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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Tuesday, April 23, 2024
A team of researchers studying the benefits of immune checkpoint inhibition in treating triple-negative breast cancer has prioritized five chemotherapy agents for further study because of their ability to enhance T-cell–mediated cytotoxicity at multiple doses and multiple timepoints: paclitaxel, bleomycin sulfate, kinesin inhibitors, ABT-751, and etoposide. Ann Richmond, PhD, of Vanderbilt University, Nashville, and colleagues found that low doses of these agents did not appear to negatively affect CD8-positive T-cell proliferation, whereas high doses may have deleterious effects on CD8-positive T-cell functioning. The investigators are currently exploring the dose dependency of MHC-I and MHC-II induction, as well as the minimum dose required to cause immunogenic cell death. The team presented their findings at the American Association for Cancer Research (AACR) Annual Meeting 2024 (Abstract LB082/18).
“The results from the KEYNOTE-355 and KEYNOTE-522 trials led to the approvals of anti–PD-1 in combination with physician’s choice chemotherapy for triple-negative breast cancer in adjuvant and neoadjuvant settings. However, few patients achieve a durable response, and there remains a need to optimize combination strategies to enhance the benefits of immune checkpoint inhibition,” the investigators noted. “[Our results] provide mechanistic insight into potential new chemotherapy partners to enhance anti–PD-1 efficacy [in this population] and suggest benefit to further investigating the immunostimulatory potential of low-dose chemotherapy.”
The researchers developed a high-throughput co-culture screening assay to identify compounds that may enhance T-cell–mediated cytotoxicity; they included co-cultures of three cell types: mKate2-labeled PyMT tumor cells expressing the OVA antigen, BPF-labeled PyMT cells, and CD8-positive OT-1 T cells. They evaluated more than 400 U.S. Food and Drug Administration–approved compounds or agents under investigation for oncology indications at five concentrations (3 µM–12 nM) and across three points in time (24 hours, 48 hours, and 72 hours), assessing cell viability via image analysis at each timepoint. Enhanced cell death in the PyMT-OVA cells compared with the non-OVA PyMT cells was considered evidence of enhanced T-cell–mediated cytotoxicity.
Disclosure: The study authors reported no conflicts of interest.
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