JITC Digest January 2020


Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

Welcome to the first JITC Digest of 2020! The past decade has seen cancer immunotherapy advance to an incredible degree, and the pace of innovation is not looking to slow down any time soon. It is an exciting time for the field and for the journal as JITC continues to expand and evolve to serve the community.

To support our continued growth, JITC has partnered with a new publisher, BMJ, which will allow the journal to offer an improved experience for authors, editors, reviewers and readers at all steps during the publication process. You can read more about the transition in a special editorial in the January issue.

Additionally, JITC will now offer two new sections focusing on exciting emerging areas in our field: Immune Cell Therapy and Immune Cell Engineering, edited by Dr. Marcela V Maus, and Oncolytic Immunotherapy, edited by Dr. Howard L Kaufman. We’re thrilled to help usher these important and innovative approaches into more widespread clinical use.

The highlighted papers in this month’s digest truly exemplify the tremendous pace of advancement within the cancer immunotherapy field, especially in the area of immune checkpoints. When the journal was first established in 2013, no agents targeting the programmed death (PD)-1 receptor or its ligand had been approved by the FDA and now checkpoint blockade has become a mainstay in the treatment of numerous malignancies.

Kidney cancer is one such disease for which checkpoint blockade has radically altered the treatment landscape, motivating SITC to update its Cancer Immunotherapy Guidelines. You can read the Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma by Brian Rini et al. in this issue.

And our understanding of immune checkpoints continues to progress. Almost every aspect in the translational research pipeline is represented in the manuscripts in this month’s digest, including characterization of the tumor microenvironment, pre-clinical validation for two novel checkpoint blockade strategies, and the first retrospective study of the tolerability of anti-PD-1 or anti-PD-L1 therapy in patients with pre-existing or newly diagnosed paraneoplastic syndromes.

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

JITC Editor Picks

High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation

Heather L. MacGregor, Azin Sayad, Andrew Elia, Ben X. Wang, Sarah Rachel Katz, Patricia A. Shaw, Blaise A. Clarke, Sarah Q. Crome, Celine Robert-Tissot, Marcus Q. Bernardini, Linh T. Nguyen & Pamela S. Ohashi
Journal for ImmunoTherapy of Cancer 2019, 7:357 (31 December 2020)


Checkpoint inhibitors targeting the PD-1/PD-L1 axis have yielded disappointingly low overall response rates in epithelial ovarian cancer (EOC), which remains the foremost cause of death among gynecological malignancies. Clinical trials investigating agents targeting other members of the B7 protein family beyond PD-L1 are ongoing, yet the expression patterns of these key immune-regulatory cell-surface protein ligands remains poorly defined in the context of EOC. Using flow cytometry, immunohistochemistry, and genomic analyses, Heather MacGregor et al. determined the patterns of B7-H3, B7-H4 and PD-L1 expression by tumor, stromal, and immune cells in the ovarian tumor microenvironment. Stromal cells of the ovarian TME expressed high levels of B7-H3 whereas B7-H4 expression was restricted to tumor cells. The proportion of tumor cells calculated from H&E stained slides strongly correlated with the proportion of B7-H3low cells as assessed by flow cytometry, indicating that B7-H3 can be used to assess the tumor-to-stroma ratio. High tumor-to-stroma ratio was associated with higher frequencies of PD-1high CD8+ T cells, and increased PD-L1 expression by antigen-presenting cells. Expression of PD-L1 was also restricted to stromal cells, which suggests that combination therapies against both molecules will target different cell populations in the ovarian TME offering opportunities for additive or synergistic effects.

Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study

Guillaume Manson, Alexandre Thibault Jacques Maria, Florence Poizeau, François-Xavier Danlos, Marie Kostine, Solenn Brosseau, Sandrine Aspeslagh, Pauline Du Rusquec, Maxime Roger, Maud Pallix-Guyot, Marc Ruivard, Léa Dousset, Laurianne Grignou, Dimitri Psimaras, Johan Pluvy, Gilles Quéré, Franck Grados, Fanny Duval, Frederic Bourdain, Gwenola Maigne, Julie Perrin, Benoit Godbert, Beatris Irina Taifas, Alexandra Forestier, Anne-Laure Voisin, Patricia Martin-Romano, Capucine Baldini, Aurélien Marabelle, Christophe Massard, Jérôme Honnorat, Olivier Lambotte & Jean-Marie Michot
Journal for ImmunoTherapy of Cancer 2019, 7:337 (3 December 2020)


Paraneoplastic syndromes (PNSs) are rare but potentially serious autoimmune disorders that specifically arise in cancer patients. Little is known about the use of immune checkpoint inhibitors in patients with PNSs, and Guillame Manson and colleagues have undertaken the first study to describe the tolerability of immunotherapy in this population. In a nationwide, observational, multicenter study, 1304 adult patients who had received anti-PD-1 or anti-PD-L1 therapy in France were screened and PNSs were identified in 32 (2.45%). Of the 32 PNS cases, 16 were pre-existing prior to the initiation of checkpoint blockade and 16 arose after patients received therapy. Half of the patients with pre-existing PNSs experienced worsening of symptoms with anti-PD1 or anti-PD-L1 therapy. In the cohort of patients who presented with PNSs after the initiation of immunotherapy, neurologic conditions were the most frequently observed pathologies (n=7). Four patients died as a result of progression of a neurologic PNS—a rare but serious adverse event revealed by the large-scale survey that might not have been apparent in individual studies or clinical trials. The results show that PNSs may be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy underscoring the importance for physicians to carefully monitor patients for autoimmune pathology when inititating immunotherapy.

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC)

Brian I. Rini, Dena Battle, Robert A. Figlin, Daniel J. George, Hans Hammers, Tom Hutson, Eric Jonasch, Richard W. Joseph, David F. McDermott, Robert J. Motzer, Sumanta K. Pal, Allan J. Pantuck, David I. Quinn, Virginia Seery, Martin H. Voss, Christopher G. Wood, Laura S. Wood & Michael B. Atkins
Journal for ImmunoTherapy of Cancer 2019, 7:354 (20 December 2020)
Position Article and Guidelines


For more than 20 years, cytokine therapy, such as high-dose IL-2, was the only option for immunotherapy-based treatment of advanced renal cell carcinoma (aRCC). Since 2015, a series of approvals has vastly expanded the available options in the immunotherapy repertoire, motivating the Society for Immunotherapy of Cancer to reconvene the Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee, chaired by Brian Rini and Michael Atkins, to generate updated consensus recommendations for the treatment of patients with aRCC. Drawing upon evidence from multiple phase 3 trials, the new consensus statement advocates that all aRCC patients should receive regimens containing checkpoint inhibitors as front-line therapy. Potential biomarkers for identifying the patients who will derive the most benefit and the role of immunotherapy in non-clear cell pathology are also discussed. Additionally, the consensus statement describes strategies for monitoring response to treatment, managing toxicities and supporting quality of life in patients receiving immunotherapies, all of which may differ markedly from traditional approaches due to the unique nature of immunotherapy agents. The guidelines will be a valuable resource for the oncology community.

Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition

Julie Voeller, Amy K. Erbe, Jacob Slowinski, Kayla Rasmussen, Peter M. Carlson, Anna Hoefges, Sabrina VandenHeuvel, Ashley Stuckwisch, Xing Wang, Stephen D. Gillies, Ravi B. Patel, Alvin Farrel, Jo Lynne Rokita, John Maris, Jacquelyn A. Hank, Zachary S. Morris, Alexander L. Rakhmilevich & Paul M. Sondel
Journal for ImmunoTherapy of Cancer 2019, 7:344 (6 December 2020)


Immunotherapy for the treatment of solid cancers in children has generally had limited success, in part because these tumors are characterized by low mutation burdens with few neoantigens and limited immune cell infiltration. Using mouse models of neuroblastoma (the most common extracranial solid cancer in pediatrics), Julie Voeller and colleagues developed a novel innate and adaptive immunotherapeutic approach that generated potent antitumor effects as well as memory responses against an immunologically “cold” tumor. To simulate clinically high-risk disease, Voeller et al. generated an N-MYC driven, low TMB, and high-GD2-expressing syngeneic murine neuroblastoma model. Tumor regression was achieved in 80% of mice following treatment with external beam radiation therapy and intratumoral injection of a novel immunocytokine fusion protein consisting of human anti-GD2 mAb linked to IL-2 in combination with anti-CTLA-4 and CpG and anti-CD40. Upon rechallenge, there was significant slowing of tumor growth, with average tumor volumes on day 30 of 15.4 mm3 in previously treated mice compared to 51.5 mm3 in naïve mice (p = 0.012). The combination treatment also led to increased numbers of tumor-infiltrating CD4+ T cells, higher numbers of monocytes/macrophages, an elevated CD8+ to Treg ratio and a reduction of Tregs compared to controls. Such novel immunotherapeutic approaches could potentially improve outcomes while reducing reliance on genotoxic high-dose chemotherapy and radiation.

Functional characterization of the selective pan-allele anti-SIRPalpha antibody ADU-1805 that blocks the SIRPalpha–CD47 innate immune checkpoint

Erik Voets, Marc Paradé, David Lutje Hulsik, Sanne Spijkers, Wout Janssen, Joost Rens, Inge Reinieren-Beeren, Gilbert van den Tillaart, Sander van Duijnhoven, Lilian Driessen, Maurice Habraken, Peter van Zandvoort, Joost Kreijtz, Paul Vink, Andrea van Elsas & Hans van Eenennaam
Journal for ImmunoTherapy of Cancer 2019, 7:340 (4 December 2020)


Numerous human cancers overexpress CD47, a “don’t eat me” checkpoint molecule found on red blood cells and platelets among other tissues that primarily acts on myeloid lineage cells through interaction with the inhibitory immune receptor signal-regulatory protein alpha (SIRPalpha). Agents targeting CD47 have demonstrated encouraging anti-tumor responses in clinical trials. However two studies were halted due to toxicity such as severe anemia and thrombocytopenias. To avert potential on-target toxicity and overcome the antigen sink effects of the broad expression pattern of CD47, Erik Voets and colleagues generated a humanized anti-SIRPalpha antibody, with potent binding across the most abundant alleles among the human population. The antibody, ADU-1805, enhanced rituximab-mediated phagocytosis of Raji cells by human macrophages and trogocytosis by neutrophils. Unlike anti-CD47 antibodies, ADU-1805 did not affect T cell activation and proliferation, nor did it bind red blood cells or platelets or trigger hemagglutination in vitro. Safety and pharmacodynamics of ADU-1805 were established in vivo in a single dose infusion in cynomologus monkeys, where administration was well-tolerated and none of the primates developed anemia. The results support further development of ADU-1805 as a novel checkpoint inhibitor with favorable safety profile compared to other agents targeting the CD47/SIRPalpha axis.

Correction to: Pericardial effusion under nivolumab: case-reports and review of the literature

Anastasia Saade, Audrey Mansuet-Lupo, Jennifer Arrondeau, Constance Thibault, Mariana Mirabel, François Goldwasser, Stéphane Oudard & Laurence Weiss
Journal for ImmunoTherapy of Cancer 2019, 7:335 (2 December 2019)

Multiple nivolumab-induced CNS demyelination with spontaneous resolution in an asymptomatic metastatic melanoma patient

Vincent Pillonel, Vincent Dunet, Andreas F. Hottinger, Gregoire Berthod, Luis Schiappacasse, Solange Peters, Olivier Michielin & Veronica Aedo-Lopez
Journal for ImmunoTherapy of Cancer 2019, 7:336 (2 December 2019)
Case Report

Rapid and sustained response to immune checkpoint inhibition in cutaneous squamous cell carcinoma after allogenic hematopoietic cell transplant for sézary syndrome

Karam Khaddour, Amy Musiek, Lynn A. Cornelius, Farrokh Dehdashti, Peter Westervelt, Ryan Fields & George Ansstas
Journal for ImmunoTherapy of Cancer 2019, 7:338 (4 December 2019)
Case Report

Tumor microenvironment dictates regulatory T cell phenotype: Upregulated immune checkpoints reinforce suppressive function

Hye Ryun Kim, Hyo Jin Park, Jimin Son, Jin Gu Lee, Kyung Young Chung, Nam Hoon Cho, Hyo Sup Shim, Seyeon Park, Gamin Kim, Hong In Yoon, Hyun Gyung Kim, Yong Woo Jung, Byoung Chul Cho, Seong Yong Park, Sun Young Rha & Sang-Jun Ha
Journal for ImmunoTherapy of Cancer 2019, 7:339 (4 December 2019)

Incidence rates of immune-related adverse events and their correlation with response in advanced solid tumours treated with NIVO or NIVO+IPI: a systematic review and meta-analysis

Puyuan Xing, Fan Zhang, Guoqiang Wang, Yu Xu, Chengcheng Li, Shouzheng Wang, Yiying Guo, Shangli Cai, Yan Wang & Junling Li
Journal for ImmunoTherapy of Cancer 2019, 7:341 (4 December 2019)

A phase Ib study of utomilumab (PF-05082566) in combination with mogamulizumab in patients with advanced solid tumors

Ezra E. W. Cohen, Michael J. Pishvaian, Dale R. Shepard, Ding Wang, Jared Weiss, Melissa L. Johnson, Christine H. Chung, Ying Chen, Bo Huang, Craig B. Davis, Francesca Toffalorio, Aron Thall & Steven F. Powell
Journal for ImmunoTherapy of Cancer 2019, 7:342 (4 December 2019)

Tumor microenvironment-derived S100A8/A9 is a novel prognostic biomarker for advanced melanoma patients and during immunotherapy with anti-PD-1 antibodies

Nikolaus B. Wagner, Benjamin Weide, Mirko Gries, Maike Reith, Kathrin Tarnanidis, Valerie Schuermans, Charlotte Kemper, Coretta Kehrel, Anne Funder, Ramtin Lichtenberger, Antje Sucker, Esther Herpel, Tim Holland-Letz, Dirk Schadendorf, Claus Garbe, Viktor Umansky, Jochen Utikal & Christoffer Gebhardt
Journal for ImmunoTherapy of Cancer 2019, 7:343 (5 December 2019)

Genetic instability as a driver for immune surveillance

Guim Aguadé-Gorgorió & Ricard Solé
Journal for ImmunoTherapy of Cancer 2019, 7:345 (11 December 2019)

Blocking CD47 efficiently potentiated therapeutic effects of anti-angiogenic therapy in non-small cell lung cancer

Xuyao Zhang, Yichen Wang, Jiajun Fan, Wei Chen, Jingyun Luan, Xiaobin Mei, Shaofei Wang, Yubin Li, Li Ye, Song Li, Wenzhi Tian, Kai Yin & Dianwen Ju
Journal for ImmunoTherapy of Cancer 2019, 7:346 (11 December 2019)

Chemotherapy accelerates immune-senescence and functional impairments of Vdelta2pos T cells in elderly patients affected by liver metastatic colorectal cancer

Elena Bruni, Valentina Cazzetta, Matteo Donadon, Matteo Cimino, Guido Torzilli, Gianmarco Spata, Gloria Leonardi, Francesco Dieli, Joanna Mikulak & Domenico Mavilio
Journal for ImmunoTherapy of Cancer 2019, 7:347 (11 December 2019)
Short Report

Development of a prognostic composite cytokine signature based on the correlation with nivolumab clearance: translational PK/PD analysis in patients with renal cell carcinoma

Rui Wang, Junying Zheng, Xiao Shao, Yuko Ishii, Amit Roy, Akintunde Bello, Richard Lee, Joshua Zhang, Megan Wind-Rotolo & Yan Feng
Journal for ImmunoTherapy of Cancer 2019, 7:348 (11 December 2019)
Short Report

Correction to: Immunostimulatory RNA leads to functional reprogramming of myeloid-derived suppressor cells in pancreatic cancer

Philipp Metzger, Sabrina V. Kirchleitner, Michael Kluge, Lars M. Koenig, Christine Hörth, Carlotta A. Rambuscheck, Daniel Böhmer, Julia Ahlfeld, Sebastian Kobold, Caroline C. Friedel, Stefan Endres, Max Schnurr & Peter Duewell
Journal for ImmunoTherapy of Cancer 2019, 7:349 (16 December 2019)

Immunogenic cell death induced by a new photodynamic therapy based on photosens and photodithazine

Victoria D. Turubanova, Irina V. Balalaeva, Tatiana A. Mishchenko, Elena Catanzaro, Razan Alzeibak, Nina N. Peskova, Iuliia Efimova, Claus Bachert, Elena V. Mitroshina, Olga Krysko, Maria V. Vedunova & Dmitri V. Krysko
Journal for ImmunoTherapy of Cancer 2019, 7:350 (16 December 2019)

High OX-40 expression in the tumor immune infiltrate is a favorable prognostic factor of overall survival in non-small cell lung cancer

Erminia Massarelli, Vincent K. Lam, Edwin R. Parra, Jaime Rodriguez-Canales, Carmen Behrens, Lixia Diao, Jing Wang, Jorge Blando, Lauren A. Byers, Niranjan Yanamandra, Sara Brett, Peter Morley, Padmanee Sharma, James Allison, Ignacio I. Wistuba & John V. Heymach
Journal for ImmunoTherapy of Cancer 2019, 7:351 (16 December 2019)
Short Report

Correction to: Impact of antibiotic therapy on the development and response to treatment of immune checkpoint inhibitor-mediated diarrhea and colitis

Hamzah Abu-Sbeih, Lauren Nicholas Herrera, Tenglong Tang, Mehmet Altan, Anne-Marie Chaftari, Pablo C. Okhuysen, Robert R. Jenq & Yinghong Wang
Journal for ImmunoTherapy of Cancer 2019, 7:352 (17 December 2019)

Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection

Neil J. Shah, Ghassan Al-Shbool, Matthew Blackburn, Michael Cook, Anas Belouali, Stephen V. Liu, Subha Madhavan, Aiwu Ruth He, Michael B. Atkins, Geoffrey T. Gibney & Chul Kim
Journal for ImmunoTherapy of Cancer 2019, 7:353 (17 December 2019)

Interleukin-15 in cancer immunotherapy: IL-15 receptor complex versus soluble IL-15 in a cancer cell-delivered murine leukemia model

Alexandra Berger, Sarah J. Colpitts, Melanie S. S. Seabrook, Caren L. Furlonger, Maura B. Bendix, Joshua M. Moreau, William M. McKillop, Jeffrey A. Medin & Christopher J. Paige
Journal for ImmunoTherapy of Cancer 2019, 7:355 (19 December 2019)

Positron emission tomography as an adjuvant diagnostic test in the evaluation of checkpoint inhibitor-associated acute interstitial nephritis

David Qualls, Harish Seethapathy, Halla Bates, Shahein Tajmir, Pedram Heidari, Paul Endres, Kerry Reynolds, Donald Lawrence & Meghan Sise
Journal for ImmunoTherapy of Cancer 2019, 7:356 (21 December 2019)
Case Report

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.