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Updated: Jun 7, 2025
Generation of Human Chimeric Antigen Receptor Regulatory T Cells
Published on: January 3, 2025
Generation of chimeric antigen receptor T cells targeting p95HER2 in solid tumors
Macarena Román Alonso1,2,3, Ariadna Grinyó-Escuer1,2,3, Santiago Duro-Sánchez1,2,3,4
1Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, 08035, Spain.
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.
Insights
New CAR T-cells targeting p95HER2 show promise for solid tumors. Combining these engineered T-cells with bispecific antibodies achieved complete tumor regression in HER2-positive models.
Area of Science:
- Immunotherapy
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is effective for hematological cancers but not solid tumors.
- Targeting tumor-specific antigens is a key strategy for improving CAR T-cell therapy efficacy.
Purpose of the Study:
- To develop and evaluate CAR T-cells targeting p95HER2, a tumor-specific antigen in HER2-amplified solid tumors.
- To enhance the specificity and efficacy of CAR T-cells for HER2-positive solid tumors.
Main Methods:
- Development of CAR T-cells engineered to target the p95HER2 antigen.
- Arming p95HER2-specific CAR T-cells with affinity-tuned HER2 x CD3 bispecific antibodies.
- Testing the combination therapy in HER2-positive patient-derived xenograft mouse models.
Main Results:
- p95HER2-specific CAR T-cells demonstrated activity against p95HER2-expressing cell lines.
- The combination of p95HER2 CAR T-cells and HER2 x CD3 bispecific antibodies resulted in complete tumor regression in three different HER2-positive xenograft models.
- The affinity-tuned bispecific antibodies successfully redirected T-cells specifically to HER2-amplified tumor cells.
Conclusions:
- The combination of p95HER2-specific CAR T-cells and HER2 x CD3 bispecific antibodies is a promising strategy for treating a subset of HER2-positive solid tumors.
- This approach enhances T-cell redirection to target HER2-amplified cancer cells, overcoming limitations of previous CAR T-cell strategies.
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