Murine Study Suggests Novel I-O Combo May Be Effective in CRC

Combining a multiple-receptor tyrosine kinase inhibitor and a programmed cell death protein 1 (PD-1) inhibitor may be a potentially effective regimen for treating colorectal cancer (CRC), say early study findings published in Frontiers in Cell and Developmental Biology.

The murine study, which assessed the combination of foretinib (the TKI) and an anti–PD-1 antibody, found that the regimen enhanced antitumor activity, offering promise in a cancer that has seen less success with immunotherapies than others.

“The response rates of [immunotherapies] are higher than the traditional therapy protocols, but not all types of cancer can benefit from [immune checkpoint blockade]; only 20% to 40% of cancer patients have a favorable response, and CRC is at the lower end of the spectrum,” explained the researchers. “To enhance the antitumor effect, various trials have sought to establish combination treatments that utilize [immune checkpoint inhibitors] and other therapies, such as chemotherapy, targeted therapies, radiotherapy, and other immunotherapies.”

In the current study, the researchers found that the novel combination stumped tumor growth and improved tumor regression without relapse. In MC38 cells, there was complete tumor regression in half of 6 mice, with recurrent-free survival observed over 120 days.

When the dose was increased to 10 mg/kg from 5 mg/kg, the effect of foretinib was even stronger, demonstrating an 83% complete rate of tumor regression. According to the researchers, this finding suggests that the synergistic antitumor activity of the combination was foretinib dosage dependent.

In CT26 tumors, there was an observed 83% complete tumor clearance, as well as improved overall survival, verifying the responses seen in the MC38 cells.

The higher responses observed in the CT26 cells, explain the researchers, may be because these types of cells form highly immunogenic tumors, which have previously demonstrated higher responses to immunotherapy than MC38 tumors.

“The combination treatment also effectively reduced the metastasis of CT26-Luc cells to the lungs when compared with the monotherapies,” wrote the researchers. “Furthermore, the number of T cells were increased moderately, and there was a decrease in the number of [regulatory T cells], TAMs [tumor-associated macrophages], and M2 phenotype TAMs in the lungs after the combination therapy, which indicates that there was an amelioration of the immune microenvironment in the lungs.”

However, the researchers note that inhibitory effects of metastasis to the lung were poor in vivo, which they say suggests there may be additional relevant immune regulatory mechanisms in the tumor microenvironment of the lung.

“This investigation forms a rational basis for the further exploration of a foretinib/anti-PD-1 combination treatment strategy,” they concluded, “to enhance immunotherapy outcomes for CRC patients.”

Reference

Fu Y, Peng Y, Zhao S, et al. Combination foretinib and anti-PD-1 antibody immunotherapy for colorectal carcinoma. Front Cell Dev Biol. Published online July 8, 2021. doi:10.3389/fcell.2021.689727