Distinct effect of neoadjuvant PD1 alone, PD1+IPI, and PD1+lenvatinib in the peripheral immune profile of melanoma patients (pts) and correlation with pathological (path) response.

9568 Background: Neoadjuvant immunotherapy (NeoIT) has significantly improved clinical outcomes for pts with macroscopic stage III resectable melanoma and is the current standard of care for these pts. Here, we analysed longitudinal peripheral immune profiles and their correlation with path response for 3 different PD1-based NeoIT regimens. Methods: Pts with macroscopic stage III resectable melanoma treated with neoadjuvant PD1-based regimens (PD1 alone, PD1+IPI and PD1+Lenvatinib) for 6 weeks, followed by surgery, were included. Cytometry by time-of-flight (CYTOF; 39-marker panel) was performed on peripheral blood mononuclear cells (PBMCs) at baseline and week 6 (wk 6; pre-surgery). Results: Of 64 pts included, 17 PD1 alone (7 [41%] had major pathological response [MPR; ≤ 10% of viable tumour cells at the surgical specimen]), 26 PD1+IPI (20 [77%] had MPR) and 21 PD1+Lenvatinib (12 [57%] had MPR). We analysed >200 peripheral immune cell types/phenotypes, and present the statistically significant treatment effects (from baseline to wk 6), overall and based on path response (MPR vs. non-MPR), in patients treated with PD1 alone, PD1+IPI and PD1+lenvatinib (see Table). Conclusions: IPI+PD1 and PD1+Lenvatinib induced stronger peripheral blood immune activation, compared with PD1 alone, irrespective of path response. There were differences in the MPR vs non-MPR pts, particularly for PD1 alone. A more in-depth analysis of the effects of these PD1-based regimens and their association with recurrence is underway to identify key immune cell types/phenotypes associated with response & resistance to NeoIT. Effect of neoadjuvant PD1 alone, PD1+IPI and PD1+lenvatinib in the peripheral immune profile of melanoma patients. Overall treatment effect MPR (vs. non-MPR) Non-MPR (vs. MPR) PD1 Increase in:- OX40+ / ICOS+ regulatory T cells (Tregs)- KI67+ ICOS+ CD4 T cells Increase in:- GZM+ CD4+ & CD8+ T cells- Double negative [CD27- IgD-] B cells Increase in:- Non-classic [CD14low+CD16++] HLA-DR+ monocytesDecrease in:- CD4 T effector memory cells- Th1 cells PD1+IPI Increase in:- Tregs- Activated [ICOS+ / LAG3+ / TIGIT+] CD4+ T cells- TIM3+ CD4+ & CD8+ T cells- Non-classic [CD14low+CD16++] monocytes- Cytotoxic [CD56dim CD16+] NK cellsDecrease in:- Stem-like [TCF7+] CD4+ & CD8+ T cells Increase in:- OX40+ / T-BET+ CD127- CD8+ T effector memory cells PD1+lenvatinib Similar changes seen with PD1+IPI, as well as an increase in:- Th1- Th17- CD8+ T effector memory cellsDecrease in:- Double negative [CD27- IgD-] B cells Increase in:- CD127- Tregs Increase in:- HLA-DR+ non-classic [CD14low+CD16++] monocytes