BackgroundWe report a case of sarcoidosis in a patient with metastatic melanoma managed with combination ipilimumab/nivolumab. Sarcoid development has been linked with single agent immunotherapy but, to our knowledge, it has not been reported with combination ipilimumab/nivolumab treatment. This case raises unique management challenges for both the melanoma and the immunotherapy-related toxicity.Case presentationA 46 year old Caucasian female with M1c-metastatic melanoma was managed with ipilimumab/nivolumab combination. Patient experienced response in baseline lesions but developed new clinical and radiographic findings. Biopsy of new lesions at two different sites both demonstrated tumefactive sarcoidosis. Staining of the biopsy tissue for PD-L1 expression demonstrated strong PD-L1 staining of the histiocytes and lymphocytes within the granulomas. Monotherapy nivolumab was continued without progression of sarcoid findings or clinical deterioration.ConclusionsTissue biopsy for evaluation of new lesions on immunotherapy is an important step to help guide decision making, as non-melanoma lesions can mimic disease progression.

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 IFNγ. 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 6 of 9 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 they 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.

Desmoplastic melanomas (DM) have unique and challenging clinical presentations and histomorphology. A characteristic feature is the presence of scattered lymphoid aggregates. However, the nature of these aggregates is not defined. We hypothesized that they may be tertiary lymphoid structures (TLS), and may be associated with programmed death ligand 1 (PD-L1) expression. We searched our tissue database for 'pure' DMs and for scars as control tissues, collected clinical information, and reviewed H&E histology. We performed multispectral imaging after staining for CD8, CD20, PNAd, FoxP3, CD83, and Ki67, and assessed PD-L1 expression by immunohistochemistry. Pure DM samples were evaluable in 11 patients. All had desmoplastic stroma and lymphoid aggregates on H&E. The lymphoid aggregates of eight of the 11 (72%) DM samples and only three of the 11 scars contained features of TLS, defined as distinct clusters of B cells and CD8 T cells, CD83 dendritic cells in T-cell zones, and PNAd vasculature resembling high endothelial venules. PD-L1 was expressed by at least 1% of melanoma cells in six and by at least 5% of immune cells in 10 of the 11 DM samples. We found that most lymphoid aggregates in DM are organized, classical TLS. PD-L1 expression was detected in most cases and was highest in two cases of DM with TLS. However, low PD-L1 expression in some cases suggests that some DM cells may be unresponsive to interferon-γ. TLS support antigen presentation and T-cell responses in chronic inflammation and cancer. Their presence in DM likely reflects an adaptive immune response, which may be enhanced with immune therapies.

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 (12MP) 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 (TME) 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 were 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.

We report a series of four cases of individual patients with coexisting diagnoses of some combination of MF, LyP, and pcALCL, whose lesions presented in nontraditional sequence and demonstrated a retained clone by gene rearrangement analysis.