Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma

Abstract

Purpose: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma.

Patients and methods: Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS).

Results: Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs.

Conclusions: With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167.

Figure 1.. Clinical trial design and efficacy measures.

(A) Schematic depiction of the treatment and correlative sample collection schedule implemented in this clinical trial. (B) Waterfall plot depicting best overall responses (BOR) according to RECIST v1.1 criteria. (C) Spider plot depicting changes in target lesion size over time. (D) Comparisons of best of overall response, overall response rate, and disease control rate. (E) Survival curve showing the probability of progression free survival analyzed using the Kaplan-Meyer method, with data censored at first sign of progression, death, or last known follow-up. (F) Representative images from computerized tomography (CT) scans showing responses in the labeled organs.

Figure 2.. The combination of ATRA and pembrolizumab decreases the number of circulating PMN-MDSCs.

(A) Representative flow cytometric gating strategy to identify and quantify circulating MDSC subsets. (B) The suppressive function of MDSCs depicted as a percent change in T cell proliferation from T cells stimulated with anti-CD3/CD28 comparing HLA-DR+ myeloid cells (DR+) to MDSCs. Connecting lines indicate paired analysis from each patient. (C) Comparisons of the number of circulating MDSC subsets in pre-treatment (pre-TX) and post-ATRA blood samples, from all patients (pts), responding (R) patients, and non-responding (NR) patients. Connecting lines indicate paired analysis from each patient. (D) Summary of the percent change from pre- to post-ATRA timepoints in myeloid cell populations. (E) Comparisons of number of circulating HLA-DR+ mature myeloid cells in all patients (pts), responding (R) patients, and non-responding (NR) patients. Colored box denotes the time when the patients were being treated with ATRA. * Denotes p < 0.05, ** p < 0.01, *** p < 0.001. Cycle 2 Day 0 (C2D0), Cycle 4 Day 0 (C4D0).

Figure 3.. The combination of ATRA and pembrolizumab promotes cytokine production and tumor-specific T cell activation.

(A) Analysis of circulating cytokine concentrations. (B) Comparisons of the frequency of tumor antigen-specific (NyESO, tyrosinase, and gp100) T cells, identified as CD8⁺CD107⁺IFNγ⁺ T cells. (C) Analysis of the number of circulating white blood cell populations from clinical complete blood count (CBC) testing. Colored box denotes the time when the patients were being treated with ATRA. * Denotes p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.