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Background: PRAME (preferentially expressed antigen in melanoma) is a promising immunohistochemical marker in distinguishing benign from malignant primary cutaneous melanocytic lesions and lymph node deposits. We hypothesize that PRAME may also reliably identify melanoma metastases that are clinically detected in skin, lymph nodes, or small intestine. Methods: A total of 155 cases of metastatic melanoma to lymph node (N = 54) and non‐lymph node (N = 101) sites were stained with an antibody against PRAME. Nuclear expression was scored in tumor cells as negative, 1% to 25% (1+), 26% to 50% (2+), 51% to 75% (3+), or 76% to 100% (4+). Results: PRAME expression was seen in 151/155 (97.4%) cases, with 4+ expression in 64 cases (41.3%), 3+ expression in 46 cases (29.7%), 2+ expression in 18 cases (11.6%), and 1+ expression in 23 cases (14.8%). Lymph node metastases were more likely to show lower expression as compared to metastases to other anatomic sites (P = 0.003). Conclusions: A high level of PRAME immunoreactivity was identified in this cohort of metastatic melanoma. Lymph node metastases showed more focal or absent PRAME expression as compared to metastases to other sites. Overall, PRAME is a useful tool for confirming the diagnosis of melanoma in a metastatic setting, in both nodal and visceral deposits. [ABSTRACT FROM AUTHOR]

The incidence of pancreatic cancer has been increasing while its 5-year survival rate has not changed in decades. In the era of personalized medicine, immunotherapy has emerged as a promising treatment modality in a variety of malignancies, including pancreatic cancer. This review will discuss the unique pancreatic tumor microenvironment, including the cells and receptors that transform the pancreas from its normal architecture into a complex mix of suppressor immune cells and dense extracellular matrix that allows for the unrestricted growth of cancer cells. Next, we will highlight the recently completed immunotherapy clinical trials in pancreatic cancer. Finally, we will explore the on-going immunotherapy clinical trials and future directions of this engaging and changing field. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the second most common cause of cancer death worldwide. Current treatment options for patients with intermediate and advanced HCC are limited, and there is an unmet need for novel therapeutic approaches. HCC is an attractive target for immunomodulation therapy, since it arises in an inflammatory milieu due to hepatitis B and C infections and cirrhosis. However, a major barrier to the development and success of immunotherapy in patients with HCC is the liver’s inherent immunosuppressive function. Recent advances in the field of cancer immunology allowed further characterization of immune cell subsets and function, and created new opportunities for therapeutic modulation of the immune system. In this review, we present the different immune cell subsets involved in potential immune modulation of HCC, discuss their function and clinical relevance, review the variety of immune therapeutic agents currently under investigation in clinical trials, and outline future research directions. [ABSTRACT FROM AUTHOR]

Introduction: Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases. Patients and methods: Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression. Results and conclusions: Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Introduction: Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9-11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases. Patients and methods: Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ intratumorally. Effects on the tumor microenvironment were evaluated in sequential tumor biopsies. Adverse events (AEs) were recorded. T cell responses to vaccination were assessed in PBMC by IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression. Results: Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures. Conclusion: The melanoma vaccine induced circulating T cell responses, but it failed to infiltrate metastases, thus highlighting the need for combination strategies to support T cell infiltration. A single intratumoral injection of IFNγ induced T cell-attracting chemokines; however, it also induced secondary immune regulation that may paradoxically limit immune infiltration and effector functions. Alternate dosing strategies or additional combinatorial treatments may be needed to promote trafficking and retention of tumor-reactive T cells in melanoma metastases. [ABSTRACT FROM AUTHOR]

Abstract: To date, most peptide-based vaccines evaluated for the treatment of cancer have consisted of one or few peptides. However, as a greater number of peptide antigens become available for use in experimental therapies, it is important to establish the feasibility of combining multi-peptide reagents as individual peptide mixtures. We have found that mixtures of up to 12 peptides can be analyzed accurately for identity, purity, and stability (for at least 5 years) using a combination of high-performance liquid chromatography (HPLC) and mass spectrometry and these complex peptide mixtures have been acceptable for use in human clinical trials. We have also identified some specific concerns for degradation products that should be considered in multi-peptide vaccine preparation and follow-up quality assurance studies. Results from these analyses have implications for changing the way peptide-based vaccines are manufactured and demonstrate that multi-peptide vaccines are reliable reagents for use in peptide-based immune therapies. [Copyright &y& Elsevier]

Background: Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. Methods: To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. Results: The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. Conclusion: These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy. [ABSTRACT FROM AUTHOR]