JITC Digest March 2020


Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

The COVID-19 pandemic is a global emergency of unprecedented scale, placing an incredible burden on the healthcare system in every affected nation. As JITC readers, you are at the forefront of the outbreak, and, on behalf of the journal as well as SITC as a whole, we wholeheartedly offer gratitude for your ongoing efforts while wishing health and safety for you, your families and your patients.

Publication at JITC continues with this March edition of the JITC digest, which spotlights our commitment to publishing high quality scholarly work in a variety of formats. The journal is quickly becoming not only a leading repository of original research papers in the immunotherapy field, but also a go-to source for top-tier reviews and cutting-edge short hypotheses and case reports.   

Original research articles in this month's JITC digest are similar inasmuch as they describe processes for building tools, but they originate from opposite ends of the translational research spectrum. In a fully computational work that performed all experiments in silico with publically available datasets, Jie Sun and colleagues identify a long non-coding RNA signature as an indicator of immune cell infiltration in non-small cell lung cancer that was predictive of patient outcomes and response to checkpoint blockade. The other paper, from Ssu-Hsueh Tseng et al., describes extensive and elegant "wet" lab work to develop and validate a novel genetically induced mouse model of peritoneal metastasis in high-grade serous carcinoma.

Publishing excellent reviews is a priority for the journal, and we're proud this month to feature a comprehensive discussion of adenosinergic signaling in tumor immunosuppression with a focus on the potential of CD39 as a potential target for checkpoint therapy by David Allard, Bertrand Allard and John Stagg. This is part of JITC's growing Immune Checkpoints Beyond PD-1 review series.  

Finally, Esther Lutgens and Tom Seijkens present a hypothesis that checkpoint inhibition could promote the inflammatory processes in the vascular wall that drive atherosclerosis progression—a concept that merits further study.

As JITC continues to grow and thrive, the efforts and insights of the journal's peer reviewers are always appreciated. It's this "behind the scenes" work that ensures JITC remains the leading journal in the immunotherapy field. If you would like to support the journal while also gaining the many benefits of being a peer reviewer, we are welcoming applications, which you may submit through the SITC Volunteer Portal.


Best regards,

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

JITC Editor Picks

On the mechanism of anti-CD39 immune checkpoint therapy*

David Allard, Bertrand Allard, John Stagg
Journal for ImmunoTherapy of Cancer 2020;8:e000186 (24 February 2020)

Part of JITC's Immune Checkpoints Beyond PD-1 series*


Hydrolysis of extracellular ATP into adenosine potently limits immune responses and numerous human cancers maintain immunosuppressive tumor microenvironments, in part, through overexpression of the ATP-hydrolyzing ectoenzyme CD39. In a comprehensive review, David Allard, Bertrand Allard and John Stagg survey the varied mechanisms by which adenosinergic signaling through CD39 impairs both innate and adaptive anti-tumor immune activity, highlighting evidence for potential synergies between targeted blockade of ATP hydrolysis and checkpoint inhibition. A case for therapeutic targeting of CD39 is built based on evidence that the enzyme's activity has been shown to influence key phenotypes for a wide array of immune cells, including (but not limited to) macrophage phagocytosis, neutrophil chemotaxis, T cell exhaustion, Treg function, and myeloid-derived suppressor cell infiltration into the tumor microenvironment. In preclinical models, CD39 inhibition has been shown to impair secondary site growth as well as synergize with checkpoint blockade in models of metastatic lung cancer, and promising anti-tumor effects have been seen with targeted blockade or genetic depletion of CD39 in models of liver cancer, sarcoma and subcutaneous cancers as well. Although sustained inhibition of adenosinergic signaling may lead to toxicities due to altered platelet function, the review makes a compelling case for further investigation of CD39 as a therapeutic target due to its multi-faceted regulatory effects on the tumor-immunity cycle.

Cancer patients receiving immune checkpoint inhibitor therapy are at an increased risk for atherosclerotic cardiovascular disease

Esther Lutgens, Tom T.P. Seijkens

Journal for ImmunoTherapy of Cancer 2020;8:e000300  (6 February 2020)


Immune checkpoint inhibitors have become the standard of care for multiple cancer types, and rapid-onset cardiovascular adverse events such as myocarditis, arrhythmia and cardiomyopathy have been well-documented in patients treated with these agents. Gradually developing cardiovascular diseases, such as atherosclerosis, in the context of checkpoint blockade have received relatively little attention, by contrast, despite robust evidence for the role of immune checkpoint proteins in vessel wall pathogenesis. Drawing on published data in preclinical models that demonstrates modulation of atherosclerotic progression through interventions directed toward PD-1 and CTLA-4, Esther Lutgens and Tom Seijkens' hypothesis makes a case for further study into the effects of checkpoint inhibition on inflammatory plaque formation and progression inside vessel walls. In human trials, myocardial infarctions or strokes have been reported at rates ranging from 1% to 3% in patients receiving checkpoint blockade for lung cancer, indicating that treatment may have aggravated existing plaques. Furthermore, autopsy studies have revealed altered immune cell composition in atherosclerotic lesions from patients treated with checkpoint blockade, specifically a marked bias toward T cell infiltration into vessel plaques. The paper provides rationale for more active risk-management in patients treated with checkpoint blockade, in order to reduce the risk of long-term cardiovascular disease.

Identification of tumor immune infiltration-associated lncRNAs for improving prognosis and immunotherapy response of patients with non-small cell lung cancer

Jie Sun, Zicheng Zhang, Siqi Bao, Congcong Yan, Ping Hou, Nan Wu, Jianzhong Su, Liangde Xu, Meng Zhou
Journal for ImmunoTherapy of Cancer 2020;8:e000110 (10 February 2020)


Long non-coding RNAs (lncRNAs) are critical regulatory elements that play important roles in the development and differentiation of several immune cell lineages. Reasoning that lncRNA expression could be used to develop a quantitative molecular signature of tumor-infiltrating immune cells, Jie Sun and colleagues extracted publically available datasets from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) to obtain clinical information and transcriptional profiles for a total of 1533 patients with non-small cell lung cancer. To narrow in on an immune cell specific signature, transcriptional profiles of 115 purified cell lines representing 19 cell types were obtained from GEO and processed and filtered to identify hallmark lncRNAs. Focusing on the 57 lncRNAs that were highly expressed across all 19 immune cell types, differential expression analysis revealed 17 lncRNAs that were upregulated in immune cell lines and downregulated in NSCLC, which were considered as tumor-infiltrating lymphocyte transcripts (TILncRNAs). Using univariate Cox proportional hazard ratio analysis to identify transcripts that associated with patient overall survival time, a prognostic signature was developed based on 7 TILncRNAs. Across three different datasets, with gene expression quantified by multiple platforms, patients stratified as high-risk by the TILncRNA signature had significantly lower 5-year overall survival rates than the low-risk group. Furthermore, the TILncRNA signature had discriminatory power in patients with similar checkpoint gene expression levels. Although further validation is needed, the signature could be a promising biomarker to identify patients who will benefit from checkpoint blockade.

Novel, genetically induced mouse model that recapitulates the histological morphology and immunosuppressive tumor microenvironment of metastatic peritoneal carcinomatosis

Ssu-Hsueh Tseng, Sung-Taek Park, Brandon Lam, Ya-Chea Tsai, Max A Cheng, Emily Farmer, Deyin Xing Chien-Fu Hung
Journal for ImmunoTherapy of Cancer 2020;8:e000480 (27 February 2020)


Pre-clinical evaluation of immunotherapies is hindered by both the necessity of immunocompromised hosts for xenograft models and the failure to recapitulate important micreoenvironmental aspects of stepwise initiation, progression and spread for tumors derived from syngenic cell lines in immunocompetent hosts. To overcome some of these limitations, Ssu-Hsue Tseng and colleagues developed a clinically relevant, genetically induced model of peritoneal carcinamotosis. After intraperitoneal injection and electroporation of oncogenic plasmids, 100% penetrance was evident at 21 days, which manifested as aggressive growth and spread of tumor nodules across organ surfaces as well as in the ascites. The plasmids carried small hairpin RNAs designed to knock down tumor-suppressor p53 as well as overexpression cassettes for AKT and c-Myc, in addition to a luciferase marker for tracking transfected cells and a sleeping beauty transposon, which allows for cut-and-paste insertion into the genome at TA sites. Importantly, all three genetic changes: loss of function of p53 combined with gain-of-function for AKT and c-Myc were required for carcinogenesis. The tumors displayed histological morphologies similar to those seen in human high-grade serous carcinomas and tumor-infiltrating lymphocytes expressed high levels of PD-1, TIM3 and TIGIT, indicative of an immunosuppressive microenvironment. Interestingly, plasmids bearing c-Myc and AKT together with clinically relevant p53 mutants (as opposed to shRNA knockdown constructs) failed to induce tumors in mice with intact immune systems. This system could be an ideal preclinical model for evaluating oncogenic pathways as well as anti-tumor properties of novel therapies in fully immunocompetent hosts.

High-dimensional immune-profiling in cancer: implications for immunotherapy

Samuel Chuah, Valerie Chew
Journal for ImmunoTherapy of Cancer 2020;8:e000363  (6 February 2020)

Poor outcome with anti-programmed death-ligand 1 (PD-L1) antibody due to poor pharmacokinetic properties in PD-1/PD-L1 blockade-sensitive mouse models

Taiki Kurino, Reiko Matsuda, Ayu Terui, Hiroyuki Suzuki, Tomomi Kokubo, Tomoya Uehara, Yasushi Arano, Akihiro Hisaka, Hiroto Hatakeyama
Journal for ImmunoTherapy of Cancer 2020;8:e000400  (10 February 2020)

Management of hepatitis B in the era of checkpoint inhibition

Janice Dutcher

Journal for ImmunoTherapy of Cancer 2020;8:e000276  (11 February 2020)

T lymphocyte-targeted immune checkpoint modulation in glioma

William James Kelly, Amber Jin Giles, Mark Gilbert
Journal for ImmunoTherapy of Cancer 2020;8:e000379  (11 February 2020)

Interferon gamma inhibits CXCL8–CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer

Mingjie Zhang, Lifeng Huang, Guoping Ding, Huilian Huang, Guoliang Cao, Xu Sun, Neng Lou, Qiang Wei, Tao Shen, Xiaodong Xu, Liping Cao, Qiang Yan
Journal for ImmunoTherapy of Cancer 2020;8:e000308  (12 February 2020)

Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2-negative endocrine-refractory metastatic breast cancer

Ami N Shah, Lisa Flaum, Irene Helenowski, Cesar A Santa-Maria, Sarika Jain, Alfred Rademaker, Valerie Nelson, Dean Tsarwhas, Massimo Cristofanilli, William Gradishar
Journal for ImmunoTherapy of Cancer 2020;8:e000173  (13 February 2020)

Safety and efficacy of restarting immune checkpoint inhibitors after clinically significant immune-related adverse events in metastatic renal cell carcinoma

Sarah Abou Alaiwi, Wanling Xie, Amin H Nassar, Shaan Dudani, Dylan Martini, Ziad Bakouny, John A Steinharter, Pier Vitale Nuzzo, Ronan Flippot, Nieves Martinez-Chanza, Xiao Wei, Bradley A McGregor, Marina D Kaymakcalan, Daniel Y C Heng, Mehmet A Bilen, Toni K Choueiri, Lauren C Harshman
Journal for ImmunoTherapy of Cancer 2020;8:e000144  (16 February 2020)

Propensity score–weighted analysis of chemotherapy after PD-1 inhibitors versus chemotherapy alone in patients with non–small cell lung cancer (WJOG10217L)

Ryoji Kato, Hidetoshi Hayashi, Yasutaka Chiba, Eriko Miyawaki, Junichi Shimizu, Tomohiro Ozaki, Daichi Fujimoto, Ryo Toyozawa, Atsushi Nakamura, Toshiyuki Kozuki, Kentaro Tanaka, Shunsuke Teraoka, Kazuhiro Usui, Kazumi Nishino, Osamu Hataji, Keiichi Ota, Noriyuki Ebi, Sho Saeki, Yuki Akazawa, Motoyasu Okuno, Nobuyuki Yamamoto, Kazuhiko Nakagawa
Journal for ImmunoTherapy of Cancer 2020;8:e000350  (16 February 2020)

Rapid recovery of postnivolumab vemurafenib-induced Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome after tocilizumab and infliximab administration

Natalia Maximova, Alessandra Maestro, Davide Zanon, Annalisa Marcuzzi
Journal for ImmunoTherapy of Cancer 
2020;8:e000388 (16 February 2020)
Case Report

Dual targeting of TGF-beta and PD-L1 via a bifunctional anti-PD-L1/TGF-beta-RII agent: status of preclinical and clinical advances

Hanne Lind, Sofia R Gameiro, Caroline Jochems, Renee N. Donahue, Julius Strauss, James L Gulley MD, Claudia Palena, Jeffrey Schlom
Journal for ImmunoTherapy of Cancer 2020;8:e000433  (19 February 2020)

Current evidence and future perspectives of immune-checkpoint inhibitors in unresectable malignant pleural mesothelioma

Katsuyuki Hotta, Nobukazu Fujimoto
Journal for ImmunoTherapy of Cancer 2020;8:e000461  (24 February 2020)

CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency

Feng Li, Yuqiao Sheng, Weizhou Hou, Padma Sampath, Daniel Byrd, Stephen Thorne, Yi Zhang
Journal for ImmunoTherapy of Cancer 2020;8:e000131  (24 February 2020)

Repurposing infectious disease vaccines for intratumoral immunotherapy

Ignacio Melero PhD, Maria Gato, Tala Shekarian, Angela Aznar, Sandrine Valsesia-Wittmann, Christophe Caux, Iñaki Etxeberrria, Alvaro Teijeira, Aurelien Marabelle
Journal for ImmunoTherapy of Cancer 
2020;8:e000443  (25 February 2020)

Comparison of iRECIST versus RECIST V.1.1 in patients treated with an anti-PD-1 or PD-L1 antibody: pooled FDA analysis

Flora Mulkey, Marc R Theoret, Patricia Keegan, Richard Pazdur, Rajeshwari Sridhara
Journal for ImmunoTherapy of Cancer 2020;8:e000146  (26 February 2020)

ARID1A alterations function as a biomarker for longer progression-free survival after anti-PD-1/PD-L1 immunotherapy

Ryosuke Okamura, Shumei Kato, Suzanna Lee, Rebecca E Jimenez, Jason K Sicklick, Razelle Kurzrock
Journal for ImmunoTherapy of Cancer 2020;8:e000438  (27 February 2020)
Short Report

T-cell lymphoma secondary to checkpoint inhibitor therapy

Kartik Anand, Joe Ensor, Sai Ravi Pingali, Patrick Hwu, Madeleine Duvic, Stephen Chiang, Roberto Miranda, Youli Zu and Swaminathan Iyer
Journal for ImmunoTherapy of Cancer 
2020;8:e000104  (28 February 2020)
Case Report

Salvage ipilimumab associated with a significant response in sarcomatoid renal cell carcinoma

Gemlyn George, Laura Schmidt, Parag Tolat, Mathew Riese, Deepak Kilari
Journal for ImmunoTherapy of Cancer 2020;8:e000584 (28 February 2020)
Case Report

Sixth Immunotherapy of Cancer conference (ITOC): advances and perspectives—a meeting report

Catarina Pinto, Michael Bergmann, Daria Briukhovetska, Volkmar Nuessler, Mario Sznol, Michael von Bergwelt-Baildon, Sebastian Kobold MD
Journal for ImmunoTherapy of Cancer 2020;8:e000268  (28 February 2020)
Meeting Report

TriMix and tumor antigen mRNA electroporated dendritic cell vaccination plus ipilimumab: link between T-cell activation and clinical responses in advanced melanoma

Brenda De Keersmaecker, Sofie Claerhout, Javier Carrasco, Isabelle Bar, Jurgen Corthals, Sofie Wilgenhof, Bart Neyns and Kris Thielemans
Journal for ImmunoTherapy of Cancer 2020;8:e000329  (28 February 2020)

Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer

Michael Overman, Milind Javle, Richard E Davis, Pankaj Vats, Chandan Kumar-Sinha, Lianchun Xiao, Niharika B Mettu, Edwin R Parra, Al B Benson, Charles D Lopez, Veerendra Munugalavadla, Priti Patel, Lin Tao, Sattva Neelapu and Anirban Maitra
Journal for ImmunoTherapy of Cancer 
2020;8:e000587 (28 February 2020)

SITC Members Receive 50 Percent Submission Discount in 2020

*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 members with a 50 percent discount on processing fees for all JITC articles accepted in 2020.