Preclinical Trial Explores Anti–PD-1 Strategies for Triple-Negative Breast Cancer
Posted: Thursday, January 7, 2021
Results of preclinical work using humanized mouse models indicate that in a specific subgroup of triple-negative breast cancer, the use of the adenovirus interleukin-12 (IL-12) plus docetaxel followed by anti–PD-1 therapy may be therapeutically beneficial. Jenny Chang, MD, of Houston Methodist Research Institute, and colleagues presented their findings during the 2020 Society for Immunotherapy of Cancer (SITC) Annual Meeting (Abstract 437) and also published them in the Journal for ImmunoTherapy of Cancer.
Although triple-negative breast cancer expresses high levels of PD-L1, benefits gained in human patients from checkpoint inhibitor therapy have been modest, the scientists described. “We hypothesized that the induction of cell death [with] docetaxel, coupled with an immunoactivated milieu [of] locally injected adenovirus IL-12, would prime the tumor to respond to anti–PD-1 therapy,” they said.
The team injected the mammary fat pads of mice with two syngeneic cell lines, E0771 and 4T1. Compared with mice who received a single therapy, the mice who received docetaxel, adenovirus IL-12, and anti–PD-1 therapy developed more tumor-infiltrating lymphocytes. Significantly, however, differences emerged between the E0771 and 4T1 triple-therapy mice: The 4T1 mice had increased infiltration of CD8 and CD4 effector cells; significantly decreased neutrophils; downregulation of protumorigenic cytokines including IL-6, LIF, and IL-1b; and downregulation of anti-inflammatory cytokines including IL-9 and IL-10. In comparison, the E0771 mice experienced higher levels of IL-6, IL-1b, LIF, KC, TNF-alpha, and VEGF levels at the end of the study than they did at the beginning. The triple-combination E0771 mice did survive a mean of 18 days longer than the mice treated with E0771 mice treated with a single therapy.
To learn why the combination seemed to work better in the 4T1 mice, “we are actively studying the molecular difference between the two models,” stated Dr. Chang and colleagues. Also, they are “investigating the clinical relevance of these markers using our extensive repertoire of patient-derived xenografts in a humanized mice model.”
Disclosure: For full disclosures of the study authors, visit jitc.bmj.com.