Richard P Tobin1, Kimberly R Jordan2, William A Robinson3, Dana Davis4, Virginia F Borges5, Rene Gonzalez6, Karl D Lewis7, Martin D McCarter8. 1. University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Surgical Oncology, Department of Surgery, USA. Electronic address: richard.tobin@ucdenver.edu. 2. University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Department of Immunology and Microbiology, USA. Electronic address: kimberly.jordan@ucdenver.edu. 3. University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Medical Oncology, Department of Medicine, USA; University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: william.robinson@ucdenver.edu. 4. University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Surgical Oncology, Department of Surgery, USA. Electronic address: dana.davis@ucdenver.edu. 5. University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Medical Oncology, Department of Medicine, USA; Young Women's Breast Cancer Translational Program, USA; University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: virginia.borges@ucdenver.edu. 6. University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Medical Oncology, Department of Medicine, USA; University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: rene.gonzalez@ucdenver.edu. 7. University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Medical Oncology, Department of Medicine, USA; University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: karl.lewis@ucdenver.edu. 8. University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Surgical Oncology, Department of Surgery, USA; University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: martin.mccarter@ucdenver.edu.
Abstract
BACKGROUND: Immune checkpoint inhibitors have improved overall survival rates for many cancers, yet the majority of patients do not respond to treatment and succumb to disease progression. One tumor-related mechanism limiting the efficacy of immunotherapies in melanoma is the recruitment and expansion of myeloid-derived suppressor cells (MDSCs). Therefore, targeting MDSCs in combination with immunotherapies is an attractive strategy to improve response rates and effectiveness. METHODS: We tested this strategy by designing a randomized phase II clinical trial treating advanced melanoma patients with eitherIpilimumab monotherapy or Ipilimumab plus all-trans retinoic acid (ATRA). Clinicaltrails.gov identifier (NCT02403778). The frequency of circulating MDSCs and the activation of CD8(+) T cells was measured by flow cytometry. Expression of immunosuppressive genes was measured with quantitative real time-PCR. T cell suppressive functions were measured by mixed lymphocyte reaction. RESULTS: Here we show that in vitro treatment with ATRA decreases immunosuppressive function of MDSCs in mixed lymphocyte reactions. Additionally, ATRA reduces the expression of immunosuppressive genes including PD-L1, IL-10, and indoleamine 2,3‑dioxygenase by MDSCs. Furthermore, the addition of ATRA to standard of care Ipilimumab therapy appears safe, as ATRA did not increase the frequency of grade 3 or 4 adverse events. Finally, ATRA significantly decreased the frequency of circulating MDSCs compared to Ipilimumab treatment alone in advanced-stage melanoma patients. CONCLUSIONS: These results illustrate the importance of MDSCs in immunotherapy resistance and provide evidence that targeting MDSCs in cancer patients may augment immunotherapeutic approaches.
RCT Entities:
BACKGROUND: Immune checkpoint inhibitors have improved overall survival rates for many cancers, yet the majority of patients do not respond to treatment and succumb to disease progression. One tumor-related mechanism limiting the efficacy of immunotherapies in melanoma is the recruitment and expansion of myeloid-derived suppressor cells (MDSCs). Therefore, targeting MDSCs in combination with immunotherapies is an attractive strategy to improve response rates and effectiveness. METHODS: We tested this strategy by designing a randomized phase II clinical trial treating advanced melanomapatients with either Ipilimumab monotherapy or Ipilimumab plus all-trans retinoic acid (ATRA). Clinicaltrails.gov identifier (NCT02403778). The frequency of circulating MDSCs and the activation of CD8(+) T cells was measured by flow cytometry. Expression of immunosuppressive genes was measured with quantitative real time-PCR. T cell suppressive functions were measured by mixed lymphocyte reaction. RESULTS: Here we show that in vitro treatment with ATRA decreases immunosuppressive function of MDSCs in mixed lymphocyte reactions. Additionally, ATRA reduces the expression of immunosuppressive genes including PD-L1, IL-10, and indoleamine 2,3‑dioxygenase by MDSCs. Furthermore, the addition of ATRA to standard of care Ipilimumab therapy appears safe, as ATRA did not increase the frequency of grade 3 or 4 adverse events. Finally, ATRA significantly decreased the frequency of circulating MDSCs compared to Ipilimumab treatment alone in advanced-stage melanomapatients. CONCLUSIONS: These results illustrate the importance of MDSCs in immunotherapy resistance and provide evidence that targeting MDSCs in cancerpatients may augment immunotherapeutic approaches.
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