Model predicts immunotherapy response in colon and GI cancers

The dynamics of circulating immune cells at the beginning of immunotherapy treatment can predict how a patient will respond to the therapy, according to a new study published in the Proceedings of National Academy of Science.

Although immunotherapy can treat a myriad of cancers, a large percentage of patients—approximately 40%—show no improvement. Consequently, a noninvasive method to gauge if immunotherapy will be effective early on during treatment is needed.

To that end, researchers at Translational Genomics Research Institute, Phoenix, AZ, in collaboration with scientists at the City of Hope, Duarte, CA, developed an ecological population model to elucidate the link between circulating white blood cells and patient response to immunotherapy. They used the model to analyze data obtained from a clinical trial of patients with advanced colorectal and other gastrointestinal cancers. 

Patients in the trial received a chemotherapy regimen followed by a combination of chemotherapy and immunotherapy. Specifically, patients received pembrolizumab, an anti-PD-L1 immunotherapy.

The researchers used this mathematical model to measure the strength of the interactions between the tumor’s response to immunotherapy and the immune cells’ dynamics. 

The result: “[We found] evidence of a strong tumor–circulating immune cell interaction in responder patients but not in those patients that progress on treatment,” they wrote. “Upon initiation of therapy, immune cell abundance increased rapidly in responsive patients, and once the peak level is reached, tumor burden decreased.”

The researchers also found that T-cells differentiate into more cytotoxic states.

Predator-prey relationship

Together, these findings indicated, for the first time, that there is a predator-prey relationship between circulating immune cell activity and the tumor’s response to immunotherapy. 

“In particular, ‘predator’ T cells showed increased differentiation and activity of interferon, a protein that exerts anti-tumor effects, during immunotherapy treatment in patients that respond to treatment,” said senior author Andrea Bild, PhD, professor, Division of Molecular Pharmacology, Department of Medical Oncology & Therapeutics Research at City of Hope.

These reactions were absent in nonresponder patients, she added.

The cancer–immune interaction model allowed Dr. Bild and colleagues to make predictions about which patient populations would benefit the most from immunotherapy. The model predicted that patients who have tumors with an immunosuppressive phenotype, such as those expressing high levels of PD-L1, would have fewer immune cells before treatment since immune cell proliferation is inhibited. The researchers expected that patients with a low peripheral blood mononuclear cell (PBMC) count would benefit from anti-PD-L1 immunotherapy—and, indeed, they observed lower PBMC abundances in patients who responded to treatment at the beginning of therapy. These patients had increased immune cell counts over the course of the therapy compared with decreased immune cell counts in nonresponders. 

The model also predicted that chemotherapy can be detrimental in some cases when used as a combination therapy with immunotherapy. While chemotherapy promotes tumor cell death and leads to the recruitment of immune cells, it also kills immune progenitor cells, which decreases the abundance of immune cells. The authors suggested that chemotherapy is a double-edged sword—high levels might reduce the effectiveness of immunotherapy, yet low levels won’t promote immune reactivation.

Test to predict immunotherapy response

Overall, this study demonstrates the presence of a predator-prey-like relationship between peripheral immune cell abundance and tumor size in patients that respond well to immunotherapy. While future studies are needed to confirm that peripheral immune cell phenotypes can be used as a biomarker, this research provides a foundation for the idea that immune cell phenotypes are a reliable way to predict patient response to immunotherapy.

“We believe there is potential to measure a tumor’s response to specific drugs using circulating immune cell dynamics, which are accessible and collected from a blood draw,” Dr. Bild said.

The researchers hope that a noninvasive test to measure immune-tumor interaction strength would lead to better personalized medicine for cancer patients, with the potential to improve overall outcomes.