The clinical challenge for treating HER2 (human epidermal growth factor receptor 2)-low breast cancer is the paucity of actionable drug targets. However, the discovery of immune checkpoint inhibitors has made immunotherapy an emerging new treatment modality for breast cancer. Moreover, several chemotherapeutic agents are known to induce immunogenic cell death by activating the immune system. Therefore, we hypothesized that modulating the tumour microenvironment using trastuzumab and or trastuzumab deruxtecan (T-Dxd) in breast organoids co-cultured with T-cells might enhance the response to immunotherapy.
We established a panel of HER2-low breast cancer patient-derived organoids (PDOs), recapitulating the derived tumour. These PDOs were cocultured with immune cells (T- cells and Natural killer cells (NK cells)) and treated with T-Dxd and or trastuzumab in combination with durvalumab. Levels of cytotoxic markers were assessed using flow cytometry and cytokine assays.
Our findings revealed synergistic effects in HER2-low BC patient-derived organoids when treated with T-Dxd and or trastuzumab in combination with durvalumab. We also observed antibody-dependent cellular cytotoxicity (ADCC) response with trastuzumab in combination with durvalumab. These results highlight the need to develop a combination treatment of PD-1/PD-L1 inhibitors with targeted therapies, and other immunotherapies to maximize clinical efficacy.
Altogether, despite preliminary, these findings support the rationale for combining anti-HER2 therapies with immunotherapy in HER2-low BC patients.
M. Arshad.
King's College London.
The author has declared no conflicts of interest.