1662MO - Longitudinal analysis of circulating immune cell subsets in melanoma patients (pts) treated with neo-adjuvant ipilimumab (ipi) & nivolumab (nivo)

Background

Immune checkpoint inhibition (ICI) has improved outcomes for pts with stage II-IV melanoma, although drug resistance and/or immune-related adverse events (irAEs) impact the majority of pts. Here we present a longitudinal analysis of immune cell subsets and correlation with pathological response and irAEs in pts on the neoadjuvant OpACIN-neo & PRADO trials (NCT02977052).

Methods

All pts with resectable stage III melanoma received combination neoadjuvant therapy with ipi and nivo for 6 weeks followed by surgical resection of the involved lymph node basin or index node. Paired pre (baseline) and post (wk 6) treatment PBMCs were comprehensively profiled using mass cytometry (CyTOF).

Results

Of 71 pts included, 53 (75%) had a pathological response (pCR, near-pCR and pPR) and 60 (85%) experienced at least one irAE; 16 (23%) Gd 3 or higher. Irrespective of clinical outcome, treatment was associated with a decreased frequency (% total CD45+) of both CD4+ and CD8+ naive T cells (CD45RA+CCR7+) (P< 0.0001, P= 0.0006) and an increased frequency of effector memory T cell (Tem) populations (CD45RA- CCR7-) (P=0.0165, P=0.0096). Significantly, gut homing CD8+ Tem (IntegrinB7+ CCR9+) increased with treatment (P< 0.0001). Pathological response was associated with increased Th1 (P=0.0055) and decreased Th2 (P=0.0037) populations, as well as a decreased frequency of circulating CD25+ FoxP3+ regulatory T cells (Tregs) (P= 0.0016). Pts that developed Gd 3 or higher irAEs had a significant reduction in both the frequency of Tregs (P=0.0293) and the ratio of Tregs to CD8+ Tem (P=0.0290) at week 6, however 75% (12/16) received immunosuppressants before/at wk 6.

Conclusions

Neoadjuvant treatment with ipilimumab and nivolumab promotes the systemic expansion of effector T cell populations including gut homing subsets. In particular, response is associated with an increase in circulating type 1 T cell subsets and a reduction in Tregs. Understanding systemic immune dynamics during treatment could inform the development of therapeutic strategies and interventions that increase treatment efficacy, reduce irAE occurrence, and allow for more targeted treatment of irAEs.

Clinical trial identification

NCT02977052.

Editorial acknowledgement

Legal entity responsible for the study

Melanoma Institute Australia & The Netherlands Cancer Institute.

Funding

Melanoma Institute Australia, The University of Sydney.

Disclosure

A.M. Menzies: Financial Interests, Personal, Advisory Board, advisory board: BMS, MSD, Novartis, Roche, Pierre Fabre, QBiotics. R.P.M. Saw: Financial Interests, Personal, Invited Speaker: Bristol Myers Squib, Novartis; Financial Interests, Personal, Advisory Board: Novartis, MSD, Qbiotics; Financial Interests, Personal, Other, On Faculty, support of University of Sydney salary: Melanoma Institute Australia. C.U. Blank: Financial Interests, Institutional, Advisory Board: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre; Financial Interests, Personal, Expert Testimony: Third Rock Ventures; Financial Interests, Personal, Stocks/Shares: Uniti Cars, co-founder Immagene BV; Financial Interests, Institutional, Invited Speaker: BMS, Novartis, NanoString, 4SC. R.A. Scolyer: Financial Interests, Personal, Advisory Role, fees for professional services: Evaxion, Provectus Biopharmaceuticals Australia, F. Hoffmann-La Roche Ltd., Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, Amgen Inc., Bristol Myers Squibb, Myriad Genetics, GlaxoSmithKline. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc., Amgen Inc., Array Biopharma Inc., Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Merck Sharpe & Dohme (Australia) Pty Limited, Novartis Pharma AG, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, Regeneron Pharmaceuticals Inc.; Financial Interests, Personal, Advisory Board, Consultant Advisor: Highlight Therapeutics S.L. All other authors have declared no conflicts of interest.