Generation of chimeric antigen receptor T cells targeting p95HER2 in solid tumors
Year: 2024
Type: article
Abstract: 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. Chimeric antigen receptor T (CAR-T) cell therapy is efficient in certain haematologic malignancies, but clinical success in solid tumours has been hampered by scarcity of tumour-specific antigens. Here authors show that combination therapy using CAR T cells targeting p95HER2 and bispecific antibodies against HER2 and CD3 consistently leads to complete regression in HER2-positive, patient-derived xenografts tumours in mouse models.
Source: Nature Communications
Authors: Macarena Román Alonso, Ariadna Grinyó-Escuer, Santiago Duro-Sánchez, Irene Rius-Ruiz, Marta Bort-Brusca, Marta Escorihuela, Susana Maqueda-Marcos, Sandra Pérez-Ramos, Judit Gago, Vanesa Nogales, Martín Espinosa-Bravo, Vicente Peg, Santiago Escrivá-de-Romaní, Laia Foradada, Laura Soucek, Irene Braña, Vladimir Galvao, Silvia Martín-Lluesma, Ekkehard Moessner, Christian Klein, Elena Garralda, Cristina Saura, Joaquín Arribas
Institutions: Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Cáncer, Vall d'Hebron Institute of Oncology, Hospital del Mar Research Institute, Universitat Pompeu Fabra, Vall d'Hebron Hospital Universitari, Institució Catalana de Recerca i Estudis Avançats, Universidad San Pablo CEU, Roche (Switzerland)
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,790
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
Awards: G181761721, Immune-Image: Specific Imaging of Immune Cell Dynamics Using Novel Tracer Strategies, G2262748287, G2299438251, Inmunoterapia contra tumores HER2 positivos, G3005324705, G3088702384, G3203138580, G3480869486, G3681454997, G4042783231, Immune4ALL. Explorando la viabilidad de biomarcadores predictivos y farmacodinámicos de inmunoterapia en tumores sólidos, G425668148, G4634382728, G4688950647, G5852091828, G6656126374, G7084143925
OpenAlex ID: W4404486737