Login / Signup

Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo.

Laura Díez-AlonsoAïda FalgasJavier Arroyo-RódenasPaola A RomencínAlba Martínez-MorenoMarina Gómez-RoselBelén BlancoAnaïs Jiménez-ReinosoAndrea MayadoAlba Pérez-PonsOscar Aguilar-SopeñaÁngel Ramírez-FernándezAlejandro Segura-TudelaLorena Perez-AmillAntonio Tapia-GalisteoCarmen Domínguez-AlonsoLaura Rubio-PérezMaria JaraFrancisco SoléOana HangiuLaura AlmagroÁngela AlbitrePetronila PenelaLaura SanzEduardo AnguitaAntonio ValeriAlmudena García-OrtizPaula RioManel JuanJoaquín Martínez-LópezPedro Roda-NavarroBeatriz Martin-AntonioAlberto OrfaoPablo MenéndezClara BuenoLuis Alvarez-Vallina
Published in: Science translational medicine (2024)
Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)-directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell-limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.
Keyphrases