Tumor Immune Profiling-Based Neoadjuvant Immunotherapy for Locally Advanced Melanoma

Abstract

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.

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Acknowledgment

We gratefully acknowledge the patients who participated in this study. This work was supported by grants to Michael D. Rosenblum (NIH DP2-AR068130, K08-AR062064, AR066821 Burroughs Wellcome CAMS-1010934), Adil I. Daud (Amoroso and Cook fund, Parker Institute for Cancer Immunotherapy), and Lauren S. Levine (Conquer Cancer Foundation Young Investigator Award CA-0122026). Kelly M. Mahuron was supported by the NIH T32 training grant in Gastrointestinal Surgery T32DK007573.

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Correspondence to Adil I. Daud MBBS.

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Alain P. Algazi discloses institutional research funding from Novartis, Merck, BMS OncoSec, Acerta, AstraZeneca, MedImmune, Tessa, Celldex, and Celgene; consulting with stock options for Oncosec and Valitor; paid advisory board positions for Array and Regeneron; and an unpaid advisory role with Sensei Biotherapeutics. Adil I. Daud discloses research funding from the Amoroso and Cook fund, Parker Institute for Cancer Immunotherapy, Novartis, Merck, BMS, Incyte, AbbVie, OncoSec, Xencor, Pfizer, Roche/Genentech, and Exelixis; Advisory Board participation from Amgen, Array, and Roche/Genentech; and stock ownership in Trex Bio and Pionyr Immunotherapeutics. Matthew F. Krummel is the founder and board member of Pionyr Immunotherapeutics. Lauren S. Levine has received research funding from the Conquer Cancer Foundation CA-0122026. Kelly M. Mahuron received support by the NIH T32 training grant in Gastrointestinal Surgery T32DK007573. Michael D. Rosenblum is a consultant with equity ownership for Trex Bio, holds equity in Sitryx Bio, and has received funding on grants NIH DP2-AR068130, K08-AR062064, AR066821 Burroughs Wellcome CAMS-1010934. Matthew H. Spitzer discloses research funding from Genentech/Roche, Pfizer, Valitor Inc., and Bristol-Myers Squibb, and is a paid consultant for Five Prime Therapeutics, Ono Pharmaceutical, and January, Inc. Katy K. Tsai discloses institutional research funding from BMS, Parker Institute for Cancer Immunotherapy, Oncosec, and Regeneron. The remaining authors have no conflicts of interest.

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Levine, L.S., Mahuron, K.M., Tsai, K.K. et al. Tumor Immune Profiling-Based Neoadjuvant Immunotherapy for Locally Advanced Melanoma. Ann Surg Oncol 27, 4122–4130 (2020). https://doi.org/10.1245/s10434-020-08648-7

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