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

Author:

Díez-Alonso Laura123ORCID,Falgas Aïda45ORCID,Arroyo-Ródenas Javier123ORCID,Romencín Paola A.4ORCID,Martínez Alba4ORCID,Gómez-Rosel Marina123ORCID,Blanco Belén1235ORCID,Jiménez-Reinoso Anaïs123ORCID,Mayado Andrea678ORCID,Pérez-Pons Alba678ORCID,Aguilar-Sopeña Óscar910ORCID,Ramírez-Fernández Ángel123ORCID,Segura-Tudela Alejandro123ORCID,Perez-Amill Lorena11ORCID,Tapia-Galisteo Antonio123ORCID,Domínguez-Alonso Carmen123ORCID,Rubio-Pérez Laura12312ORCID,Jara Maria678ORCID,Solé Francesc4ORCID,Hangiu Oana12,Almagro Laura910ORCID,Albitre Ángela1314ORCID,Penela Petronila1314ORCID,Sanz Laura15ORCID,Anguita Eduardo1617ORCID,Valeri Antonio1819ORCID,García-Ortiz Almudena1819ORCID,Río Paula5202122ORCID,Juan Manel511232425,Martínez-López Joaquín51819,Roda-Navarro Pedro910,Martín-Antonio Beatriz26ORCID,Orfao Alberto678ORCID,Menéndez Pablo4572728ORCID,Bueno Clara457ORCID,Álvarez-Vallina Luis12312ORCID

Affiliation:

1. Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain.

2. Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain.

3. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.

4. Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain.

5. Red Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain.

6. Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), Universidad de Salamanca, 37007 Salamanca, Spain.

7. Centro de Investigación Biomédica en Red-Oncología (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain.

8. Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain.

9. Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.

10. Lymphocyte Immunobiology Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), 28041 Madrid, Spain.

11. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, 08036 Barcelona, Spain.

12. Chair for Immunology UFV/Merck, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, 28223 Madrid, Spain.

13. Centro de Biología Molecular Severo Ochoa CSIC-UAM, 28049 Madrid, Spain.

14. Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain.

15. Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, 28222 Madrid, Spain.

16. Department of Medicine, Medical School, Universidad Complutense de Madrid, 28040 Madrid, Spain.

17. Department of Hematology, IML, IdISSC, Hospital Clínico San Carlos, 28040 Madrid, Spain.

18. H12O-CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 28029 Madrid, Spain.

19. Department of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain.

20. Division of Hematopoietic Innovative Therapies, Biomedical Innovation Unit, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain.

21. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain.

22. Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain.

23. Servei d’Immunologia, Hospital Clínic de Barcelona, 08036 Barcelona, Spain.

24. Plataforma Immunoterapia, Hospital Sant Joan de Deu, 08950 Barcelona, Spain.

25. Universitat de Barcelona, 08007 Barcelona, Spain.

26. Department of Experimental Hematology, Instituto de Investigación Sanitaria Fundación Jiménez Diaz, (IIS-FJD), Universidad Autónoma de Madrid, 28040 Madrid, Spain.

27. Department of Biomedicine, School of Medicine, Universitat de Barcelona, 08007 Barcelona, Spain.

28. Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

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