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T-cell co-stimulation in combination with targeting FAK drives enhanced anti-tumor immunity
Marta Canel1, David Taggart1, Andrew H Sims2
1Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Abstract:
Focal Adhesion Kinase (FAK) inhibitors are currently undergoing clinical testing in combination with anti-PD-1 immune checkpoint inhibitors. However, which patients are most likely to benefit from FAK inhibitors, and what the optimal FAK/immunotherapy combinations are, is currently unknown. We identify that cancer cell expression of the T-cell co-stimulatory ligand CD80 sensitizes murine tumors to a FAK inhibitor and show that CD80 is expressed by human cancer cells originating from both solid epithelial cancers and some hematological malignancies in which FAK inhibitors have not been tested clinically. In the absence of CD80, we identify that targeting alternative T-cell co-stimulatory receptors, in particular OX-40 and 4-1BB in combination with FAK, can drive enhanced anti-tumor immunity and even complete regression of murine tumors. Our findings provide rationale supporting the clinical development of FAK inhibitors in combination with patient selection based on cancer cell CD80 expression, and alternatively with therapies targeting T-cell co-stimulatory pathways.
Insights
Focal Adhesion Kinase (FAK) inhibitors show promise with immunotherapy. Cancer cell CD80 expression predicts response, while OX-40 and 4-1BB offer alternative combinations for enhanced anti-tumor immunity.
Area of Science:
- Oncology
- Immunology
- Cancer Therapeutics
Background:
- Focal Adhesion Kinase (FAK) inhibitors are being investigated alongside anti-PD-1 immune checkpoint inhibitors.
- Optimal patient selection and combination strategies for FAK inhibitors in cancer therapy remain unclear.
Purpose of the Study:
- To identify predictive biomarkers for FAK inhibitor efficacy.
- To explore alternative immunotherapy combinations with FAK inhibitors.
Main Methods:
- Investigated the role of cancer cell CD80 expression in sensitizing tumors to FAK inhibitors in murine models.
- Evaluated combinations of FAK inhibitors with OX-40 and 4-1BB agonists in CD80-negative tumors.
Main Results:
- Cancer cell expression of CD80 enhances sensitivity to FAK inhibitors in preclinical models.
- CD80 is found in human cancers, including solid epithelial and some hematological malignancies.
- In CD80-negative settings, FAK inhibition combined with OX-40 or 4-1BB agonists promoted significant anti-tumor immunity and tumor regression.
Conclusions:
- Cancer cell CD80 expression can guide patient selection for FAK inhibitor therapy.
- Targeting OX-40 or 4-1BB in combination with FAK inhibitors presents a viable strategy for enhancing anti-tumor immunity in specific patient groups.
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