Myeloid-Derived Suppressor Cells are Associated with Disease Progression and Decreased Overall Survival in Advanced-Stage Melanoma Patients

“Myeloid-derived suppressor cells are increased in the peripheral blood of advanced-stage cancer patients; however, no studies have shown a correlation of these immunosuppressive cells with clinical outcomes in melanoma patients. We characterized the frequency and suppressive function of multiple subsets of myeloid-derived suppressor cells in the peripheral blood of 34 patients with Stage IV melanoma, 20 patients with Stage I melanoma, and 15 healthy donors. The frequency of CD14+ MDSCs (Lin CD11b+ HLA-DR CD14+ CD33+) and CD14 MDSCs (Lin CD11b+ HLA-DRCD14 CD33+) was increased in the peripheral blood of Stage IV melanoma patients relative to healthy donors. The frequency of CD14+ and CD14MDSCs correlated with each other and with the increased frequency of regulatory T cells, but not with classically defined monocytes. CD14 MDSCs isolated from the peripheral blood of Stage IV melanoma patients suppressed T cell activation more than those isolated from healthy donors, and the frequency of these cells correlated with disease progression and decreased overall survival. Our study provides the first evidence that the frequency of CD14 MDSCs negatively correlates with clinical outcomes in advanced-stage melanoma patients. These data indicate that suppressive MDSCs should be considered as targets for future immunotherapies.”


Better Performance of CARs Deprived of the PD-1 Brake

“Immunotherapies often permit combinations to increase efficacy. Two approaches are currently leading our field: adoptive therapy with T cells transfected with chimeric antigen receptors and monoclonal antibodies blocking the PD-1/PD-L1 (B7-H1) axis. In this issue of Clinical Cancer Research, preclinical evidence for a synergistic combination of such approaches is reported.”


Better Performance of CARs Deprived of the PD-1 Brake

“Immunotherapies often permit combinations to increase efficacy. Two approaches are currently leading our field: adoptive therapy with T cells transfected with chimeric antigen receptors and monoclonal antibodies blocking the PD-1/PD-L1 (B7-H1) axis. In this issue of Clinical Cancer Research, preclinical evidence for a synergistic combination of such approaches is reported.”


Better Performance of CARs Deprived of the PD-1 Brake

“Immunotherapies often permit combinations to increase efficacy. Two approaches are currently leading our field: adoptive therapy with T cells transfected with chimeric antigen receptors and monoclonal antibodies blocking the PD-1/PD-L1 (B7-H1) axis. In this issue of Clinical Cancer Research, preclinical evidence for a synergistic combination of such approaches is reported.”


Combination Therapy with a Second-Generation Androgen Receptor Antagonist and a Metastasis Vaccine Improves Survival in a Spontaneous Prostate Cancer Model

“Purpose: Enzalutamide, a second-generation androgen antagonist, was approved by the FDA for castration-resistant prostate cancer (CRPC) treatment. Immunotherapy has been shown to be a promising strategy for prostate cancer. This study is performed to provide data to support the combination of enzalutamide and immunotherapy for CRPC treatment. Experimental Design: Male C57BL/6 or TRAMP prostate cancer model mice were exposed to enzalutamide and/or a therapeutic vaccine targeting Twist, an antigen involved in epithelial-to-mesenchymal transition and metastasis. The physiological and immunological effects of enzalutamide were characterized. The generation of Twist-specific immunity by Twist-vaccine was evaluated. Finally, the combination of enzalutamide and Twist-vaccine to improve TRAMP mice overall survival was evaluated. Results: Enzalutamide mediated immunogenic modulation in TRAMP-C2 cells. In vivo, enzalutamide mediated reduced genitourinary tissue weight, enlargement of the thymus, and increased levels of T-cell excision circles. Because no changes were seen in T-cell function, as determined by CD4+ T-cell proliferation and Treg functional assays, enzalutamide was determined to be immune inert. Enzalutamide did not diminish the Twist-vaccine’s ability to generate Twist-specific immunity. Twist was confirmed as a valid tumor antigen in TRAMP mice by immunohistochemistry. The combination of enzalutamide and Twist-vaccine resulted in significantly increased overall survival of TRAMP mice compared to other treatment groups (27.5 vs. 10.3 weeks). Notably, the effectiveness of the combination therapy increased with disease stage, i.e., the greatest survival benefit was seen in mice with advanced-stage prostate tumors. Conclusions: These data support the combination of enzalutamide and immunotherapy as a promising treatment strategy for CRPC.”


Tumor Exome Analysis Reveals Neoantigen-Specific T-Cell Reactivity in an Ipilimumab-Responsive Melanoma


Inhibition of Androgen Receptor and β-Catenin Activity in Prostate Cancer

“Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective approach to treating prostate cancer. Here we provide proof-of-concept that a small-molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin–signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both β-catenin/T-cell factor and β-catenin/AR protein interaction, reflecting the fact that T-cell factor and AR have overlapping binding sites on β-catenin. Given that AR interacts with, and is transcriptionally regulated by β-catenin, C3 treatment also resulted in decreased occupancy of β-catenin on the AR promoter and diminished AR and AR/β-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and β-catenin cofactor, coactivator-associated arginine methyltransferase 1 (CARM1), providing insight into the unrecognized function of β-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model and blocked renewal of bicalutamide-resistant sphere-forming cells, indicating the therapeutic potential of this approach.”


Immunotherapy at Large: The Road to Personalized Cancer Vaccines

“The field of tumor immunology has been flooded with exciting therapeutic advances on many fronts. Immunotherapies targeting T cell inhibitory molecules have proven highly effective in some cancers, but additional strategies to induce tumor immunity, such as cancer vaccination, could further increase tumor killing. The combination of both will probably be the way forward in future immunotherapy. In ‘Bedside to Bench’, Robert Vonderheide and Katherine Nathanson discuss the potential of cancer genomics to identify specific tumor mutations in patients that may be used as targets in cancer vaccines to overcome problems linked to self-antigen epitopes used nowadays. Despite the existing biological and technical hurdles, a framework to implement personalized cancer vaccines in the clinic may be worth considering. In ‘Bench to Bedside’, Glenn Dranoff peruses the clinical efficacy and detrimental effects of two T cell immune-checkpoint inhibitors, alone and in combination, in patients with melanoma. The studies underscore the need to continue investigating specific tumor events directly involving tumor evasion to develop combinatorial strategies that will reduce drug-related pathology while achieving anti-tumor efficacy.”


Immunotherapy at Large: The Road to Personalized Cancer Vaccines

“The field of tumor immunology has been flooded with exciting therapeutic advances on many fronts. Immunotherapies targeting T cell inhibitory molecules have proven highly effective in some cancers, but additional strategies to induce tumor immunity, such as cancer vaccination, could further increase tumor killing. The combination of both will probably be the way forward in future immunotherapy. In ‘Bedside to Bench’, Robert Vonderheide and Katherine Nathanson discuss the potential of cancer genomics to identify specific tumor mutations in patients that may be used as targets in cancer vaccines to overcome problems linked to self-antigen epitopes used nowadays. Despite the existing biological and technical hurdles, a framework to implement personalized cancer vaccines in the clinic may be worth considering. In ‘Bench to Bedside’, Glenn Dranoff peruses the clinical efficacy and detrimental effects of two T cell immune-checkpoint inhibitors, alone and in combination, in patients with melanoma. The studies underscore the need to continue investigating specific tumor events directly involving tumor evasion to develop combinatorial strategies that will reduce drug-related pathology while achieving anti-tumor efficacy.”