JITC Digest January 2019

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Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

In the January edition of the JITC Digest, there are four noteworthy articles of which I would like to draw special attention. First, the article “Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradication,” by Gijs G. Zom et al. reports novel murine data demonstrating the enhanced immunological potency of the novel TLR2-ligand, Amplivant (AV), as an adjuvant in cancer immunotherapy. Such results lay the foundation for further clinical testing of AV-synthetic long peptide (SLP) conjugates.

Next, the research article, “1-Pyrroline-5-carboxylate released by prostate Cancer cell inhibit T cell proliferation and function by targeting SHP1/cytochrome c oxidoreductase/ROS Axis,” by Yutao Yan et al. establishes a crucial immunosuppressive mechanism utilized in prostate cancer by which metabolites released by prostate cancer cells directly impair T cell immunity and anti-tumor functionality.

Furthermore, the article, “Agonist redirected checkpoint, PD1-Fc-OX40L, for cancer immunotherapy,” by George Fromm et al. details the development and characterization of Agonist Redirected Checkpoint™ (ARC), a dual-sided Fc fusion protein platform for the linking of specific checkpoint and costimulatory pathways. Fromm’s group specifically reports on the anti-tumor response and potential therapeutic activity of the prototype ARC molecule, PD1-Fc-OX40L, for both human and mouse.

Finally, Larissa S. Carnevalli et al.’s article, “PI3K-alpha/delta inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity,” examines the immune response elicited by AZD8835, a dual PI3K-alpha/delta inhibitor, through preclinical syngeneic tumor models and determines how differential dosing of the inhibitor affects anti-tumor immunity through interactions with the tumor immune microenvironment.

With best regards,
Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer


JITC Editor Picks

Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradication

Gijs G. Zom, Marian M. J. H. P. Willems, Selina Khan, Tetje C. van der Sluis, Jan Willem Kleinovink, Marcel G. M. Camps, Gijsbert A. van der Marel, Dmitri V. Filippov, Cornelis J. M. Melief and Ferry Ossendorp
Journal for ImmunoTherapy of Cancer, 6:146 (12 December 2018)
Research Article

Summary:

Previous studies demonstrate the immune activating properties of covalently conjugating the TLR2-ligand, PAM3CSK4, to synthetic long peptides (SLPs) for use as cancer vaccines. The present study shows the enhanced immunological potency of the novel TLR2-ligand, Amplivant (AV), as an adjuvant in cancer immunotherapy. AV conjugated to an SLP enhanced not only activation of dendritic cells in vitro but also induced stronger in vivo T cell priming compared to Pam3CSK4 (the reference TLR2-ligand) conjugated to the same SLP, suggesting the strong therapeutic potential of AV as a TLR2-ligand and justification for further clinical testing of AV-SLP conjugates.

1-Pyrroline-5-carboxylate released by prostate Cancer cell inhibit T cell proliferation and function by targeting SHP1/cytochrome c oxidoreductase/ROS Axis

Yutao Yan, Lei Chang, Hongzhe Tian, Lu Wang, Yawei Zhang, Tao Yang, Guohao Li, Weifeng Hu, Kavita Shah, Gang Chen and Yonglian Guo
Journal for ImmunoTherapy of Cancer, 6:148 (13 December 2018)
Research Article

Summary:

This study by Yutao Yan et al. links prostate cancer cell (PCC) metabolites with T cell proliferation and function through in vitro analysis of PCC conditioned media followed by a metabolomics study using liquid chromatography mass spectroscopy (LC/MS-MS). A crucial immunosuppressive mechanism in prostate cancer was elucidated by which metabolites released by PCC directly impair T cell immunity and anti-tumor functionality through enhancing levels of 1-Pyrroline-5-carboxylate (P5C), subsequently upregulating SHP1, and increasing the levels of reactive oxygen species. Such results suggest a possibly novel target for T cell reactivation in treating prostate cancer.

Agonist redirected checkpoint, PD1-Fc-OX40L, for cancer immunotherapy

George Fromm, Suresh de Silva, Kellsey Johannes, Arpita Patel, Josiah C. Hornblower and Taylor H. Schreiber
Journal for ImmunoTherapy of Cancer, 6:149 (18 December 2018)
Research Article

Summary:

This article by George Fromm et al. details the development and characterization of Agonist Redirected Checkpoint™ (ARC), a dual-sided Fc fusion protein platform. The prototype ARC molecule (PD1-Fc-OX40L) activated primary human T cells in vitro by increasing effector cytokine production and proliferation, triggered NFkB signaling, and outperformed clinical-stage antibodies (pembrolizumab, nivolumab, tavolixizumab) in stimulating IL-2 secretion. Originally, developed to both block immune checkpoint pathways and activate TNF receptors, ARC has demonstrated the ability to bind PD-L1 and OX40 simultaneously, and appears apt to facilitate a potent anti-tumor polyfunctional T cell response.

PI3K-alpha/delta inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity

Larissa S. Carnevalli, Charles Sinclair, Molly A. Taylor, Pablo Morentin Gutierrez, Sophie Langdon, Anna M. L. Coenen-Stass, Lorraine Mooney, Adina Hughes, Laura Jarvis, Anna Staniszewska, Claire Crafter, Ben Sidders, Elizabeth Hardaker, Kevin Hudson and Simon T. Barry
Journal for ImmunoTherapy of Cancer, 6:158 (27 December 2018)
Research Article

Summary:

Inhibitors of PI3K promote activation of T cell responses through suppression of regulatory T cells or myeloid-derived suppressor cells, leading to enhanced T cell–mediated anti-tumor activity. Carnevalli et al. examined this PI3K-associated immune response through differential dosing of AZD8835, a dual PI3K-alpha/delta inhibitor, in preclinical syngeneic tumor models. Initially developed to treat solid cancers dependent on PI3K-alpha/delta signaling, this study demonstrates a clear role for AZD8835 in potentiating anti-tumor immunity and as a positive modulator of the tumor immune microenvironment in a clinically relevant framework.

Treatment duration with immune-based therapies in Cancer: an enigma

Shanta Bantia and Nirmal Choradia
Journal for ImmunoTherapy of Cancer, 6:143 (5 December 2018)
Commentary

Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor–induced colitis: a multi-center study

Hamzah Abu-Sbeih, Faisal S. Ali, Dana Alsaadi, Joseph Jennings, Wenyi Luo, Zimu Gong, David M. Richards, Aline Charabaty and Yinghong Wang
Journal for ImmunoTherapy of Cancer, 6:142 (5 December 2018)
Research Article

A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment

Yu-Tzu Liu, Tai-Chung Tseng, Ruey-Shyang Soong, Chun-Yi Peng, Yu-Hsing Cheng, Shiu-Feng Huang, Tsung-Hsien Chuang, Jia-Horng Kao and Li-Rung Huang
Journal for ImmunoTherapy of Cancer, 6:144 (7 December 2018)
Research Article

Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1+ regulatory B cell expansion

Linsen Ye, Qi Zhang, Yusheng Cheng, Xiaolong Chen, Guoying Wang, Mengchen Shi, Tong Zhang, Yingjiao Cao, Hang Pan, Liting Zhang, Genshu Wang, Yinan Deng, Yang Yang and Guihua Chen
Journal for ImmunoTherapy of Cancer, 6:145 (10 December 2018)
Research Article

Cryotherapy for nodal metastasis in NSCLC with acquired resistance to immunotherapy

Lucas C. Adam, Junaid Raja, Johannes M. Ludwig, Adebowale Adeniran, Scott N. Gettinger and Hyun S. Kim
Journal for ImmunoTherapy of Cancer, 6:147 (12 December 2018)
Case Report

Myocarditis in a patient treated with Nivolumab and PROSTVAC: a case report

Cecilia Monge, Hoyoung Maeng, Alessandra Brofferio, Andrea B. Apolo, Bharath Sathya, Andrew E. Arai, James L. Gulley and Marijo Bilusic
Journal for ImmunoTherapy of Cancer, 6:150 (18 December 2018)
Case Report

Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1

Zhi-Fa Wen, Hongxiang Liu, Rong Gao, Meng Zhou, Jie Ma, Yue Zhang, Jinjin Zhao, Yongqiang Chen, Tianyu Zhang, Fang Huang, Ning Pan, Jinping Zhang, Bernard A. Fox, Hong-Ming Hu and Li-Xin Wang
Journal for ImmunoTherapy of Cancer, 6:151 (18 December 2018)
Research Article

Non-invasive biomarkers derived from the extracellular matrix associate with response to immune checkpoint blockade (anti-CTLA-4) in metastatic melanoma patients

Christina Jensen, Daniel Hargbøl Madsen, Morten Hansen, Henrik Schmidt, Inge Marie Svane, Morten Asser Karsdal and Nicholas Willumsen
Journal for ImmunoTherapy of Cancer, 6:152 (19 December 2018)
Research Article

Taking the bull by the horn: the frontline use of infliximab for the treatment of immune checkpoint inhibitor-induced enterocolitis

Khashayar Esfahani
Journal for ImmunoTherapy of Cancer, 6:154 (22 December 2018)
Commentary

Infliximab for treatment-refractory transverse myelitis following immune therapy and radiation

Victoria A. Chang, Daniel R. Simpson, Gregory A. Daniels and David E. Piccioni
Journal for ImmunoTherapy of Cancer, 6:153 (22 December 2018)
Case Report

Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis

Yixin Zhou, Chen Chen, Xuanye Zhang, Sha Fu, Cong Xue, Yuxiang Ma, Wenfeng Fang, Yunpeng Yang, Xue Hou, Yan Huang, Hongyun Zhao, Shaodong Hong and Li Zhang
Journal for ImmunoTherapy of Cancer, 6:155 (22 December 2018)
Research Article

High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors

Saman Maleki Vareki
Journal for ImmunoTherapy of Cancer, 6:157 (27 December 2018)
Commentary

A severe case of refractory esophageal stenosis induced by nivolumab and responding to tocilizumab therapy

Alice Horisberger, Stefano La Rosa, Jean-Philippe Zurcher, Stefan Zimmermann, Francois Spertini, George Coukos and Michel Obeid
Journal for ImmunoTherapy of Cancer, 6:156 (27 December 2018)
Case Report

Immune checkpoint inhibitors in MITF family translocation renal cell carcinomas and genetic correlates of exceptional responders

A. Boilève, M. I. Carlo, P. Barthélémy, S. Oudard, D. Borchiellini, M. H. Voss, S. George, C. Chevreau, J. Landman-Parker, M-D Tabone, D. D. Chism, A. Amin, M. A. Bilen, D. Bosse, A. Coulomb-L’hermine, Xiaoping Su, T. K. Choueiri, Nizar M. Tannir and Gabriel G. Malouf
Journal for ImmunoTherapy of Cancer, 6:159 (27 December 2018)
Research Article

SITC Members Receive 60 Percent Submission Discount in 2019

*As a way to thank the SITC members who work tirelessly to advance the science and improve the lives of cancer patients, SITC will provide SITC members with a 60 percent discount on processing fees for all JITC articles accepted in 2019. To take advantage of this SITC member benefit, authors must contact JITC Managing Editor Andrea Kunz at JITCEditor@sitcancer.org or 1-414-271-2456 prior to submission to obtain a discount code and instructions.