Targeting MDSCs using ATRA: a phase I/II clinical trial combining pembrolizumab and all-trans retinoic acid for metastatic melanoma

2021 ◽  
Author(s):  
Richard Tobin ◽  
Dasha Cogswell ◽  
Victoria Vorwald ◽  
Dana Davis ◽  
Jessica Borgers ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Stage Iv ◽  
Suppressor Cells ◽  
Progression Free Survival ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Melanoma Patients

Abstract Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and are commonly associated with poor outcomes in melanoma patients treated with immune checkpoint inhibitors. Inducing the differentiation of MDSCs using all-trans retinoic acid (ATRA) alters their activity and reduces MDSC frequency. This trial seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in metastatic melanoma patients. In 24 stage IV melanoma patients, treatment with pembrolizumab Q3W plus the supplemental treatment of ATRA orally for three days surrounding each of the first four pembrolizumab infusions effectively lowered the frequency of circulating PMN-MDSCs and enhanced melanoma-specific T cell activity. The combination was well tolerated. Median progression free survival was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response. Targeting MDSCs remains a promising mechanism to enhance the efficacy of anti-PD-1 therapies and this combination merits further investigation.

Pembrolizumab and all-trans retinoic acid combination treatment of advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9536-9536
Author(s):  
Martin McCarter ◽  
Richard P. Tobin ◽  
Dasha T. Cogswell ◽  
Victoria M. Vorwald ◽  
Dana Davis ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Checkpoint Inhibitors ◽  
Stage Iv ◽  
Suppressor Cells ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Melanoma Patients ◽  
Poor Outcomes

9536 Background: Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and are commonly associated with poor outcomes in melanoma patients treated with immune checkpoint inhibitors. Inducing the differentiation of MDSCs using all-trans retinoic acid (ATRA) reduces MDSC frequency. This analysis seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in advanced melanoma patients. Methods: This single arm, single institution, phase I/II study (NCT03200847) enrolled 24 patients diagnosed with stage IV melanoma. Eligible patients were over the age of 18 and had not been previously treated anti-PD-1 therapy. Treatment consisted of 200mg Q3W pembrolizumab plus the supplemental treatment of 150 mg/m2 ATRA orally for 3 days surrounding each of the first four infusions of pembrolizumab, with patients continuing pembrolizumab for up to two years until confirmed disease progression or unacceptable toxicity. The primary endpoints were safety and reduction in circulating MDSCs. Secondary endpoints were overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) according to RECIST v1.1. Results: At data cut off (Feb, 2021) 22 patients were evaluable for tumor response. Median follow-up was 1.0 years (0.3-2 years). In general, the combination of pembrolizumab and ATRA was well tolerated. The most common treatment-related adverse events (AEs) were grade 1 or 2, including headache (22 pts, 92%), fatigue (18 pts, 75%), rash (16 pts, 66%), and nausea (8 pts, 33%), most of which corresponded with the 3-day course of ATRA treatment. Ten patients had grade 3 or higher AEs with most being common ICI-related AEs. The ORR was 60% and DCR was 83%. Six-month PFS rate was 62%. Excluding patients diagnosed with uveal melanoma (n = 2) the ORR was 72%, DCR was 86%, and the six-month PFS rate was 68%. Paired analysis showed sustained decreases in absolute numbers ( p = 0.002) and percentage ( p = 0.007) of circulating MDSCs (CD3-CD19-CD56-CD11b+CD33+HLA-DR-/low) 4-6 weeks after stopping ATRA. The study is ongoing and further data will be presented in the future. Conclusions: This study demonstrates that the combination of ATRA and pembrolizumab is well tolerated and suggests that reducing MDSCs with ATRA may enhance the efficacy of pembrolizumab. This strategy of targeting MDSCs in combination with pembrolizumab warrants further development. Research Funding: Merck. Clinical trial information: NCT03200847.

scholarly journals Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab

2018 ◽  
Vol 63 ◽  
pp. 282-291 ◽  
Author(s):  
Richard P. Tobin ◽  
Kimberly R. Jordan ◽  
William A. Robinson ◽  
Dana Davis ◽  
Virginia F. Borges ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Melanoma Patients

scholarly journals Treatment of Advanced Metastatic Melanoma

2021 ◽  
pp. 2021164S
Author(s):  
Pietro Quaglino ◽  
Paolo Fava ◽  
Luca Tonella ◽  
Marco Rubatto ◽  
Simone Ribero ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Survival Rates ◽  
National Health System ◽  
Stage Iv ◽  
Daily Practice ◽  
Long Term Results ◽  
Melanoma Patients

The introduction in clinical practice of new drug compounds both targeted therapies anti-BRAF and checkpoint inhibitors have largely improved our potential to manage advanced metastatic melanoma patients. This has led to a significant improvement in terms of response rates and particularly in the overall survival (OS). The long-term results of trials with follow-up data of patients treated with targeted or immunotherapies reported median OS rates around 24 months, with 5-year survival rates around 35-40%. As to the drugs currently available and reimbursed by the Italian National Health System, 3 combinations of anti-BRAF/anti-MEK inhibitors are available (dabrafenib/trametinib, vemurafenib/cobimetinib and the most recently introduced encorafenib/binimetinib). As for checkpoint inhibitors, first line immunotherapy is represented by anti-PD1 blockers (nivolumab and pembrolizumab), whilst the anti-CTLA-4 ipilimumab can be used as second line immunotherapy. The decision-making factors that define the best treatment approach in stage IV patients with metastatic melanoma include the mutation pattern, performance status, high/low tumor load, brain metastases, progression pattern (low/fast), and availability of clinical trials. This review will analyze the current therapeutic tools adopted for the treatment of metastatic melanoma patients. It will then focus on the latest results obtained by novel treatments (checkpoint inhibitors and targeted therapies) which can be used in the clinical daily practice.

scholarly journals Immune checkpoint inhibitors, endocrine adverse events, and outcomes of melanoma

2022 ◽  
Author(s):  
Hanna Karhapää ◽  
Siru Mäkelä ◽  
Hanna Laurén ◽  
Marjut Jaakkola ◽  
Camilla Schalin-Jäntti ◽  
...  
Keyword(s):  
Adverse Events ◽  
Treatment Outcomes ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Autoimmune Diabetes ◽  
Progression Free Survival ◽  
Electronic Patient Records ◽  
Melanoma Patients

Objective: Immune checkpoint inhibitors (ICI) can cause endocrine adverse events. However, endocrine AEs could be related to better treatment outcomes. Our aim was to investigate whether this holds true in a real-world setting of metastatic melanoma patients. Design: A retrospective single-institution study. Methods: We included 140 consecutive metastatic melanoma patients treated with ICI between January 2012 and May 2019. We assessed endocrine toxicity and best possible treatment outcomes from electronic patient records, including laboratory parameters, and radiological images. Results: Of the treated patients, 21 patients (15%) were treated with ipilimumab, 46 (33%) with nivolumab, 67 (48%) with pembrolizumab, and six (4%) with combination therapy (ipilimumab + nivolumab). Endocrine AEs appeared in 29% (41/140) patients. Three patients had two different endocrine AEs. Thyroid disorders were the most common: 26% (36/140), followed by hypophysitis: 4% (5/140). Three subjects (2%, 3/140) were diagnosed with autoimmune diabetes. Three patients had to terminate treatment due to endocrine toxicity. Radiological manifestations of endocrine AEs were found in 16 patients (39%, 16/41). Endocrine toxicity was associated with significantly better treatment outcomes. Median progression-free survival (8.1 months, range 5.1 – 11.1 months vs. 2.7 months, range 2.4 – 3.0 months, P < 0.001), and median overall survival (47.5 months, range 15.5 – 79.5 months vs. 23.7 months, range 15.3 – 32.1 months, P = 0.035) were longer for patients experiencing endocrine AEs. Conclusions: The higher number of endocrine AEs suggest regular laboratory monitoring aids in AE detection. Endocrine AEs in metastatic melanoma may correlate with better treatment outcomes.

scholarly journals Novel Use of All-Trans-Retinoic Acid in A Model of Lipopolysaccharide-Immunosuppression to Decrease the Generation of Myeloid-Derived Suppressor Cells by Reducing the Proliferation of CD34+ Precursor Cells

Shock ◽  
2017 ◽  
Vol 48 (1) ◽  
pp. 94-103 ◽  
Author(s):  
Daiana Martire-Greco ◽  
Nahuel Rodriguez-Rodrigues ◽  
Luis A. Castillo ◽  
María Belén Vecchione ◽  
Marcelo de Campos-Nebel ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Suppressor Cells ◽  
Precursor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

scholarly journals Primary Resistance to PD-1-Based Immunotherapy—A Study in 319 Patients with Stage IV Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1027 ◽  
Author(s):  
Teresa Amaral ◽  
Olivia Seeber ◽  
Edgar Mersi ◽  
Stephanie Sanchez ◽  
Ioannis Thomas ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Checkpoint Inhibitors ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Primary Resistance ◽  
Dismal Prognosis ◽  
Significant Difference ◽  
Melanoma Patients ◽  
Stage Iv Melanoma

Background: Primary resistance to immunotherapy can be observed in approximately 40–65% of the stage IV melanoma patients treated with immune checkpoint inhibitors. A minority of the patients receive a second-line therapy, and the clinical benefit is small. Patients and methods: Stage IV melanoma patients treated with first-line PD-1-based immunotherapy between January 2015 and December 2018 were investigated. Primary resistance was defined as progressive disease (PD) at the time of the first tumor assessment after starting immunotherapy. Patients with complete response, partial response, and stable disease were classified as having disease control (DC). Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier estimator. Univariate and multivariate logistic regression analyses were performed to determine prognostic factors associated with OS. Results: Three hundred and nineteen patients were included, and 40% had primary resistance to immunotherapy. The median follow-up time was 22 months. Patients with primary resistance had 1-, 2-, and 3-year OS rates of 41%, 15%, and 10%, respectively, compared to 91%, 81%, and 65% for the patients who achieved DC. The following independently significant prognostic factors for OS were identified: protein S100B level and primary tumor localization. There was a statistically significant difference for OS (p < 0.0001) but not for PFS (p = 0.230) when analyzing risk groups formed with a combination of these two variables (low-, intermediate-, and high-risk subgroups). Conclusions: Melanoma patients with primary resistance to immunotherapy have a dismal prognosis. Response at the first tumor assessment after starting immunotherapy is a stronger prognostic factor for the further course of the disease than pretreatment risk factors.

scholarly journals Inflammatory Cytokines and ctDNA Are Biomarkers for Progression in Advanced-Stage Melanoma Patients Receiving Checkpoint Inhibitors

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1414 ◽  
Author(s):  
Jesper Geert Pedersen ◽  
Anne Tranberg Madsen ◽  
Kristine Raaby Gammelgaard ◽  
Ninna Aggerholm-Pedersen ◽  
Boe Sandahl Sørensen ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Inflammatory Cytokines ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Circulating Tumor Dna ◽  
Advanced Stage ◽  
Monocyte Chemoattractant Protein 1 ◽  
Melanoma Patients

Purpose: Checkpoint inhibitors have significantly improved treatment of metastatic melanoma. However, 40–60% of patients do not respond to therapy, emphasizing the need for better predictive biomarkers for treatment response to immune checkpoint inhibitors. Prorammed death-ligand 1(PD-L1) expression in tumor cells is currently used as a predictive biomarker; however, it lacks specificity. Therefore, it is of utmost importance to identify other novel biomarkers that can predict treatment outcome. Experimental design: We studied a small cohort of 16 patients with advanced-stage melanoma treated with first-line checkpoint inhibitors. Plasma samples were collected prior to treatment initiation and continuously during the first year of treatment. Circulating tumor DNA (ctDNA) level and the expression of ten inflammatory cytokines were analyzed. Results: We found that the ctDNA-level in a blood sample collected after 6–8 weeks of therapy is predictive for response to checkpoint inhibitors. Patients with undetectable ctDNA had significantly longer progression-free survival (PFS) compared with patients with detectable ctDNA (median 26.3 vs. 2.1 months, p = 0.006). In parallel, we identified that high levels of the cytokines monocyte chemoattractant protein 1 (MCP1) and tumor necrosis factor α(TNFα) in baseline blood samples were significantly associated with longer PFS compared to low level of these cytokines (median not reached vs. 8.2 months p = 0.0008). Conclusions: These findings suggest that the levels of ctDNA, MCP1, and TNFα in baseline and early follow-up samples can predict disease progression in metastatic melanoma patients treated with checkpoint inhibitors. Potentially, these minimally invasive biomarkers may identify responders from non-responders.

Sign in / Sign up

Export Citation Format

Share Document