Junya Ohtake

First clinical trial of cancer vaccine therapy with artificially synthesized helper/ killer-hybrid epitope long peptide of MAGE-A4 cancer antigen

A patient with pulmonary metastasis of colon cancer was treated with artificially synthesized helper/killer‐hybrid epitope long peptide (H/K‐HELP) of MAGE‐A4 cancer antigen. The patient was vaccinated with MAGE‐A4‐H/K‐HELP combined with OK432 and Montanide ISA‐51. There were no severe side‐effects except for a skin reaction at the injection site. MAGE‐A4‐H/K‐HELP induced MAGE‐A4‐specific Th1 and Tc1 immune responses and the production of MAGE‐A4‐specific complement‐fixing IgG antibodies. Tumor growth and carcinoembryonic antigen tumor marker were significantly decreased in the final diagnosis. This is the first report that artificially synthesized MAGE‐A4‐H/K‐HELP induces Th1‐dependent cellular and humoral immune responses in a human cancer patient. (Cancer Sci 2012; 103: 150–153)

IL-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy.

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)‐6, a pleiotropic cytokine, is highly produced in the tumor‐bearing host. Previous studies have indicated that IL‐6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL‐6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor‐infiltrating CD11b+CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL‐6 gene, downregulated surface expression of human leukocyte antigen (HLA)‐DR, and an attenuated T cell‐stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL‐6‐mediated STAT3 activation reduced surface expression of HLA‐DR on CD14+ monocyte‐derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL‐6‐mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL‐6‐mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL‐6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients.

Identification of novel helper epitope peptides of Survivin cancer-associated antigen applicable to developing helper/killer-hybrid epitope long peptide cancer vaccine

We identified novel helper epitope peptides of Survivin cancer antigen, which are presented to both HLA-DRB1*01:01 and DQB1*06:01. The helper epitope also contained three distinct Survivin-killer epitopes presented to HLA-A*02:01 and A*24:02. This 19 amino-acids epitope peptide (SU18) induced weak responses of Survivin-specific CD4(+) and CD8(+) T cells though it contained both helper and killer epitopes. To enhance the vaccine efficacy, we synthesized a long peptide by conjugating SU18 peptide and another DR53-restricted helper epitope peptide (SU22; 12 amino-acids) using glycine-linker. We designated this artificial 40 amino-acids long peptide containing two helper and three killer epitopes as Survivin-helper/killer-hybrid epitope long peptide (Survivin-H/K-HELP). Survivin-H/K-HELP allowed superior activation of IFN-γ-producing CD4(+) Th1 cells and CD8(+) Tc1 cells compared with the mixture of its component peptides (SU18 and SU22) in the presence of OK-432-treated monocyte-derived DC (Mo-DC). Survivin-H/K-HELP-pulsed Mo-DC pretreated with OK-432 also exhibited sustained antigen-presentation capability of stimulating Survivin-specific Th1 cells compared with Mo-DC pulsed with a mixture of SU18 and SU22 short peptides. Moreover, we demonstrated that Survivin-H/K-HELP induced a complete response in a breast cancer patient with the induction of cellular and humoral immune responses. Thus, we believe that an artificially synthesized Survivin-H/K-HELP will become an innovative cancer vaccine.

IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells.

Immunosuppression in tumor microenvironments critically affects the success of cancer immunotherapy. Here, we focused on the role of interleukin (IL)-6/signal transducer and activator of transcription (STAT3) signaling cascade in immune regulation by human dendritic cells (DCs). IL-6-conditioned monocyte-derived DCs (MoDCs) impaired the presenting ability of cancer-related antigens. Interferon (IFN)-γ production attenuated by CD4+ T cells co-cultured with IL-6-conditioned MoDCs corresponded with decreased DC IL-12p70 production. Human leukocyte antigen (HLA)-DR and CD86 expression was significantly reduced in CD11b+CD11c+ cells obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors by IL-6 treatment and was STAT3 dependent. Arginase-1 (ARG1), lysosomal protease, cathepsin L (CTSL), and cyclooxygenase-2 (COX2) were involved in the reduction of surface HLA-DR expression. Gene expressions of ARG1, CTSL, COX2, and IL6 were higher in tumor-infiltrating CD11b+CD11c+ cells compared with PBMCs isolated from colorectal cancer patients. Expression of surface HLA-DR and CD86 on CD11b+CD11c+ cells was down-regulated, and T cell-stimulating ability was attenuated compared with PBMCs, suggesting that an immunosuppressive phenotype might be induced by IL-6, ARG1, CTSL, and COX2 in tumor sites of colorectal cancer patients. There was a relationship between HLA-DR expression levels in tumor tissues and the size of CD4+ T and CD8+ T cell compartments. Our findings indicate that IL-6 causes a dysfunction in human DCs that activates cancer antigen-specific Th cells, suggesting that blocking the IL-6/STAT3 signaling pathway might be a promising strategy to improve cancer immunotherapy.

IL-11 induces differentiation of myeloid-derived suppressor cells through activation of STAT3 signalling pathway

Myeloid-derived suppressor cells (MDSCs) are immune negative regulators in the tumour microenvironment. Interleukin (IL)-11, a member of IL-6 family cytokines, functions through the unique receptor IL-11 receptor α coupled with the common signal transducer gp130. IL-11-gp130 signalling causes activation of the JAK/STAT3 pathway. IL-11 is highly upregulated in many types of cancers and one of the most important cytokines during tumourigenesis and metastasis. However, the precise effect of IL-11 on differentiation into MDSCs is still unknown. Here, we found that CD11b+CD14+ monocytic MDSCs were generated from peripheral blood mononuclear cells (PBMCs) of healthy donors in the presence of IL-11. IL-11-conditioned PBMCs induced higher expression of immunosuppressive molecules such as arginase-1. A reduction of T-cell proliferation was observed when MDSCs generated in the presence of IL-11 were co-cultured with CD3/CD28-stimulated, autologous T cells of healthy donors. Culture of normal PBMCs with IL-11 led to STAT3 phosphorylation and differentiation into MDSCs via STAT3 activation. We confirmed expressions of both IL-11 and phosphorylated STAT3 in tumour tissues of colorectal cancer patients. These findings suggest that monocytic MDSCs may be induced by IL-11 in the tumour microenvironment. Thus, IL-11-mediated regulation in functional differentiation of MDSCs may serve as a possible target for cancer immunotherapy.

Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells.

Title Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells Author(s) Ohtake, Junya; Kaneumi, Shun; Tanino, Mishie; Kishikawa, Takuto; Terada, Satoshi; Sumida, Kentaro; Masuko, Kazutaka; Ohno, Yosuke; Kita, Toshiyuki; Iwabuchi, Sadahiro; Shinohara, Toshiya; Tanino, Yoshinori; Takemura, Tamiko; Tanaka, Shinya; Kobayashi, Hiroya; Kitamura, Hidemitsu Citation Journal of Allergy and Clinical Immunology, 136(6): 1690-1694

Association between soluble immune mediators and tumor responses in patients with non-small cell lung cancer treated with anti-PD-1 inhibitor: Association between soluble immune mediators and tumor responses in patients with non-small cell lung cancer treated with anti-PD-1 inhibitor

Although programmed death (PD)‐1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti‐PD‐1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD‐1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti‐PD‐1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3‐like‐1 and GM‐CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNα2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment‐related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti‐PD‐1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD‐1 inhibitor therapy.

Are peptide vaccines viable in combination with other cancer immunotherapies

Cancer Vaccine Center, Kanagawa Cancer Center, Yokohama, Japan *Author for correspondence: tsasada@kcch.jp

Personalized peptide vaccines for cancer therapy: current progress and state of the art

ABSTRACT Introduction: Accumulating evidence for the feasibility and efficacy of cancer immunotherapy is ushering in a paradigm shift for cancer treatment. Notably, immune checkpoint inhibitors, such as antibodies against cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death-1/programmed cell death ligand 1, show substantial clinical benefits in certain types of cancers. Nevertheless, the response rates to immune checkpoint inhibitors are only 20–30% of patients at most, possibly because the activated immune response is not sufficiently specific. The activation of non-tumor-specific cells leads, theoretically, to autoimmunity and not to tumor regression. Therefore, other approaches that can activate tumor-specific immune cells, such as cancer peptide vaccines, must be developed to improve cancer immunotherapeutic options. Areas covered: In this review, the authors discuss current and future perspectives on cancer-specific immunotherapies, particularly cancer peptide vaccines. Expert commentary: Personalized peptide vaccines against peptides that are recognized by patient T cells elicit immediate, tumor-specific immune responses. Furthermore, advances in genomics and bioinformatics have facilitated the generation of personalized peptide vaccines derived from neo-antigens, which have proven safe in clinical trials. In the future, combination therapies that utilize checkpoint inhibitors and peptide vaccines may improve response rates and patient outcomes.

Personalized immunotherapy in colorectal cancer

ABSTRACT The fields of cancer immunology and immunotherapy have made dramatic progress in the past 20 years. Various approaches to cancer immunotherapies, including cancer vaccines using peptides, proteins, DNA, and dendritic cells, have been developed to activate antigen-specific immune cells and their efficacy has been clinically examined. Herein, we summarize previously performed clinical trials of various immunotherapies against colorectal cancer (CRC), including our own novel immunotherapeutic approach, the “personalized peptide vaccine”, in which human leukocyte antigen (HLA)-matched vaccine peptides are selected based on pre-existing host immunity before vaccination. In the near future, neoepitopes identified through massive DNA sequencing of the genetic alterations in tumor cells, combined with robust T cell epitope predictions in each patient might be targeted as a personalized immunotherapy for CRC.