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Background:  :   Incidence of hepatocellular cancer (HCC) in the Bronx is 61% higher than the rest of New York State. Underserved populations are not well represented in clinical trials of immune checkpoint inhibitors (ICI). Methods: Demographics were tabulated for 194 patients treated with ICI at the Montefiore-Einstein Comprehensive Cancer Center (MECCC) between 2017 and 2022. Categorical variables were analyzed by Chi-squared test, and survival was analyzed using Kaplan–Meier (KM) curves. Results: MECCC patients were 40.7% Hispanic and 20.6% Black, compared with 3% and 2%, respectively, in the landmark IMbrave 150 study. Median overall survival (mOS) on ICI was 9.0 months, 25.0 months for the 100 (51.5%) favorable-prognosis Child Pugh A (CPA) patients included in HCC clinical trials. Disease control rate (DCR) was 58.5% among 123 evaluable patients per mRECIST 1.1. Baseline liver function, as defined by CP and the Model for End-Stage Liver Disease-Sodium (MELD-Na), correlated with survival (p < 0.001). Hepatitis C Virus (HCV) and alcoholism were over-represented relative to National Cancer Institute (NCI) data (56.2% vs 4.7% and 38.7% vs 8.2%, respectively). HCV treatment correlated with prolonged survival in infected patients (p = 0.0017). AFP decline correlated with response (p = 0.001). Hispanic patients lived longer when clinical variables were controlled for (mOS 52 vs 23 months; p = 0.011). Conclusion: In an underserved HCC population, ICI yielded a DCR of 58.5% and low rates of severe toxicity. This work highlights ICI efficacy in minority groups, a need for earlier HCC diagnosis and for studies of genetic and environmental factors in Hispanics with HCC. [ABSTRACT FROM AUTHOR]

Talimogene Laherparepvec (OncoVEXmGMCSF), an oncolytic virus, immune checkpoint inhibitor anti-programmed cell death protein 1 (anti-PD1), and BRAF inhibition (BRAFi), are all clinically approved for treatment of melanoma patients and are effective through diverse mechanisms of action. Individually, these therapies also have an effect on the tumor immune microenvironment (TIME). Evaluating the combination effect of these three therapies on the TIME can help determine when combination therapy is most appropriate for further study. In this study, we use a transgenic murine melanoma model (Tyr::CreER; BRAFCA/+; PTENflox/flox), to evaluate the TIME in response to combinations of BRAFi, anti-PD1, and OncoVEXmGMCSF. We find that mice treated with the triple combination BRAFi + anti-PD1 + OncoVEXmGMCSF have decreased tumor growth compared to BRAFi alone and prolonged survival compared to control. Flow cytometry shows an increase in percent CD8 + /CD3 + cytotoxic T Lymphocytes (CTLs) and a decrease in percent FOXP3 + /CD4 + T regulatory cells (Tregs) in tumors treated with OncoVEXmGMCSF compared to mice not treated with OncoVEXmGMCSF. Immunogenomic analysis at 30d post-treatment shows an increase in Th1 and interferon-related genes in mice receiving OncoVEXmGMCSF + BRAFi. In summary, treatment with combination BRAFi + anti-PD1 + OncoVEXmGMCSF is more effective than any single treatment in controlling tumor growth, and groups receiving OncoVEXmGMCSF had more tumoral infiltration of CTLs and less intratumoral Tregs in the TIME. This study provides rational basis to combine targeted agents, oncolytic viral therapy, and checkpoint inhibitors in the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy, specifically immune checkpoint inhibitors (ICIs), including anti‐programmed cell death 1 (anti‐PD1), has recently received clinical approval for the treatment of adult hepatocellular carcinoma (HCC). However, the safety and efficacy of ICIs prior to solid organ transplant are unknown, especially in pediatrics. Safety reports are variable in adults, with some series describing subsequent allograft rejection and loss while others report successful transplants without allograft rejection.As ICIs stimulate the immune system by blocking the interaction between PD1 and the ligand‐receptor pair programmed cell death‐ligand 1 (PDL1), the downstream effects of T‐cell activation increase the risk of graft rejection. Methods: Here, we present a case of an adolescent with moderately differentiated non‐fibrolamellar HCC treated with pembrolizumab, an anti‐PD1 therapy, who subsequently underwent successful orthotopic liver transplantation (OLT). Results: Our patient received an OLT 138 days from the last pembrolizumab dose with graft preservation. The patient has no evidence of recurrent disease or any episode of allograft rejection 48 months post OLT. Staining of tumor and normal tissues from longitudinal specimens finds PDL1 positive Kupffer cells present in normal liver and peritumoral areas with no changes post anti‐PD1 therapy. In contrast, tumor cells were negative for PDL1. Conclusion: This case represents a basis for optimism in potential use of anti‐PD1 therapy in liver transplant candidates and supports further investigation of immune checkpoint inhibitors use in this unique patient population. [ABSTRACT FROM AUTHOR]

Purpose: To compare the prognostic value of imaging biomarkers derived from a quantitative analysis of baseline 18F-FDG-PET/CT in patients with mucosal melanoma (Muc-M) or cutaneous melanoma (Cut-M) treated with immune checkpoint inhibitors (ICIs). Methods: In this retrospective monocentric study, we included 56 patients with non-resectable Muc-M (n = 24) or Cut-M (n = 32) who underwent baseline 18F-FDG-PET/CT before treatment with ICIs between 2011 and 2017. Parameters were extracted from (i) tumoral tissues: SUVmax, SUVmean, TMTV (total metabolic tumor volume), and TLG (total lesion glycolysis) and (ii) lymphoid tissues: BLR (bone marrow-to-liver SUVmax ratio) and SLR (spleen-to-liver SUVmax ratio). Association with survival and response was evaluated using Cox prediction models, Student's t tests, and Spearman's correlation respectively. p < 0.05 was considered significant. Results: Majority of ICIs were anti-PD1 (92.9%, n = 52/56). All 18F-FDG-PET/CT were positive. Overall (Muc-M to Cut-M), ORR was 33%:42%, DCR was 56%:69%, median follow-up was 25.0:28.9 months, median PFS was 4.7:10.7 months, and median OS was 23.9:28.3 months. In Muc-M, increased tumor SUVmax was associated with shorter OS while it was not correlated with PFS, ORR, or DCR. In Cut-M, increased TMTV and increased BLR were independently associated with shorter OS, shorter PFS, and lower response (ORR, DCR). Conclusion: While all Muc-M and Cut-M were FDG avid, prognostic imaging biomarkers differed. For Muc-M patients treated with ICI, the only prognostic imaging biomarker was a high baseline maximal glycolytic activity (SUVmax), whereas for Cut-M patients, baseline metabolic tumor burden or bone marrow metabolism was negatively correlated to ICI response duration. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has changed the landscape of treatment modalities available for many different types of malignancies. However, the factors that influence the success of immunotherapeutics have not been as clearly seen in advanced prostate cancer, likely due to immunosuppressive factors that exist within the prostate cancer tumor microenvironment. While there have been many immunotherapeutics used for prostate cancer, the majority have targeted a single immunosuppressive mechanism resulting in limited clinical efficacy. More recent research centered on elucidating the key mechanisms of immune resistance in the prostate tumor microenvironment has led to the discovery of a range of new treatment targets. With that in mind, many clinical trials have now set out to evaluate combination immunotherapeutic strategies in patients with advanced prostate cancer, in the hopes of circumventing the immunosuppressive mechanisms. The use of immunotherapy has become a critical treatment modality in many advanced cancers. However, immunotherapy in prostate cancer has not been met with similar success. Multiple interrelated mechanisms, such as low tumor mutational burden, immunosuppressive cells, and impaired cellular immunity, appear to subvert the immune system, creating an immunosuppressive tumor microenvironment and leading to lower treatment efficacy in advanced prostate cancer. The lethality of metastatic castrate-resistant prostate cancer is driven by the lack of therapeutic regimens capable of generating durable responses. Multiple strategies are currently being tested to overcome immune resistance including combining various classes of treatment modalities. Several completed and ongoing trials have shown that combining vaccines or checkpoint inhibitors with hormonal therapy, radiotherapy, antibody–drug conjugates, chimeric antigen receptor T cell therapy, or chemotherapy may enhance immune responses and induce long-lasting clinical responses without significant toxicity. Here, we review the current state of immunotherapy for prostate cancer, as well as tumor-specific mechanisms underlying therapeutic resistance, with a comprehensive look at the current preclinical and clinical immunotherapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and impaired cellular immunity that have largely limited the utility of immunotherapy in advanced prostate cancer. [ABSTRACT FROM AUTHOR]