{"doi":"10.1101/2024.12.31.630941","title":"A framework integrating multiscale in-silico modeling and experimental data predicts CD33CAR-NK cytotoxicity across target cell types","abstract":"Uncovering mechanisms and predicting tumor cell responses to CAR-NK cytotoxicity is essential for improving therapeutic efficacy. Currently, the complexity of these effector-target interactions and the donor-to-donor variations in NK cell receptor (NKR) repertoire require functional assays to be performed experimentally for each manufactured CAR-NK cell product and target combination. Here, we developed a computational mechanistic multiscale model which considers heterogenous expression of CARs, NKRs, adhesion receptors and their cognate ligands, signal transduction, and NK cell-target cell population kinetics. The model trained with quantitative flow cytometry and in vitro cytotoxicity data accurately predicts the short- and long-term cytotoxicity of CD33CAR-NK cells against leukemia cell lines across multiple CAR designs. Furthermore, using Pareto optimization we explored the effect of CAR proportion and NK cell signaling on the differential cytotoxicity of CD33CAR-NK cells to cancer and healthy cells. This model can be extended to predict CAR-NK cytotoxicity across many antigens and tumor targets.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556976,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":716951,"name":"Kun Xing","orcid":"0000-0001-7074-5217","position":1,"is_corresponding":false},{"id":564146,"name":"Harshana Rajakaruna","orcid":null,"position":2,"is_corresponding":false},{"id":431798,"name":"William C. Stewart","orcid":"0000-0002-6153-6613","position":3,"is_corresponding":false},{"id":1456656,"name":"Kyle A. Beckwith","orcid":"0000-0001-8025-2512","position":4,"is_corresponding":false},{"id":1332057,"name":"Indrani Nayak","orcid":"0000-0002-4257-8965","position":5,"is_corresponding":false},{"id":267496,"name":"Meisam Naeimi Kararoudi","orcid":"0000-0002-2880-1796","position":6,"is_corresponding":false},{"id":267502,"name":"Dean A. Lee","orcid":"0000-0001-6693-5392","position":7,"is_corresponding":false},{"id":816508,"name":"Jayajit Das","orcid":"0000-0001-9649-4698","position":8,"is_corresponding":false},{"id":1177132,"name":"Saeed Ahmad","orcid":"0000-0001-6910-7613","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T02:55:13.130091Z","pmid":"39803543","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":[]}