{"doi":"10.1101/2024.02.24.581875","title":"Targeting high-risk multiple myeloma genotypes with optimized anti-CD70 CAR-T cells","abstract":"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. One sentence summary Structure-optimized CD27-based CAR-T cells targeting CD70 are a promising therapeutic option for high-risk multiple myeloma patients who are most likely to relapse on current BCMA-targeting cellular therapies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":484320,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1037061,"name":"Adila Izgutdina","orcid":"0000-0002-3296-3261","position":1,"is_corresponding":false},{"id":846444,"name":"Bonell Patiño-Escobar","orcid":"0000-0003-2622-4822","position":2,"is_corresponding":false},{"id":1272961,"name":"Amrik S. Kang","orcid":"0000-0003-0445-5654","position":3,"is_corresponding":false},{"id":1326003,"name":"Nikhil Chilakapati","orcid":"0009-0004-3456-8144","position":4,"is_corresponding":false},{"id":252828,"name":"Naomi Akagi","orcid":null,"position":5,"is_corresponding":false},{"id":506547,"name":"Haley Johnson","orcid":"0000-0001-7522-5552","position":6,"is_corresponding":false},{"id":1326514,"name":"Tasfia Rashid","orcid":null,"position":7,"is_corresponding":false},{"id":1326004,"name":"Juwita Werner","orcid":"0009-0007-9635-2519","position":8,"is_corresponding":false},{"id":1163404,"name":"Abhilash Barpanda","orcid":"0000-0001-8158-4949","position":9,"is_corresponding":false},{"id":272482,"name":"Huimin Geng","orcid":"0000-0001-5339-5446","position":10,"is_corresponding":false},{"id":28921,"name":"Yu-Hsiu T. Lin","orcid":"0000-0002-7157-4330","position":11,"is_corresponding":false},{"id":1204591,"name":"Sham Rampersaud","orcid":"0000-0001-7473-4144","position":12,"is_corresponding":false},{"id":1326005,"name":"Daniel Gil-Alós","orcid":"0009-0002-8504-2842","position":13,"is_corresponding":false},{"id":423630,"name":"Amin Sobh","orcid":"0000-0003-3635-8138","position":14,"is_corresponding":false},{"id":626992,"name":"Daphné Dupéré-Richer","orcid":null,"position":15,"is_corresponding":false},{"id":993559,"name":"Gianina Wicaksono","orcid":"0000-0001-5524-0245","position":16,"is_corresponding":false},{"id":1326515,"name":"K.M. Kawehi Kelii","orcid":null,"position":17,"is_corresponding":false},{"id":986345,"name":"Radhika Dalal","orcid":"0000-0002-7128-5635","position":18,"is_corresponding":false},{"id":847345,"name":"Emilio Ramos","orcid":null,"position":19,"is_corresponding":false},{"id":1326516,"name":"Anjanaa Vijayanarayanan","orcid":null,"position":20,"is_corresponding":false},{"id":842934,"name":"Fernando Salangsang","orcid":null,"position":21,"is_corresponding":false},{"id":357627,"name":"Paul Phojanakong","orcid":null,"position":22,"is_corresponding":false},{"id":841673,"name":"Juan A. Cámara","orcid":"0000-0001-7494-1127","position":23,"is_corresponding":false},{"id":1326517,"name":"Ons Zakraoui","orcid":null,"position":24,"is_corresponding":false},{"id":1326518,"name":"Isa Tariq","orcid":null,"position":25,"is_corresponding":false},{"id":323012,"name":"Veronica Steri","orcid":"0000-0003-2499-6618","position":26,"is_corresponding":false},{"id":275300,"name":"Mala Shanmugam","orcid":"0000-0002-4415-8083","position":27,"is_corresponding":false},{"id":28928,"name":"Lawrence Boise","orcid":"0000-0001-9436-8815","position":28,"is_corresponding":false},{"id":106697,"name":"Tanja Kortemme","orcid":"0000-0002-8494-680X","position":29,"is_corresponding":false},{"id":317922,"name":"Elliot Stieglitz","orcid":"0000-0001-7032-4623","position":30,"is_corresponding":false},{"id":237415,"name":"Jonathan D. Licht","orcid":"0000-0002-3942-1369","position":31,"is_corresponding":false},{"id":722459,"name":"William Karlon","orcid":null,"position":32,"is_corresponding":false},{"id":28922,"name":"Benjamin G. Barwick","orcid":"0000-0001-9810-3566","position":33,"is_corresponding":false},{"id":28927,"name":"Arun P. Wiita","orcid":"0000-0002-7465-6964","position":34,"is_corresponding":false},{"id":53177,"name":"Corynn Kasap","orcid":"0000-0002-3667-8097","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T02:07:38.055693Z","pmid":"38463958","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}