Anti-PD-1 antibody monotherapy versus anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy in unresectable or metastatic mucosal melanoma: a retrospective, multicenter study of 329 Japanese cases (JMAC study).

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients. PATIENTS AND METHODS: We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4. RESULTS: Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001). CONCLUSIONS: First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events.

Intradermal injections of polyarginine-containing immunogenic antigens preferentially elicit Tc1 and Th1 activation and antitumour immunity.

Background We previously have shown that nona-arginine protein transduction domain (R9-PTD) induced efficient protein-antigen (Ag) transduction of dendritic cells (DCs) in vitro, resulting in the efficient induction of strong Ag-specific immune responses mediated by CD8+ and CD4+ T cells and in superior antitumour effects in vivo in cancer-bearing mice. Objectives The Ag-specific immune responses caused by intradermal (i.d.) injections of R9-PTD-containing protein Ags without DC preparation were investigated. We also investigated the antitumour effects by intratumoral (i.t.) injections of rR9-containing protein Ags. Methods Synthesized SIINFEKL peptide, or recombinant ovalbumin fusion proteins (rOVA, rR9-OVA), were directly injected into abdominal skin in naïve C57BL/6 mice. OVA-specific cytotoxic T lymphocyte (CTL) activity, serum IgG titre and cytokine profiles were investigated. Histopathological analyses were also performed. In a cancer vaccination model, EG.7 (OVA-cDNA transfectants thymoma) cells were inoculated intradermally in C57BL/6 mice, and the antitumour effects were evaluated by i.t. injections of rR9-OVA in a treatment setting. Results i.d. injections of rR9-OVA into naïve C57BL/6 mice elicited OVA-specific CTLs and produced IgG2-dominant immunoglobulin. The i.d. injections of rR9-OVA also induced inflammatory cell infiltrates containing neutrophils, monocytes and lymphocytes, as well as production of inflammatory cytokines such as interferon (IFN)-gamma, interleukin-2 and IFN-inducible protein 10, with presenting SIINFEKL epitopes on major histocompatibility complex (MHC) class I molecules at the injection area. i.t. injections of rR9-OVA into EG.7 tumour mass significantly suppressed tumour growth, and these effects were completely abrogated by the depletion of CD8+ T cells. These antitumour effects were superior to those elicited by i.t. injections of rR9-OVA-treated DCs. Conclusions i.d. injections of rR9-containing immunogenic Ag without adjuvants simultaneously induce dual immunological effects: the induction of Tc1- and Th1-dominant immune responses, and the induction of inflammatory and CTL-mediated immune responses at the injection area by expressing Ag epitopes on MHC class I molecules as targets. This simple vaccination approach with R9-PTD-containing fusion proteins might be useful as prophylactic immunotherapy for cancer or infectious diseases.

T cell immune responses against melanoma and melanocytes in cancer and autoimmunity.

T cell responses specific for melanoma cells and melanocytes appear to be involved in the rejection of melanoma tumors, as well as in the development of autoimmune reactions in patients with Vogt-Koyanagi-Harada disease (VKH), sympathetic ophthalmia, or autoimmune vitiligo. Some of the target antigens for those T cells have been isolated using cDNA expression cloning with melanoma reactive T cells derived from lymphocytes tumor infiltrating (TIL) of patients with melanoma. These include melanocyte specific proteins, such as tyrosinase, TRP1, TRP2, gp100, and MART-1, cancer-testis antigens, and mutated peptides derived from genetic alterations in melanoma cells. Some of the melanoma reactive T cells appear to respond to cryptic or subdominant self epitopes in melanosomal proteins. Modification of those epitopes to increase their immunogenicity by replacement of amino acids at primary anchor residues for peptide/MHC binding, allowed an improvement in immunotherapy for patients with melanoma. Targets for autoreactive T cells against melanocytes in those autoimmune disorders remain to be identified. Isolation of novel target antigens is important for understanding these pathological T cell responses, as well as for developing new diagnostic and treatment methods for these diseases. A variety of techniques, including cDNA expression cloning with T cells, serological analysis of recombinant cDNA expression libraries (SEREX), cDNA subtraction with representational differential analysis (RDA), and serial analysis of gene expression (SAGE) are now being applied to identify novel melanoma/melanocyte antigens recognized by T cells and antibodies.