Gut Microbiota and Metabolites Influence CAR-T Cell Persistence, Efficacy and Predict Outcomes in Multiple Myeloma

Carlos Fernández de Larrea – 30, Hospital Clínic Barcelona -IDIBAPS; Europa Azucena González-Navarro – 29, Hospital Clínic Barcelona -IDIBAPS; MV Mateos – 26, Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca; Mariona Pascal – 27, Hospital Clínic Barcelona -IDIBAPS; Álvaro Urbano-Ispizua – 28, Hospital Clínic Barcelona -IDIBAPS; Valentin Cabañas – 19, ospital Clínico Universitario Virgen de la Arrixaca. IMIB-Arrixaca. University of Murcia.; Julio Delgado – 16, Hospital Clínic Barcelona -IDIBAPS; Verónica González-Calle – 18, Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca; Joaquin Martínez-López – 25, Hospital Universitario 12 de Octubre, Complutense University, i+12, CNIO; Beatriz Martin-Antonio – 20, Instituto de Salud Carlos III, Departamento de Desarrollo de Medicamentos de Terapias Avanzadas; Iñaki Ortiz de Landazuri – 17, Hospital Clínic Barcelona -IDIBAPS; Lorena Pérez-Amill – 21, IDIBAPS; bruno Pavia – 24, Clínica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, CIBERONC Pamplona, Pamplona, Spain.; JL Reguera-Ortega – 22, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla; Paula Rodríguez-Otero – 23, Clínica Universidad de Navarra, Centro de Investigacion Medica Aplicada; Núria Amigó – 12, Biosfer Teslab; Daniel Benítez-Ribas – 11, Hospital Clínic Barcelona -IDIBAPS; Nela Klein-González – 10, Hospital Clínic Barcelona -IDIBAPS; Erik Mihelic – 9, IDIBAPS; Valentin Ortiz-Maldonado – 14, Hospital Clínic Barcelona -IDIBAPS; Luis Rodríguez-Lobato – 15, Hospital Clínic Barcelona -IDIBAPS; andrea Vergara – 13, Hospital Clínic Barcelona -IDIBAPS; Valeria Brunello – 8, IDIBAPS; Roberto Martínez – 6, IDIBAPS; Elisa rubio – 7, Hospital Clínic Barcelona; Maria Val-Casals – 5, IDIBAPS; Marta Español-Rego – 4, Hospital Clínic Barcelona; Neus Martínez-Micaelo – 3, Biosfer Teslab; Aina Oliver-Caldés – 2, Hospital Clínic Barcelona -IDIBAPS; Mireia Uribe-Herranz – 1, Hospital Clínic Barcelona -IDIBAPS

Abstract Text: Multiple myeloma is a hematologic malignancy that remains incurable despite advances in immunotherapies like CAR-T cell therapy. This study investigates the role of gut microbiota in clinical outcomes for multiple myeloma patients treated with the humanized BCMA-directed CAR-T therapy, ARI0002h. Gut microbial metabolites, particularly succinate, were associated with CAR-T cell phenotypes and persistence. In CAR-T cell cultures, higher succinate levels correlated positively with CD4+ central memory cells, enhancing respiratory capacity. In a murine myeloma model, a diet increasing intestinal succinate levels improved CAR-T cell persistence and tumor control. Furthermore, specific bacterial taxa like Acidaminococcaceae, Monoglobaceae, or Akkermansiaceae and metabolites like tyrosine associated with CAR-T cell clinical outcomes. These microbial profiles were integrated into predictive response models that identified patients likely to achieve a complete response by day 100 and 180 post-infusion. Additionally, a response improvement model effectively identified patients likely to improve their response from a partial to a complete response by day 100 post-infusion These findings suggest that gut microbiota correlates with CAR-T cell therapy efficacy and can be a valuable tool for risk prediction.