Faculty Profiles - Togashi Yosuke

Papers - Togashi Yosuke

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Aging, cancer, and antitumor immunity. Invited Reviewed

Hideki Ikeda, Yosuke Togashi

International journal of clinical oncology 2021.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Aging leads to numerous changes that affect many components of the immune system, called "immunosenescence". Indeed, elderly individuals exhibit dysregulated immune responses against pathogens, poor responses to vaccination, and increased susceptibility to many diseases including cancer, autoimmune disorders, and other chronic inflammatory diseases. Despite progressed understanding of immunosenescence, its detailed mechanisms are still not fully understood. With advances in medicine, the population of older cancer patients is expected to rapidly increase in the coming years. Cancer immunotherapies, including immune checkpoint inhibitors (ICIs), have been shown to be effective for multiple cancer types, whereas to date, few specific data for elderly individuals have been published. Some systemic reviews have demonstrated that ICIs exhibit similar efficacy in older cancer patients, but they seem to be less effective in very old patients. In addition, toxicities might be more frequently observed in such patients. Here, we provide a summary to better understand immunosenescence and an overview of its relationship with cancer and antitumor immunity, including the efficacy and toxicity of ICIs.

DOI： 10.1007/s10147-021-01913-z

HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs. Reviewed International journal

Sho Watanabe, Yasushi Goto, Hiroyuki Yasuda, Takashi Kohno, Noriko Motoi, Yuichiro Ohe, Hiroyoshi Nishikawa, Susumu S Kobayashi, Kazuyoshi Kuwano, Yosuke Togashi

Thoracic cancer 12 ( 5 ) 631 - 642 2021.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third-generation EGFR-TKIs overcome this resistance by selectively inhibiting EGFR with EGFR-TKI-sensitizing and T790M mutations, acquired resistance to third-generation EGFR-TKIs invariably develops. METHODS: Next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M-mutated NSCLC patient who had progressed after a third-generation EGFR-TKI, TAS-121. EGFR-mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR-TKIs and a heat shock protein 90 (HSP90) inhibitor. RESULTS: NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M-mutated cell line was sensitive to osimertinib or TAS-121 in vitro, EGFR-overexpressing cell lines displayed resistance to these EGFR-TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third-generation EGFR-TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines. CONCLUSIONS: EGFR amplification confers resistance to third-generation EGFR-TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification-mediated resistance.

DOI： 10.1111/1759-7714.13839

Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens. Reviewed International journal

Yukie Kashima, Yosuke Togashi, Shota Fukuoka, Takahiro Kamada, Takuma Irie, Ayako Suzuki, Yoshiaki Nakamura, Kohei Shitara, Tatsunori Minamide, Taku Yoshida, Naofumi Taoka, Tatsuya Kawase, Teiji Wada, Koichiro Inaki, Masataka Chihara, Yukihiko Ebisuno, Sakiyo Tsukamoto, Ryo Fujii, Akihiro Ohashi, Yutaka Suzuki, Katsuya Tsuchihara, Hiroyoshi Nishikawa, Toshihiko Doi

Scientific reports 11 ( 1 ) 341 - 341 2021.1

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Single-cell level analysis is powerful tool to assess the heterogeneity of cellular components in tumor microenvironments (TME). In this study, we investigated immune-profiles using the single-cell analyses of endoscopically- or surgically-resected tumors, and peripheral blood mononuclear cells from gastric cancer patients. Furthermore, we technically characterized two distinct platforms of the single-cell analysis; RNA-seq-based analysis (scRNA-seq), and mass cytometry-based analysis (CyTOF), both of which are broadly embraced technologies. Our study revealed that the scRNA-seq analysis could cover a broader range of immune cells of TME in the biopsy-resected small samples of tumors, detecting even small subgroups of B cells or Treg cells in the tumors, although CyTOF could distinguish the specific populations in more depth. These findings demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of TME in small biopsy tumors, which would provide a novel strategies to overcome a therapeutic difficulties against cancer heterogeneity in TME.

DOI： 10.1038/s41598-020-79385-w

Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants. Reviewed International journal

Ayumu Arakawa, Hitoshi Ichikawa, Takashi Kubo, Noriko Motoi, Tadashi Kumamoto, Miho Nakajima, Kan Yonemori, Emi Noguchi, Kuniko Sunami, Kouya Shiraishi, Hiroki Kakishima, Hiroshi Yoshida, Tomoro Hishiki, Naonori Kawakubo, Takafumi Kuroda, Takako Kiyokawa, Kyosuke Yamada, Nozomu Yanaihara, Kazuaki Takahashi, Aikou Okamoto, Shinsuke Hirabayashi, Daisuke Hasegawa, Atsushi Manabe, Kentaro Ono, Masaki Matsuoka, Yasuhito Arai, Yosuke Togashi, Tatsuhiro Shibata, Hiroyoshi Nishikawa, Kazunori Aoki, Noboru Yamamoto, Takashi Kohno, Chitose Ogawa

The New England journal of medicine 384 ( 1 ) 42 - 50 2021.1

Language：English Publishing type：Research paper (scientific journal)

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.).

DOI： 10.1056/NEJMoa2030391

Heterogeneity in congenital melanocytic nevi contributes to multicentric melanomagenesis. Reviewed International journal

Akiko Honobe, Kazuko Sakai, Yosuke Togashi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Kazuto Nishio, Takashi Inozume

Journal of dermatological science 100 ( 3 ) 217 - 219 2020.12

The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Reviewed International journal

Shogo Kumagai, Yosuke Togashi, Takahiro Kamada, Eri Sugiyama, Hitomi Nishinakamura, Yoshiko Takeuchi, Kochin Vitaly, Kota Itahashi, Yuka Maeda, Shigeyuki Matsui, Takuma Shibahara, Yasuho Yamashita, Takuma Irie, Ayaka Tsuge, Shota Fukuoka, Akihito Kawazoe, Hibiki Udagawa, Keisuke Kirita, Keiju Aokage, Genichiro Ishii, Takeshi Kuwata, Kenta Nakama, Masahito Kawazu, Toshihide Ueno, Naoya Yamazaki, Koichi Goto, Masahiro Tsuboi, Hiroyuki Mano, Toshihiko Doi, Kohei Shitara, Hiroyoshi Nishikawa

Nature immunology 21 ( 11 ) 1346 - 1358 2020.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1+CD8+ T cells relative to that of PD-1+ regulatory T (Treg) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8+ T cells and Treg cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1+CD8+ T cells and enhanced PD-1+ Treg cell-mediated immunosuppression. A profound reactivation of effector PD-1+CD8+ T cells rather than PD-1+ Treg cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.

DOI： 10.1038/s41590-020-0769-3

Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial. Reviewed International journal

Hidetoshi Hayashi, Yuichi Takiguchi, Hironobu Minami, Kohei Akiyoshi, Yoshihiko Segawa, Hiroki Ueda, Yasuo Iwamoto, Chihiro Kondoh, Koji Matsumoto, Shin Takahashi, Hisateru Yasui, Toshiyuki Sawa, Yusuke Onozawa, Yasutaka Chiba, Yosuke Togashi, Yoshihiko Fujita, Kazuko Sakai, Shuta Tomida, Kazuto Nishio, Kazuhiko Nakagawa

JAMA oncology 6 ( 12 ) 1931 - 1938 2020.10

Language：English Publishing type：Research paper (scientific journal)

Importance: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. Objective: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. Design, Setting, and Participants: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. Interventions: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. Main Outcomes And Measures: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. Results: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. Conclusions and Relevance: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. Trial Registration: UMIN Identifier: UMIN000016794.

DOI： 10.1001/jamaoncol.2020.4643

The critical role of CD4+ T cells in PD-1 blockade against MHC-II-expressing tumors such as classic Hodgkin lymphoma. Reviewed International journal

Joji Nagasaki, Yosuke Togashi, Takeaki Sugawara, Makiko Itami, Nobuhiko Yamauchi, Junichiro Yuda, Masato Sugano, Yuuki Ohara, Yosuke Minami, Hirohisa Nakamae, Masayuki Hino, Masahiro Takeuchi, Hiroyoshi Nishikawa

Blood advances 4 ( 17 ) 4069 - 4082 2020.9

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)/CD8+ T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD4+ T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD4+ T cells highly infiltrated the tumor microenvironment of MHC-II-expressing cHL, regardless of MHC-I expression status. Consequently, CD4+ T-cell, but not CD8+ T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II-expressing cHL associated with CD4+ T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD4+ T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I-MHC-II+ tumors but not on MHC-I-MHC-II- tumors, in a cytotoxic CD4+ T-cell-dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD4+ T cells in MHC-II-expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II-expressing tumors such as cHL that are mediated by cytotoxic CD4+ T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.

DOI： 10.1182/bloodadvances.2020002098

Enhanced tumor response to radiotherapy after PD-1 blockade in metastatic gastric cancer. Reviewed

Akinori Sasaki, Yoshiaki Nakamura, Yosuke Togashi, Hirofumi Kuno, Hidehiro Hojo, Shunichiro Kageyama, Naoki Nakamura, Kenji Takashima, Tomohiro Kadota, Yusuke Yoda, Saori Mishima, Kentaro Sawada, Daisuke Kotani, Akihito Kawazoe, Yasutoshi Kuboki, Hiroya Taniguchi, Takashi Kojima, Toshihiko Doi, Takayuki Yoshino, Tomonori Yano, Tatsushi Kobayashi, Tetsuo Akimoto, Hiroyoshi Nishikawa, Kohei Shitara

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 23 ( 5 ) 893 - 903 2020.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Immune checkpoint inhibitors may enhance the efficacy of radiotherapy (RT) in cancer treatment but the effect remains unknown in metastatic gastric cancer (mGC). This study aimed to compare the tumor shrinkage by palliative RT for mGC patients with or without previous exposure to anti-PD-1 therapy. METHODS: Data of 36 mGC patients who had received palliative RT from April 2013 to May 2019 were analyzed. Primary tumor responses were evaluated through a volumetric measurement-based method using computed tomography (CT) and endoscopic responses were evaluated in patients who underwent endoscopy before and after RT. Tumor microenvironment (TME) immune status was investigated by analyzing tumor-infiltrating lymphocytes by flow cytometry. RESULTS: Among 36 patients, 18 had previous exposure to anti-PD-1 before RT showing no significant differences in baseline characteristics with the other 18 patients without exposure to anti-PD-1 treatment. Tumor responses were observed in 28% (5/18) and none (0/18) in the anti-PD-1-exposed vs. naïve group, respectively (P = 0.045). Five out of eight patients in the anti-PD-1-exposed group, who underwent endoscopy after RT showed partial response, but none in the anti-PD-1-naïve patients showed response (P = 0.026). Increase in the CD8+ T cell/effector regulatory T cell ratio in TILs after anti-PD-1 therapy was noted in three responders to RT, but not in the other three non-responders. CONCLUSIONS: Prior exposure to anti-PD-1 therapy increases tumor response to RT. Immune profiling suggests that anti-PD-1 therapy may enhance the efficacy of RT by immunoactivation in the TME.

DOI： 10.1007/s10120-020-01058-4

Multicenter phase 1/2 Trial of napabucasin and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503/SCOOP Trial). Reviewed International journal

Akihito Kawazoe, Yasutoshi Kuboki, Eiji Shinozaki, Hiroki Hara, Tomohiro Nishina, Yoshito Komatsu, Satoshi Yuki, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Takeshi Kuwata, Masahito Kawazu, Hiroyuki Mano, Yosuke Togashi, Hiroyoshi Nishikawa, Takayuki Yoshino

Clinical cancer research : an official journal of the American Association for Cancer Research 26 ( 22 ) 5887 - 5894 2020.7

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: This is a phase 1/2 trial of napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC). EXPERIMENTAL DESIGN: Phase 1 was conducted to determine the recommended phase 2 dose (RP2D) in a dose escalation design of napabucasin (240mg to 480 mg twice daily) with 200mg pembrolizumab every 3 weeks. Phase 2 included cohort A (n = 10, microsatellite instability high) and cohort B (n = 40, microsatellite stable). The primary endpoint was immune-related objective response rate (irORR). PD-L1 combined positive score (CPS), genomic profiles and the consensus molecular subtypes (CMS) of colorectal cancer were assessed. RESULTS: A total of 55 patients were enrolled in this study. In phase 1, no patients experienced dose-limiting toxicities and napabucasin 480 mg was determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS <1, 1≤ CPS <10 and CPS ≥10, respectively. Patients with objective response tended to have higher tumor mutation burden than those without. Of evaluable 18 patients for CMS classification in cohort B, the irORR was 33.3%, 0%, 33.3% and 33.3% in CMS1, CMS2, CMS3 and CMS4, respectively. The common grade 3 or higher treatment-related adverse events included fever (10.0%) in cohort A and decreased appetite (7.5%) and diarrhea (5.0%) in cohort B. CONCLUSIONS: Napabucasin with pembrolizumab showed anti-tumor activity with acceptable toxicities for MSS mCRC patients as well as MSI-H mCRC, although it did not meet the primary end point.

DOI： 10.1158/1078-0432.CCR-20-1803

An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells. Reviewed International journal

Shogo Kumagai, Yosuke Togashi, Chika Sakai, Akihito Kawazoe, Masahito Kawazu, Toshihide Ueno, Eiichi Sato, Takeshi Kuwata, Takahiro Kinoshita, Masami Yamamoto, Sachiyo Nomura, Tetsuya Tsukamoto, Hiroyuki Mano, Kohei Shitara, Hiroyoshi Nishikawa

Immunity 53 ( 1 ) 187 - 203 2020.7

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Only a small percentage of patients afflicted with gastric cancer (GC) respond to immune checkpoint blockade (ICB). To study the mechanisms underlying this resistance, we examined the immune landscape of GC. A subset of these tumors was characterized by high frequencies of regulatory T (Treg) cells and low numbers of effector T cells. Genomic analyses revealed that these tumors bore mutations in RHOA that are known to drive tumor progression. RHOA mutations in cancer cells activated the PI3K-AKT-mTOR signaling pathway, increasing production of free fatty acids that are more effectively consumed by Treg cells than effector T cells. RHOA mutant tumors were resistant to PD-1 blockade but responded to combination of PD-1 blockade with inhibitors of the PI3K pathway or therapies targeting Treg cells. We propose that the metabolic advantage conferred by RHOA mutations enables Treg cell accumulation within GC tumors, generating an immunosuppressive TME that underlies resistance to ICB.

DOI： 10.1016/j.immuni.2020.06.016

Association between the mutational smoking signature and the immune microenvironment in lung adenocarcinoma. Reviewed International journal

Kei Sato, Sachiyo Mimaki, Riu Yamashita, Yosuke Togashi, Tomoyuki Naito, Hibiki Udagawa, Shinya Katsumata, Shoko Nakasone, Tomohiro Miyoshi, Kenta Tane, Keiju Aokage, Masato Sugano, Motohiro Kojima, Satoshi Fujii, Takeshi Kuwata, Atsushi Ochiai, Koichi Goto, Masahiro Tsuboi, Katsuya Tsuchihara, Genichiro Ishii

Lung cancer (Amsterdam, Netherlands) 147 12 - 20 2020.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Mutational signatures associated with tobacco smoking (mutational smoking signatures: SS) are characterized mainly by C > A mutations. The aim of this study was to characterize the association between the tumor immune microenvironment and the SS in lung adenocarcinoma. METHODS: Lung adenocarcinomas surgically resected from 96 patients, for which whole exome sequencing data was available, were included in the study. We extracted the SS from whole exome sequencing data, calculated the weights of SS using deconstructSigs, and compared the clinicopathological features of SS positive (SS+) and negative (SS-) adenocarcinomas. We selected 18 tumor pairs from SS + and SS- adenocarcinomas (sex, EGFR mutation, and tumor size-matched) and examined the expression of five immune markers (CD20, CD8, FOXP3, CD204, and PD-L1) by immunohistochemistry. RESULTS: Of 96 specimens, there were 33 (34 %) SS + adenocarcinoma tumors. The smoking index significantly correlated with the weight of the SS (R = 0.43). Between SS + and SS- tumors, there was no significant difference in clinicopathological factors excluding smoking history. Immunohistochemistry revealed that the number of FOXP3 + T cells in SS + adenocarcinomas was significantly higher than that in the SS- adenocarcinomas (median number 58 vs. 36, p < 0.01). Also, the number of CD20 + B cells in SS + adenocarcinomas was significantly higher than that in the SS- adenocarcinomas (median number 77 vs. 29, p < 0.01); however; these phenomena could not be confirmed when stratified by smoking history. CONCLUSION: In lung adenocarcinoma, SS is associated with an immunosuppressive tumor microenvironment.

DOI： 10.1016/j.lungcan.2020.06.029

Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603). Reviewed International journal

Shota Fukuoka, Hiroki Hara, Naoki Takahashi, Takashi Kojima, Akihito Kawazoe, Masako Asayama, Takako Yoshii, Daisuke Kotani, Hitomi Tamura, Yuichi Mikamoto, Nami Hirano, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Takeshi Kuwata, Yosuke Togashi, Hiroyoshi Nishikawa, Kohei Shitara

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 38 ( 18 ) 2053 - 2061 2020.6

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: This is a phase Ib trial of regorafenib plus nivolumab for gastric and colorectal cancer. PATIENTS AND METHODS: Enrolled patients received regorafenib plus nivolumab in a dose-finding part to estimate the maximum tolerated dose. Additional patients were enrolled in a dose-expansion part. Regorafenib of 80-160 mg was administered once daily for 21 days on/7 days off with nivolumab 3 mg/kg every 2 weeks. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks to estimate the recommended dose. RESULTS: Fifty patients (25 each with gastric and colorectal cancer) were enrolled. All patients had received ≥ 2 previous lines of chemotherapy, including anti-angiogenetic inhibitors in 96% of patients. Seven patients with gastric cancer had previously been treated with immune checkpoint inhibitors. One patient had microsatellite instability-high colorectal cancer, whereas the remaining patients had microsatellite stable or mismatch repair-proficient tumors. Three DLTs (grade 3 colonic perforation, maculopapular rash, and proteinuria) were observed with regorafenib 160 mg; none were observed with 80 or 120 mg. During the dose-expansion part, regorafenib dose was reduced from 120 to 80 mg because of frequent maculopapular rash. The common grade ≥ 3 treatment-related adverse events were rash (12%), proteinuria (12%), and palmar-plantar erythrodysesthesia (10%). Objective tumor response was observed in 20 patients (40%), including 11 with gastric cancer (44%) and 9 with colorectal cancer (36%). Median progression-free survival was 5.6 and 7.9 months in patients with gastric and colorectal cancer, respectively. CONCLUSION: The combination of regorafenib 80 mg plus nivolumab had a manageable safety profile and encouraging antitumor activity in patients with gastric and colorectal cancer, which warrants additional investigations in larger cohorts.

DOI： 10.1200/JCO.19.03296

TENERGY: multicenter phase II study of Atezolizumab monotherapy following definitive Chemoradiotherapy with 5-FU plus Cisplatin in patients with unresectable locally advanced esophageal squamous cell carcinoma. Reviewed International journal

Hideaki Bando, Daisuke Kotani, Takahiro Tsushima, Hiroki Hara, Shigenori Kadowaki, Ken Kato, Keisho Chin, Kensei Yamaguchi, Shun-Ichiro Kageyama, Hidehiro Hojo, Masaki Nakamura, Hidenobu Tachibana, Masashi Wakabayashi, Miki Fukutani, Yosuke Togashi, Nozomu Fuse, Hiroyoshi Nishikawa, Takashi Kojima

BMC cancer 20 ( 1 ) 336 - 336 2020.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is definitive chemoradiotherapy (CRT) using 5-FU plus cisplatin. However, complete response (CR) rates are low at 11-25%, resulting in 9-10 months of median overall survival (OS). An improved therapeutic efficacy by combining immunotherapy with radiation has been reported in patients with locally advanced non-small cell lung cancer. The results using ESCC cell lines suggest sequential treatment with anti-PD-L1 agents soon after completion of CRT is the most effective combination. METHODS: TENERGY trial is a multicenter, phase II, proof-of-concept study to assess the efficacy and safety of atezolizumab following definitive CRT in patients with locally advanced ESCC. The main inclusion criteria are unresectable locally advanced ESCC without distant metastasis, completion of 60 Gy of radiation plus two concomitant cycles of chemotherapy (cisplatin 70 mg/m2 on day 1 and 5-FU 700 mg/m2 on days 1-4, every 28 days), and adequate organ function. Within 6 weeks after CRT, participants will start taking 1200 mg of atezolizumab every three weeks and continue until 12 months or disease progression. The primary endpoint is the confirmed CR rate by the investigator's assessment. Secondary endpoints include overall response rate, progression-free survival (PFS), OS, adverse events, and confirmed CR rate by central assessment. We will enroll 50 patients (40 with primary locally advanced ESCC and 10 with postoperative locoregionally recurrent ESCC). We will obtain biopsies from the primary site and will collect blood at 3 time points (before CRT, after CRT, and four weeks after the start of atezolizumab) for an exploratory biomarker study. We will analyze the phenotype of immune-competent cells, neoantigens, tumor mutational burden, PD-L1 status, and Human Leukocyte Antigen haplotyping. DISCUSSION: The synergistic efficacies of the sequential combination of CRT and atezolizumab should improve the CR rate, resulting in survival improvement for patients with unresectable locally advanced ESCC. Because CRT is a standard treatment option for patients with early stage to locally advanced ESCC, the sequential combination of CRT and atezolizumab has the potential to change the standard ESCC treatments. TRIAL REGISTRATION: UMIN000034373, 10/04/2018 and EPOC1802.

DOI： 10.1186/s12885-020-06716-5

The potential application of PD-1 blockade therapy for early-stage biliary tract cancer. Reviewed International journal

Kumiko Umemoto, Yosuke Togashi, Yasuhito Arai, Hiromi Nakamura, Shinichiro Takahashi, Tokiyoshi Tanegashima, Mikiya Kato, Tsubasa Nishikawa, Daisuke Sugiyama, Motohiro Kojima, Naoto Gotohda, Takeshi Kuwata, Masafumi Ikeda, Tatsuhiro Shibata, Hiroyoshi Nishikawa

International immunology 32 ( 4 ) 273 - 281 2020.4

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Biliary tract cancer (BTC) is an aggressive cancer with a poor prognosis partially due to the limited success in developing novel therapies, including molecularly targeted therapies and immunotherapies. Programmed cell death-1 (PD-1) blockade therapy is less effective against BTCs, necessitating further studies to understand the detailed immunological status of the tumor microenvironment (TME) in BTC. Here, we examined the immunological status of the TME in 37 BTCs with early- to late-stage disease, especially focusing on PD-1+CD8+ T cells. PD-1+CD8+ T cells, which are reportedly associated with the clinical response to PD-1 blockade therapy, were frequently observed in early-stage BTC and decreased with disease progression. Imaging mass cytometry for representative PD-1+CD8+TIL-high and -low patients demonstrated that tumor-infiltrating PD-1+CD8+ T cells were localized adjacent to tumor cells, whereas PD-1-CD8+ T cells were detected mainly in the stroma of the TME. In a mouse model, PD-1 expression by tumor-infiltrating CD8+ T cells was higher in smaller tumors and decreased with tumor growth. Consequently, large tumors became resistant to PD-1 blockade, while small tumors containing higher numbers of PD-1+CD8+ T cells were sensitive. We propose the important role of tumor-infiltrating PD-1+CD8+ T cells in anti-tumor immunity and the potential application of PD-1 blockade therapy for early-stage BTC.

DOI： 10.1093/intimm/dxz080

Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer. Reviewed International journal

Eri Sugiyama, Yosuke Togashi, Yoshiko Takeuchi, Sayoko Shinya, Yasuko Tada, Keisuke Kataoka, Kenta Tane, Eiichi Sato, Genichiro Ishii, Koichi Goto, Yasushi Shintani, Meinoshin Okumura, Masahiro Tsuboi, Hiroyoshi Nishikawa

Science immunology 5 ( 43 ) 2020.1

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

The clinical efficacy of anti-PD-1 (programmed cell death-1) monoclonal antibody (mAb) against cancers with oncogenic driver gene mutations, which often harbor a low tumor mutation burden, is variable, suggesting different contributions of each driver mutation to immune responses. Here, we investigated the immunological phenotypes in the tumor microenvironment (TME) of epidermal growth factor receptor (EGFR)-mutated lung adenocarcinomas, for which anti-PD-1 mAb is largely ineffective. Whereas EGFR-mutated lung adenocarcinomas had a noninflamed TME, CD4+ effector regulatory T cells, which are generally present in the inflamed TME, showed high infiltration. The EGFR signal activated cJun/cJun N-terminal kinase and reduced interferon regulatory factor-1; the former increased CCL22, which recruits CD4+ regulatory T cells, and the latter decreased CXCL10 and CCL5, which induce CD8+ T cell infiltration. The EGFR inhibitor erlotinib decreased CD4+ effector regulatory T cells infiltration in the TME and in combination with anti-PD-1 mAb showed better antitumor effects than either treatment alone. Our results suggest that EGFR inhibitors when used in conjunction with anti-PD-1 mAb could increase the efficacy of immunotherapy in lung adenocarcinomas.

DOI： 10.1126/sciimmunol.aav3937

Multiple modalities of single cell analyses to evaluate the tumor microenvironment in clinical specimens Reviewed

Yukie Kashima, Shota Fukuoka, Yosuke Togashi, Takahiro Kamada, Ayako Suzuki, Yoshiaki Nakamura, Kohei Shitara, Akihiro Ohashi, Taku Yoshida, Naofumi Taoka, Tatsuya Kawase, Teiji Wada, Kocihiro Inaki, Masataka Chihara, Yutaka Suzuki, Katsuya Tsuchihara, Susumu S. Kobayashi, Hiroyoshi Nishikawa, Toshihiko Doi

MOLECULAR CANCER THERAPEUTICS 18 ( 12 ) 2019.12

Clinical and immune profiling for cancer of unknown primary site. Reviewed

Haratani K, Hayashi H, Takahama T, Nakamura Y, Tomida S, Yoshida T, Chiba Y, Sawada T, Sakai K, Fujita Y, Togashi Y, Tanizaki J, Kawakami H, Ito A, Nishio K, Nakagawa K

Journal for immunotherapy of cancer 7 ( 1 ) 251 2019.9

Selective inhibition of low-affinity memory CD8⁺ T cells by corticosteroids. Reviewed International journal

Tokunaga A, Sugiyama D, Maeda Y, Warner AB, Panageas KS, Ito S, Togashi Y, Sakai C, Wolchok JD, Nishikawa H

The Journal of experimental medicine 216 ( 12 ) 2701 - 2713 2019.9

Language：English Publishing type：Research paper (scientific journal)

Patients treated with immune checkpoint blockade (ICB) sometimes experience immune-related adverse events (irAEs), requiring immuno-suppressive drugs such as corticosteroids despite the possibility that immunosuppression may impair the antitumor effects of ICB. Here, we address the dilemma of using corticosteroids for the treatment of irAEs induced by ICB. ICB augments neoantigen-specific CD8+ T cell responses, resulting in tumor regression. In our model, simultaneous, but not late, administration of corticosteroids impaired antitumor responses with reduction of CD8+ T cell proliferation. Secondary challenge using tumors with/without the neoantigen showed selective progression in tumors lacking the neoantigen when corticosteroids were administered. Corticosteroids decreased low- but not high-affinity memory T cells by suppressing fatty acid metabolism essential for memory T cells. In a small cohort of human melanoma patients, overall survival was shorter after treatment with CTLA-4 blockade in patients who received early corticosteroids or had low tumor mutation burden. Together, low-affinity memory T cells are dominantly suppressed by corticosteroids, necessitating careful and thoughtful corticosteroid use.

DOI： 10.1084/jem.20190738

Analysis of the Tumor Reactivity of Tumor-Infiltrating Lymphocytes in a Metastatic Melanoma Lesion that Lost Major Histocompatibility Complex Class I Expression after Anti-PD-1 Therapy. Reviewed International journal

Takashi Inozume, Tomonori Yaguchi, Ryo Ariyasu, Yosuke Togashi, Takehiro Ohnuma, Akiko Honobe, Hiroyoshi Nishikawa, Yutaka Kawakami, Tatsuyoshi Kawamura

The Journal of investigative dermatology 139 ( 7 ) 1490 - 1496 2019.7

Language：English Publishing type：Research paper (scientific journal)

Major histocompatibility complex class I loss due to the abnormality of β2-microglobulin gene is one of the mechanisms underlying delayed relapses in melanoma patients long after the initial positive responses to anti-PD-1 therapy. However, the tumor-specific reactivity of tumor-infiltrating lymphocytes in tumor lesions that lost major histocompatibility complex class I expression has not been well evaluated. We report the case of a 55-year-old woman with two metastatic melanoma lesions. After a 12-month period of successful tumor suppression by anti-PD-1 antibody therapy, one lesion started to grow again. We resected both lesions and examined the tumor cells and tumor-infiltrating lymphocytes. The shrinking lesion consisted of necrotic tissue and macrophages, and the enlarged lesion consisted of both necrotic tissue and viable tumor cells. The tumor cells completely lost major histocompatibility complex class I expression, but it was restored upon retroviral transduction of the normal β2-microglobulin gene. When we checked the tumor-specific reactivity of tumor-infiltrating lymphocytes derived from the relapsing lesion, we found that these tumor-infiltrating lymphocytes failed to recognize the native tumor cells derived from the lesion, but strongly recognized the major histocompatibility complex class-I-recovered cells by β2-microglobulin transduction. Our report emphasizes the limitations of T-cell-based immunotherapy and highlights the importance of developing alternative strategies for such cases.

DOI： 10.1016/j.jid.2019.01.007

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