Generation of chimeric antigen receptor T cells targeting p95HER2 in solid tumors
The redirection of T lymphocytes against tumor-associated or tumor-specific antigens, using bispecific antibodies or chimeric antigen receptors (CAR), has shown therapeutic success against certain hematological malignancies. However, this strategy has not been effective against solid tumors. Here, we describe the development of CAR T cells targeting p95HER2, a tumor-specific antigen found in HER2-amplified solid tumors. These CAR T cells display robust activity against p95HER2-expressing cell lines but demonstrate limited efficacy against patient-derived xenografts. As p95HER2 is invariably detectable on tumor cells that overexpress HER2, but not those that express HER2 at normal levels, we arm p95HER2-specific CAR T cells with affinity-tuned bispecific antibodies against HER2 and CD3 in order to redirect them only to HER2-amplified cells. The combination of p95HER2.CAR T cells and HER2 x CD3 bispecific antibodies lead to a complete regression in three HER2-positive, patient-derived mouse xenografts tumor models. This combination represents a promising strategy to redirect T cells against a subset of HER2-positive tumors.
Authors
- Silvia Martin Lluesma (ORCID: https://orcid.org/0000-0001-7491-1876)
- Jolanta Gago (ORCID: https://orcid.org/0009-0007-2317-1629)
- Vicente Peg (ORCID: https://orcid.org/0000-0002-5203-6166)
- Susana Maqueda-Marcos
- Vanesa Nogales (ORCID: https://orcid.org/0000-0002-4905-5278)
- Vladimir Galvao (ORCID: https://orcid.org/0009-0007-8139-8215)
- Laia Foradada (ORCID: https://orcid.org/0000-0002-0589-4360)
- Irene Rius Ruiz (ORCID: https://orcid.org/0000-0002-6097-7572)
- Ariadna Grinyo i Escuer (ORCID: https://orcid.org/0000-0003-0185-2734)
- Macarena Román Alonso (ORCID: https://orcid.org/0000-0001-8128-9528)
- Marta Escorihuela (ORCID: https://orcid.org/0000-0001-9074-2339)
- Laura Soucek (ORCID: https://orcid.org/0000-0002-4750-7971)
- Elena Garralda (ORCID: https://orcid.org/0000-0002-4412-7842)
- Sandra Pérez‐Ramos (ORCID: https://orcid.org/0000-0002-3612-4027)
- Ekkehard Moessner
- Santiago Duro‐Sánchez (ORCID: https://orcid.org/0000-0002-3829-7562)
- Christian Klein (ORCID: https://orcid.org/0000-0001-7594-7280)
- Martín Espinosa-Bravo (ORCID: https://orcid.org/0000-0002-4293-3875)
- Santiago Escrivá-de-Romaní (ORCID: https://orcid.org/0000-0001-7816-7589)
- Joaquı́n Arribas (ORCID: https://orcid.org/0000-0002-0504-0664)
- Irene Braña (ORCID: https://orcid.org/0000-0002-1068-9601)
- Cristina Saura (ORCID: https://orcid.org/0000-0001-8296-5065)
- Marta Bort-Brusca
Institutions
- Roche (Switzerland) (CH)
- Universidad San Pablo CEU (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Hebron University (PS)
- Universitat Autònoma de Barcelona (ES)
- Universitat Pompeu Fabra (ES)
- Vall d'Hebron Institut de Recerca (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Hospital Del Mar (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Vall d'Hebron Institute of Oncology (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-18
- DOI
- https://doi.org/10.1038/s41467-024-53265-7
- Citations
- 6
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 1.70
Funders
- Breast Cancer Research Foundation
- Fundación BBVA
- Fundación Cellex
- European Federation of Pharmaceutical Industries and Associations
- Centres de Recerca de Catalunya
- European Commission
- Fundación Científica Asociación Española Contra el Cáncer
- Generalitat de Catalunya
- Banco Bilbao Vizcaya Argentaria
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación