Generation of chimeric antigen receptor T cells targeting p95HER2 in solid tumors

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 and Joaquín Arribas ()
Additional contact information
Macarena Román Alonso: Vall d’Hebron Barcelona Hospital Campus
Ariadna Grinyó-Escuer: Vall d’Hebron Barcelona Hospital Campus
Santiago Duro-Sánchez: Vall d’Hebron Barcelona Hospital Campus
Irene Rius-Ruiz: Vall d’Hebron Barcelona Hospital Campus
Marta Bort-Brusca: Hospital del Mar Research Institute
Marta Escorihuela: Vall d’Hebron Barcelona Hospital Campus
Susana Maqueda-Marcos: Vall d’Hebron Barcelona Hospital Campus
Sandra Pérez-Ramos: Vall d’Hebron Barcelona Hospital Campus
Judit Gago: Vall d’Hebron Barcelona Hospital Campus
Vanesa Nogales: Hospital del Mar Research Institute
Martín Espinosa-Bravo: Vall d’Hebron University Hospital
Vicente Peg: Vall d’Hebron University Hospital
Santiago Escrivá- de-Romaní: Vall d’Hebron Institute of Oncology (VHIO)
Laia Foradada: Peptomyc S.L
Laura Soucek: Vall d’Hebron Barcelona Hospital Campus
Irene Braña: Vall d’Hebron Institute of Oncology (VHIO)
Vladimir Galvao: Vall d’Hebron Institute of Oncology (VHIO)
Silvia Martín-Lluesma: Vall d’Hebron Barcelona Hospital Campus
Ekkehard Moessner: Roche Pharma Research and Early Development
Christian Klein: Roche Pharma Research and Early Development
Elena Garralda: Vall d’Hebron Institute of Oncology (VHIO)
Cristina Saura: Vall d’Hebron Institute of Oncology (VHIO)
Joaquín Arribas: Vall d’Hebron Barcelona Hospital Campus

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53265-7

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