Tumor Immune Profiling-Based Neoadjuvant Immunotherapy for Locally Advanced Melanoma

• Published in: Annals of surgical oncology 2020-10, Vol.27 (11), p.4122-4130
• Main Authors: Levine, Lauren S., Mahuron, Kelly M., Tsai, Katy K., Wu, Clinton, Mattis, Daiva M., Pauli, Mariela L., Oglesby, Arielle, Lee, James C., Spitzer, Matthew H., Krummel, Matthew F., Algazi, Alain P., Rosenblum, Michael D., Alvarado, Michael, Daud, Adil I.
• Format: Article
• Language: English
• Subjects: Anaphylaxis; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - immunology; CTLA-4 protein; Cytotoxicity; Flow cytometry; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Kaplan-Meier Estimate; Lymphocytes T; Medicine; Medicine & Public Health; Melanoma; Melanoma - immunology; Melanoma - therapy; Metastases; Neoadjuvant Therapy; Oncology; Patients; PD-1 protein; Pneumonitis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Solid tumors; Surgery; Surgical Oncology; Terminology; Tumor Microenvironment
• ISSN: 1068-9265; 1534-4681
• DOI: 10.1245/s10434-020-08648-7

Background The frequency of “exhausted” or checkpoint-positive (PD-1 + CTLA-4 + ) cytotoxic lymphocytes (Tex) in the tumor microenvironment is associated with response to anti-PD-1 therapy in metastatic melanoma. The current study determined whether pretreatment Tex cells in locally advanced melanoma predicted response to neoadjuvant anti-PD-1 blockade. Methods Pretreatment tumor samples from 17 patients with locally advanced melanoma underwent flow cytometric analysis of pretreatment Tex and regulatory T cell frequency. Patients who met the criteria for neoadjuvant checkpoint blockade were treated with either PD-1 monotherapy or PD-1/CTLA-4 combination therapy. Best overall response was evaluated by response evaluation criteria in solid tumors version 1.1, with recurrence-free survival (RFS) calculated by the Kaplan–Meier test. The incidence and severity of adverse events were tabulated by clinicians using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. Results Of the neoadjuvant treated patients, 10 received anti-PD-1 monotherapy and 7 received anti-CTLA-4/PD-1 combination therapy. Of these 17 patients, 12 achieved a complete response, 4 achieved partial responses, and 1 exhibited stable disease. Surgery was subsequently performed for 11 of the 17 patients, and 8 attained a complete pathologic response. Median RFS and overall survival (OS) were not reached. Immune-related adverse events comprised four grade 3 or 4 events, including pneumonitis, transaminitis, and anaphylaxis. Conclusion The results showed high rates of objective response, RFS, and OS for patients undergoing immune profile-directed neoadjuvant immunotherapy for locally advanced melanoma. Furthermore, the study showed that treatment stratification based upon Tex frequency can potentially limit the adverse events associated with combination immunotherapy. These data merit further investigation with a larger validation study.