Immune-Cell Numbers Determine Combination Immunotherapy Response in Melanoma Patients

The Journal of Clinical Investigation Insight recently published a study that analyzed 112 different melanoma tumors in attempt to correlate partially exhausted cytotoxic lymphocytes (peCTLs) and regulatory T lymphocyte (Treg) levels with response to combination immunotherapy.

The patients were treated with anti-programmed death 1 (PD-1) monotherapy or combination therapy and their responses, Treg levels, and demographics were compared. PD-1 inhibition activates the peCTLs and can induce tumor regression.

“We previously showed that the peCTL fraction predicts response to anti—PD-1 monotherapy,” the authors wrote. “Here, we sought to correlate peCTL and Treg levels with response to combination immunotherapy, and with demographic/disease characteristics, in metastatic melanoma patients.”

The study found that low peCTL correlated with the female sex and liver metastasis, but not with lactate dehydrogenase, tumor stage, or age. Patients with low peCTL who were given combination therapy showed higher overall response rates than patients who received the monotherapy. However, in patients with high peCTL, overall response rates to anti-PD-1 monotherapy and combination therapy were similar. The researcher had defined low versus high peCTL (≤20% vs >20%) during a previous study.

“Using this cutoff, derived from our previous analysis in patients treated with anti—PD-1 monotherapy, we found that low-peCTL patients had increased response rates with combination checkpoint blockade, while high-peCTL patients had equivalent response rates with either combination or monotherapy,” the researchers wrote. “Taken together, these results suggest that fewer tumor-infiltrating peCTLs are required to achieve a response to ipilimumab/nivolumab combination therapy.”

The research concluded that fewer tumor-infiltrating peCTLs may be necessary to achieve a response to combination immunotherapy. The revealed correlation of low peCTL among women with liver metastasis demonstrates the need for further studies for new specific therapies to be developed that are personalized for certain host factors.

“There is a complex interplay between the environment, the microbiome, the host immune system, and the tumor. The results presented here provide a framework with which we can begin to understand why specific patient subsets have a paucity of tumor-infiltrating peCTLs and thus a lower likelihood of responding to immune checkpoint blockade,” the authors concluded.