JITC Digest September 2019

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Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

There are several recent articles I would like to highlight in this September issue of the JITC digest, pointing to the progress we’ve been making toward understanding the immune system and cancer.

First, “PD-1 silencing impairs the anti-tumor function of chimeric antigen receptor modified T cells by inhibiting proliferation activity” by Jianshu Wang et al demonstrates yet another function of PD-1 in T cells. In this case, knock-down of PD-1 does not lead to increased anti-tumor activity; rather, silencing of PD-1 in CAR T cells inhibits their proliferation capability and differentiation, and impairs their anti-tumor effects.

“Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1” by Suzanne Thomas et al outlines the potential of a novel HSV-1-based oncolytic platform, whereby the engineered virus is armed with various modifications to increase its therapeutic effects, essentially allowing effective combination therapy through a single administered agent.

In the article, “Concurrent therapy with immune checkpoint inhibitors and TNFα blockade in patients with gastrointestinal immune-related adverse events”, Yousef R. Badran and co-authors provide insight into management of one of the most common immune-related adverse events, enterocolitis. They describe five patients treated concurrently with checkpoint inhibitors and infliximab, all of whom had symptom resolution and disease control, providing physicians an example for management or severe cases of this common side effect. While the efficacy of this combination to control immune related enterocolitis awaits formal confirmation in controlled clinical trials, the results are indeed in line with recent observations in pre-clinical studies (Perez-Ruiz et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy, Nature 2019).

Daruka Mahadevan et al describe a novel immune checkpoint inhibitor in “Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200”. In this first-in-human study, the authors observed encouraging efficacy through blockade of CD200 in hematologic malignancies, recommending further dosing optimization for future investigations.

Finally, “Characterization of a whole blood assay for quantifying myeloid-derived suppressor cells” by Minjun C. Apodaca et al addresses a pressing issue with a promising biomarker: quantification of circulating myeloid-derived suppressor cells. They identify a common pathway to their quantification using flow cytometry, and also point out a few pre-analytical variables that have significant impact on MDSC levels as well.

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


JITC Editor Picks

PD-1 silencing impairs the anti-tumor function of chimeric antigen receptor modified T cells by inhibiting proliferation activity

Jianshu Wei, Can Luo, Yao Wang, Yelei Guo, Hanren Dai, Chuan Tong, Dongdong Ti, Zhiqiang Wu & Weidong Han
Journal for ImmunoTherapy of Cancer, 7:209 (7 August 2019)
Research

Summary:

Short hairpin RNA (shRNA)-mediated silencing of PD-1 allowed for investigation of the impact of PD-1 signaling on the behavior of CAR T cells by Wei et al. In in vitro co-culture experiments, the blockade of PD-1 was not found to enhance the cytotoxicity of the CD19-targeted CAR T cells; rather, while the CAR T cells had significantly increased resistance to PD-L1-mediated immunosuppression, the PD-1-knockdown CAR T cells were less effective at killing CD19-positive tumor cells, especially at low CAR T-to-tumor cell ratios. These findings were mirrored in vivo, where decreased CAR T cell proliferation and differentiation resulted in low CAR T cell expansion and weak tumor clearance. These findings point to the many roles of PD-1 signaling in anti-tumor immunity and T cell function.

Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1

Suzanne Thomas, Linta Kuncheria, Victoria Roulstone, Joan N. Kyula, David Mansfield, Praveen K. Bommareddy, Henry Smith, Howard L. Kaufman, Kevin J. Harrington & Robert S. Coffin
Journal for ImmunoTherapy of Cancer, 7:214 (10 August 2019)
Research

Summary:

Oncolytic viruses have been employed to increase the immunogenicity of cell death and to induce systemic host anti-tumor immunity. Thomas et al developed a new HSV-1-based oncolytic immunotherapy with potent anti-tumor capabilities. The new strain was engineered to express the envelope glycoprotein of gibbon ape leukemia virus, leading to immunogenic cell death in vitro as well as local and distant tumor responses in in vivo preclinical models. Further engineering of the virus to express mGM-CSF along with mCTLA-4, mCD40L, m4-1BBL, or mOX40L led to increased anti-tumor activity, particularly evident in non-injected tumors. The developed HSV-1-based platform thus offers a flexible approach for future development of oncolytic immunotherapies.

Concurrent therapy with immune checkpoint inhibitors and TNF-alpha blockade in patients with gastrointestinal immune-related adverse events

Yousef R. Badran, Justine V. Cohen, Priscilla K. Brastianos, Aparna R. Parikh, Theodore S. Hong & Michael Dougan
Journal for ImmunoTherapy of Cancer, 7:226 (22 August 2019)
Short Report

Summary:

The emergence of immune-related adverse events, particularly immune-related enterocolitis (irEC), often prompts disruption or discontinuation of immune checkpoint inhibitors (ICIs). Traditional first-line treatment of irEC includes steroid treatment, but some patients do not respond and there are well-known drawbacks of long-term steroid use. Therefore, blockade of TNF-alpha presents an alternative option; however, there is limited data on the impact of this blockade when administered concurrently with ICIs on treatment outcomes. Badran et al report a case series of five patients treated with first-line steroids and then concurrent TNF-alpha blockade and ICIs, demonstrating symptom and disease control with the combination. This combination might be interesting by facilitating steroid tapering and preventing immune related enterocolitis. These results are in line with recent observations in pre-clinical studies (Perez-Ruiz et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy, Nature 2019).

Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200

Daruka Mahadevan, Mark C. Lanasa, Charles Farber, Manjari Pandey, Maria Whelden, Susan J. Faas, Terrie Ulery, Anjli Kukreja, Lan Li, Camille L. Bedrosian, Xiaoping Zhang & Leonard T. Heffner
Journal for ImmunoTherapy of Cancer, 7:227 (23 August 2019)
Research

Summary:

CD200, found on a range of cell types including B cells, T cells, and dendritic cells, and also overexpressed by a variety of tumor cells, acts to inhibit immune activity upon ligation with its receptor, CD200R. Therefore, samalizumab, a recombinant humanized monoclonal antibody binding CD200, was explored in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) patients by Mahadevan et al. Using a 3+3 study design, dose levels from 50 to 600 mg/m2 were explored, with safety, maximum tolerated dose, and pharmacokinetics as the primary endpoints. An ORR of 4% was observed in CLL patients, with another 70% of the CLL patients exhibiting stable disease. No MM patients responded to the therapy. With further optimization of the dosing regimen, samalizumab may hold promise for immune checkpoint blockade therapy in the future.

Characterization of a whole blood assay for quantifying myeloid-derived suppressor cells

Minjun C. Apodaca, Amy E. Wright, Angela M. Riggins, William P. Harris, Raymond S. Yeung, Lei Yu & Chihiro Morishima
Journal for ImmunoTherapy of Cancer, 7:230 (28 August 2019)
Research

Summary:

High levels of circulating myeloid-derived suppressor cells (MDSCs) have been correlated with poor outcomes for cancer patients, making them a promising biomarker. However, there is currently wide variation in quantification of MDSCs amongst laboratories. Apodaca et al herein propose a whole blood, flow cytometry-based assay for quantification of MDSCs. Using their nine color, 11 parameter assay, a few pre-analysis variables were identified to have a large impact on MDSC measurement. Longer elapsed time since collection of whole blood reduced the number of identified MDSCs, as did the use of Na+heparin tubes instead of K2EDTA. These findings, along with the proposed gating strategy, hold promise to help standardize quantification of this important cell population.

State-of-the-art for CAR T-cell therapy for chronic lymphocytic leukemia in 2019

Richard Lemal & Olivier Tournilhac
Journal for ImmunoTherapy of Cancer, 7:202 (1 August 2019)
Review

A case of checkpoint inhibitor-induced celiac disease

Dana Alsaadi, Neil J. Shah, Aline Charabaty & Michael B. Atkins
Journal for ImmunoTherapy of Cancer, 7:203 (5 August 2019)
Case Report

Local and abscopal responses in advanced intrahepatic cholangiocarcinoma with low TMB, MSS, pMMR and negative PD-L1 expression following combined therapy of SBRT with PD-1 blockade

Xiaoliang Liu, Jianfei Yao, Lele Song, Sujing Zhang, Tanxiao Huang & Yu Li
Journal for ImmunoTherapy of Cancer, 7:204 (5 August 2019)
Case Report

Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges

A. Pavan, I. Attili, G. Pasello, V. Guarneri, P. F. Conte & L. Bonanno
Journal for ImmunoTherapy of Cancer, 7:205 (5 August 2019)
Review

Designing gene panels for tumor mutational burden estimation: the need to shift from ‘correlation’ to ‘accuracy’

Hao-Xiang Wu, Zi-Xian Wang, Qi Zhao, Feng Wang & Rui-Hua Xu
Journal for ImmunoTherapy of Cancer, 7:206 (6 August 2019)
Commentary

MICA immune complex formed with alpha 3 domain-specific antibody activates human NK cells in a Fc-dependent manner

Changchun Du, Jack Bevers III, Ryan Cook, T. Noelle Lombana, Kamalakannan Rajasekaran, Marissa Matsumoto, Christoph Spiess, Jeong M. Kim & Zhengmao Ye
Journal for ImmunoTherapy of Cancer, 7:207 (6 August 2019)
Research

Natural killer T cell activation increases iNOS+CD206- M1 macrophage and controls the growth of solid tumor

Sourav Paul, Sushanta Chhatar, Amrita Mishra & Girdhari Lal
Journal for ImmunoTherapy of Cancer, 7:210 (7 August 2019)
Research

miR-448 targets IDO1 and regulates CD8+ T cell response in human colon cancer

Qiong Lou, Ruixian Liu, Xiangling Yang, Weiqian Li, Lanlan Huang, Lili Wei, Huiliu Tan, Nanlin Xiang, Kawo Chan, Junxiong Chen & Huanliang Liu
Journal for ImmunoTherapy of Cancer, 7:210 (7 August 2019)
Research

Immunogenicity of pembrolizumab in patients with advanced tumors

Marianne J. H. van Vugt, Julie A. Stone, “Rik” H. J. M. M. De Greef, Ellen S. Snyder, Leslie Lipka, David C. Turner, Anne Chain, Mallika Lala, Mengyao Li, Seth H. Robey, Anna G. Kondic, Dinesh De Alwis, Kapil Mayawala, Lokesh Jain & Tomoko Freshwater
Journal for ImmunoTherapy of Cancer, 7:212 (8 August 2019)
Research

Angiosarcoma patients treated with immune checkpoint inhibitors: a case series of seven patients from a single institution

Vaia Florou, Andrew E. Rosenberg, Eric Wieder, Krishna V. Komanduri, Despina Kolonias, Mohamed Uduman, John C. Castle, Jennifer S. Buell, Jonathan C. Trent & Breelyn A. Wilky
Journal for ImmunoTherapy of Cancer, 7:213 (8 August 2019)
Case Report

Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling

Dan Wang, Li Yang, Weina Yu, Qian Wu, Jingyao Lian, Feng Li, Shasha Liu, Aitian Li, Zhiang He, Jinbo Liu, Zhenqiang Sun, Weitang Yuan & Yi Zhang
Journal for ImmunoTherapy of Cancer, 7:215 (8 August 2019)
Research

Immune microenvironment modulation unmasks therapeutic benefit of radiotherapy and checkpoint inhibition

Jared M. Newton, Aurelie Hanoteau, Hsuan-Chen Liu, Angelina Gaspero, Falguni Parikh, Robyn D. Gartrell-Corrado, Thomas D. Hart, Damya Laoui, Jo A. Van Ginderachter, Neeraja Dharmaraj, William C. Spanos, Yvonne Saenger, Simon Young & Andrew G. Sikora
Journal for ImmunoTherapy of Cancer, 7:216 (13 August 2019)
Research

PD-L1 blockade engages tumor-infiltrating lymphocytes to co-express targetable activating and inhibitory receptors

Guillaume Beyrend, Esmé van der Gracht, Ayse Yilmaz, Suzanne van Duikeren, Marcel Camps, Thomas Höllt, Anna Vilanova, Vincent van Unen, Frits Koning, Noel F. C. C. de Miranda, Ramon Arens & Ferry Ossendorp
Journal for ImmunoTherapy of Cancer, 7:217 (14 August 2019)
Research

Combination immunotherapy and radiotherapy causes an abscopal treatment response in a mouse model of castration resistant prostate cancer

Stephanie O. Dudzinski, Brent D. Cameron, Jian Wang, Jeffrey C. Rathmell, Todd D. Giorgio & Austin N. Kirschner
Journal for ImmunoTherapy of Cancer, 7:218 (14 August 2019)
Research

Safety, tolerability, pharmacokinetics, and pharmacodynamics of the afucosylated, humanized anti-EPHA2 antibody DS-8895a: a first-in-human phase I dose escalation and dose expansion study in patients with advanced solid tumors

Kohei Shitara, Taroh Satoh, Satoru Iwasa, Kensei Yamaguchi, Kei Muro, Yoshito Komatsu, Tomohiro Nishina, Taito Esaki, Jun Hasegawa, Yasuyuki Kakurai, Emi Kamiyama, Tomoko Nakata, Kota Nakamura, Hayato Sakaki & Ichinosuke Hyodo
Journal for ImmunoTherapy of Cancer, 7:219 (14 August 2019)
Research

Indocyanine green and poly I:C containing thermo-responsive liposomes used in immune-photothermal therapy prevent cancer growth and metastasis

Li Xu, Wei Zhang, Hae-Bin Park, Minseok Kwak, Junghwan Oh, Peter C. W. Lee & Jun-O Jin
Journal for ImmunoTherapy of Cancer, 7:220 (15 August 2019)
Research

The great debate at “Immunotherapy Bridge 2018”, Naples, November 29th, 2018

Paolo A. Ascierto, Lisa H. Butterfield, Sandra Demaria, Robert L. Ferris, Gordon J. Freeman, Roger S. Lo, Alberto Mantovani, Paul Nathan, Omid Hamid, Katerina Politi & Igor Puzanov
Journal for ImmunoTherapy of Cancer, 7:221 (15 August 2019)
Review

The complex relationship between body mass index and response to immune checkpoint inhibition in metastatic melanoma patients

Douglas Donnelly, Shirin Bajaj, Jaehong Yu, Miles Hsu, Arjun Balar, Anna Pavlick, Jeffrey Weber, Iman Osman & Judy Zhong
Journal for ImmunoTherapy of Cancer, 7:222 (19 August 2019)
Short Report

Small molecule immunomodulation: the tumor microenvironment and overcoming immune escape

Arsen Osipov, May Tun Saung, Lei Zheng & Adrian G. Murphy
Journal for ImmunoTherapy of Cancer, 7:224 (22 August 2019)
Review

Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of patients with advanced solid malignancies

Aung Naing, Jeffrey Infante, Sanjay Goel, Howard Burris, Chelsea Black, Shannon Marshall, Ikbel Achour, Susannah Barbee, Rena May, Chris Morehouse, Kristen Pollizzi, Xuyang Song, Keith Steele, Nairouz Elgeioushi, Farzana Walcott, Joyson Karakunnel, Patricia LoRusso, Amy Weise, Joseph Eder, Brendan Curti & Michael Oberst
Journal for ImmunoTherapy of Cancer, 7:225 (22 August 2019)
Research

Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC+ tumors respond to PD1/PD-L1 blockade therapy

Jinyu Zhang, Pablo Saenz-lopez Larrocha, Bin Zhang, Derek Wainwright, Payal Dhar & Jennifer D. Wu
Journal for ImmunoTherapy of Cancer, 7:223 (26 August 2019)
Research

PD-L1 expression is a predictive biomarker for CIK cell-based immunotherapy in postoperative patients with breast cancer

Zi-Qi Zhou, Jing-Jing Zhao, Qiu-Zhong Pan, Chang-Long Chen, Yuan Liu, Yan Tang, Qian Zhu, De-Sheng Weng & Jian-Chuan Xia
Journal for ImmunoTherapy of Cancer, 7:228 (27 August 2019)
Research

Cancer targeting by TCR gene-engineered T cells directed against Kita-Kyushu Lung Cancer Antigen-1

Bridget Marcinkowski, Sanja Stevanović, Sarah R. Helman, Scott M. Norberg, Carylinda Serna, Benjamin Jin, Nikolaos Gkitsas, Tejas Kadakia, Andrew Warner, Jeremy L. Davis, Lisa Rooper & Christian S. Hinrichs
Journal for ImmunoTherapy of Cancer, 7:229 (28 August 2019)
Short Report

Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells

Wanfeng Gao, Xiaoyun Zhang, Wendong Yang, Daolei Dou, Heng Zhang, Yuanhao Tang, Weilong Zhong, Jing Meng, Yun Bai, Yanrong Liu, Lan Yang, Shuang Chen, Huijuan Liu, Cheng Yang & Tao Sun
Journal for ImmunoTherapy of Cancer, 7:231 (28 August 2019)
Research

Isolation of T cell receptor specifically reactive with autologous tumour cells from tumour-infiltrating lymphocytes and construction of T cell receptor engineered T cells for esophageal squamous cell carcinoma

Qin Tan, Chaoting Zhang, Wenjun Yang, Ying Liu, Palashati Heyilimu, Dongdong Feng, Liying Xing, Yang Ke & Zheming Lu
Journal for ImmunoTherapy of Cancer, 7:232 (28 August 2019)
Research

A PD-L2-based immune marker signature helps to predict survival in resected pancreatic ductal adenocarcinoma

Yiyin Zhang, Jin Xu, Jie Hua, Jiang Liu, Chen Liang, Qingcai Meng, Miaoyan Wei, Bo Zhang, Xianjun Yu & Si Shi
Journal for ImmunoTherapy of Cancer, 7:233 (29 August 2019)
Research

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.