Levine LS, Mahuron KM, Tsai KK, et al. - Given that the frequency of “exhausted” or checkpoint-positive (PD-1⁺CTLA-4⁺) cytotoxic lymphocytes (Tex) in the tumor microenvironment is correlated with response to anti-PD-1 therapy in metastatic melanoma, researchers ascertained if pretreatment Tex cells in locally advanced melanoma anticipated response to neoadjuvant anti-PD-1 blockade. Pretreatment tumor samples from 17 individuals with locally advanced melanoma had flow cytometric analysis of pretreatment Tex and regulatory T cell frequency. Patients who met the neoadjuvant checkpoint blockade criteria were treated either PD-1 monotherapy or PD-1/CTLA-4 combination therapy. The findings showed high levels of objective response, RFS, and OS for locally advanced melanoma patients undergoing immune profile-directed neoadjuvant immunotherapy. In addition, the authors revealed that Tex-frequency treatment stratification can potentially limit adverse events (ie, pneumonitis, transaminitis, and anaphylaxis) associated with combination immunotherapy. With a larger validation study, such data merit further investigation.