl gDNA, and the best therapeutic effect can be achieved within 30 (7-30) days after the copy number of CAR-T cells reached 1x105 copies/µl genomic DNA. The median onset time in the nine patients was 43 (22-169) days, and the median progression-free survival was 337 (253-504). Among the 10 patients, nine (90%) had cytokine release syndrome, all of which were below grade II. There were nine (90%) patients with hematological adverse reactions, six (60%) patients with severe anemia, five (50%) patients with grade III and above leukopenia, five (50%) patients with granulocytopenia, four (40%) patients with grade III and above thrombocytopenia, and three (30%) patients with grade III and above pancytopenia. It was concluded that anti-BCMA CAR-T cell therapy is a promising treatment method for relapsed or refractory multiple myeloma and extramedullary invasion, with stable efficacy and controllable adverse effects.

Dataset Information

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

Publications

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

Similar Datasets

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