JITC Digest November 2019


Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

You are receiving this email in the weeks after SITC’s 2019 Annual Meeting and Pre-Conference Programs. This year’s meeting was a smashing success, truly highlighting the broad spectrum of basic science and clinical and translational research in immunotherapy. It is an exciting time for the field, and we are looking forward to possibly seeing some of the data presented at the meeting in upcoming issues of JITC.

Additionally, I am delighted to announce that Dr. Jason Luke, of the University of Pittsburgh Medical Center Hillman Cancer Center, has accepted the role of JITC’s social media editor! Dr. Luke will be managing the journal’s recently launched twitter handle. Be sure to take a moment to follow @JITCancer.

This month’s JITC digest exemplifies the interdisciplinary nature of immunotherapy research, with everything from basic insight into T cell metabolism and immunology to clinical trial results and next-generation sequencing.

“TLR9 acts as a sensor for tumor-released DNA to modulate anti-tumor immunity after chemotherapy” by Tae Hung and colleagues reveals new insight into how platinum-based chemotherapy can act as an immune adjuvant through innate immune danger-sensing pathways.

A review by Bridget P. Keenan et al., “Immunotherapy in hepatocellular carcinoma: the complex interface between inflammation, fibrosis, and the immune response,” describes the delicate balance between protective immunity in the liver and pathological inflammation that may lead to cirrhosis, fibrosis and cancer.

Beatris Mastelic-Gavillet et al. elucidate how adenosine within the tumor microenvironment contributes to disease progression by metabolic suppression of effector T cells. The paper, “Adenosine mediates functional and metabolic suppression of peripheral and tumor-infiltrating CD8+ T cells,” outlines potential biomarkers to monitor future immunotherapies targeting adenosine signaling.

In “Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma,” Indu Ramachandran et al. provide the first evidence for affinity-enhanced receptor engineered SPEAR T cells infiltrating solid tumors—a promising result for the treatment of synovial sarcoma and other malignancies that fail to respond to immune checkpoint blockade.

Finally, Zijun Y. Xu-Monette and colleagues undertake impressive and comprehensive ultra-deep sequencing to identify differential links between somatic hypermutation in immunoglobulin heavy and light chains and clinical outcomes in diffuse large B cell lymphomas in, “Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies.”

I hope you enjoy this issue!

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

JITC Editor Picks

TLR9 acts as a sensor for tumor-released DNA to modulate anti-tumor immunity after chemotherapy

Tae Heung Kang, Chih-Ping Mao, Young Seob Kim, Tae Woo Kim, Andrew Yang, Brandon Lam, Ssu-Hsueh Tseng, Emily Farmer, Yeong-Min Park & Chien-Fu Hung
Journal for ImmunoTherapy of Cancer, 7:260 (16 October 2019)
Short Report


Chemotherapy has been shown to enhance anti-tumor adaptive immune responses, though it remains unclear how cytotoxic agents convert immunologically “cold” malignancies into “hot” tumors, susceptible to elimination by CD8+ T cells. Tae Heung Kang et al. report evidence that the release of tumor DNA after chemotherapy and the intracellular DNA sensor TLR9 play important roles in facilitating anti-tumor responses. In two mouse models, DNase I injection profoundly impaired tumor control and led to decreased survival after cisplatin treatment and intratumoral vaccination with tumor antigen. Disease control after cisplatin and vaccination was dependent on TLR9 in mice inoculated with both TC-1 tumors (a model for human papillomavirus-associated cancers) and EG7 tumors (a model for lymphoma). Mice carrying EG7 tumors and deficient in TLR9 displayed roughly 10-fold fewer antigen-loaded dendritic cells (DCs) in the tumor draining lymph nodes after chemotherapy compared to wild-type controls. Tumor DCs from TLR9 knockout mice also displayed lower average expression of the maturation markers CD40 and CD80 after chemotherapy compared to wild-type controls. The results hint at potential explanations for the variability in immune-adjuvant effects of chemotherapy observed in the clinical setting.

Immunotherapy in hepatocellular carcinoma: the complex interface between inflammation, fibrosis, and the immune response

Bridget P. Keenan, Lawrence Fong & Robin K. Kelley
Journal for ImmunoTherapy of Cancer, 7:267 (18 October 2019)


Two PD-1 inhibitory monoclonal antibodies are approved by the U.S. Food and Drug Administration as monotherapies in the second-line setting for advanced hepatocellular carcinoma (HCC) and ongoing trials are investigating anti-CTLA-4 antibodies as well as combination regimens. Because the liver is an immune organ, the use of checkpoint inhibitors in hepatocellular carcinoma demands thoughtfully designed treatment strategies. A review by Bridget Keenan et al., describes the delicate interplay between systemic and local immune systems that can provide protective immunity in the context of a healthy liver, or, in the case of inflammatory dysfunction, lead to cirrhosis, fibrosis and oncogenesis. An immunosuppressive signaling axis has been identified in tumor samples from HCC patients, characterized by increased expression of TGFBeta, PD-L1, and chemokine networks such as CXCR3/CXCL10 and CCR6/CCL20. Clinical data are limited on predictive markers to guide patient selection due to the relatively recent approvals of checkpoint inhibitors in the HCC setting, with conflicting reports from the CheckMate040 and KEYNOTE-224 trials whether PD-L1 expression is associated with radiographic response. The review concludes with a call for further correlative and basic science studies to reveal strategies to re-shape the liver tumor microenvironment and remove barriers to successful cancer immunotherapy.

Adenosine mediates functional and metabolic suppression of peripheral and tumor-infiltrating CD8+ T cells

Beatris Mastelic-Gavillet, Blanca Navarro Rodrigo, Laure Décombaz, Haiping Wang, Giuseppe Ercolano, Rita Ahmed, Leyder Elena Lozano, Angela Ianaro, Laurent Derré, Massimo Valerio, Thomas Tawadros, Patrice Jichlinski, Tu Nguyen-Ngoc, Daniel E. Speiser, Grégory Verdeil, Nicolas Gestermann, Olivier Dormond, Lana Kandalaft, George Coukos, Camilla Jandus, Christine Ménétrier-Caux, Christophe Caux, Ping-Chih Ho, Pedro Romero, Alexandre Harari & Selena Vigano
Journal for ImmunoTherapy of Cancer, 7:257 (10 October 2019)


Adenosine within the tumor microenvironment contributes to disease progression, but the precise mechanisms by which the metabolite impairs effector T cell function remains unknown. Using a variety of in vitro assays, including a recently developed and validated RNA flow cytometry technique, Beatris Mastelic-Gavillet et al. demonstrate that adenosine signaling through the A2A receptor (A2AR) and protein kinase A (PKA) reduces T cell receptor (TCR)-dependent mTORC1 activation in CD8+ T cells and tumor-infiltrating lymphocytes, leading to metabolic dysfunction. In CD8+ T cells, adenosine reduced TCR-dependent ERK phosphorylation, with concomitant decreases in phosphorylation of downstream targets of mTORC1, specifically CREB and S6. Activated CD8+ T cells exposed to adenosine displayed decreased oxidative phosphorylation (as measured by oxygen uptake) and lower glycolysis (measured as extracellular acidification) compared to untreated cells. Adenosine also decreased autologous cell killing by tumor-infiltrating lymphocytes isolated from metastatic melanoma, corresponding with metabolic dysfunction as measured by decreased p-CREB and p-S6. The results outline potential biomarkers for monitoring the response to prospective immunotherapies targeting adenosine signaling.

Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma

Indu Ramachandran, Daniel E. Lowther, Rebecca Dryer-Minnerly, Ruoxi Wang, Svetlana Fayngerts, Daniel Nunez, Gareth Betts, Natalie Bath, Alex J. Tipping, Luca Melchiori, Jean-Marc Navenot, John Glod, Crystal L. Mackall, Sandra P. D’Angelo, Dejka M. Araujo, Warren A. Chow, George D. Demetri, Mihaela Druta, Brian A. Van Tine, Stephan A. Grupp, Albiruni R. Abdul Razak, Breelyn Wilky, Malini Iyengar, Trupti Trivedi, Erin Van Winkle, Karen Chagin, Rafael Amado, Gwendolyn K. Binder & Samik Basu
Journal for ImmunoTherapy of Cancer, 7:276 (24 October 2019)


Synovial sarcoma tumors are poorly infiltrated by T cells and tend to have a low overall mutation burden, which may account for the limited benefits seen with trials of checkpoint inhibitors in this disease setting. Indu Ramachandran and colleagues report promising outcomes from a phase 1/2 non-randomized open-label study of engineered SPEAR T cells expressing an affinity-enhanced T cell receptor recognizing the immunogenic cancer-testis antigen NY-ESO-1, which is expressed in roughly 70% of synovial sarcomas. Patients in the trial were divided into four cohorts with varying NY-ESO-1 expression and pre-infusion lymphodepletion. Of the 42 patients reported, 1 had a complete response, 14 had partial responses, 24 had stable disease and 3 had progressive disease. Lymphodepletion using single-agent cyclophosphamide was associated with poor persistence of the SPEAR T cells and worse outcomes. Patients with higher intratumoral NY-ESO-1 expression had deeper and longer responses than those with lower target antigen levels. Despite low levels of T cell infiltration prior to infusion, SPEAR T cells trafficked into the tumor microenvironment in all samples studied. Antigen loss was not observed after SPEAR T therapy. The study provides a rationale for successfully targeting checkpoint-blockade resistant tumors with adoptive cell therapy.

Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies

Zijun Y. Xu-Monette, Jianyong Li, Yi Xia, Beryl Crossley, Robert D. Bremel, Yi Miao, Min Xiao, Thomas Snyder, Ganiraju C. Manyam, Xiaohong Tan, Hongwei Zhang, Carlo Visco, Alexandar Tzankov, Karen Dybkaer, Govind Bhagat, Wayne Tam, Hua You, Eric D. Hsi, J. Han van Krieken, Jooryung Huh, Maurilio Ponzoni, Andrés J. M. Ferreri, Michael B. Møller, Miguel A. Piris, Jane N. Winter, Jeffrey T. Medeiros, Bing Xu, Yong Li, Ilan Kirsch & Ken H. Young
Journal for ImmunoTherapy of Cancer, 7:272 (22 October 2019)


Somatic hypermutation (SHM) in the variable regions of the immunoglobulin light chain (IGK/LV) and heavy chain (IGHV) genes may create neoantigens that activate T cell responses against B cell lymphoma. To determine the clinical relevance of SHM in diffuse large B cell lymphoma (DLBCL), Zijun X-Monette et al. performed ultradeep sequencing of the immunoglobulin variable regions using the immunoSEQ platform on formalin-fixed paraffin embedded samples from 378 patients treated under the auspices of the International DLBCL Rituximab-CHOP Consortium Program. A high degree of SHM in IGHV was associated with significantly better overall survival in DLBCL, as well as in patients with BCL2 rearrangement or MYC rearrangement. Neural network-derived MHC-II binding predictions revealed significantly more peptides with high HLA-DR-binding affinity in patients with high IGVH SHM compared to those with low IGVH SHM, and immunofluorescence analysis revealed an association between high IGVH and low PD-1 expression on CD8+ T cells. Conversely, however, high SHM in IGK/L, was associated with significantly poorer overall survival as well as increased PD-1 expression in CD4+ T cells and PD-L1 expression in natural killer cells. As next-generation sequencing becomes increasingly available in clinical practice, the study indicates that SHM evaluation could guide selection of PD-1/PD-L1 inhibitors and effective vaccines in DLBCL patients.

CAR-T cell therapy: a potential new strategy against prostate cancer

Giuseppe Schepisi, Maria Concetta Cursano, Chiara Casadei, Cecilia Menna, Amelia Altavilla, Cristian Lolli, Claudio Cerchione, Giovanni Paganelli, Daniele Santini, Giuseppe Tonini, Giovanni Martinelli & Ugo De Giorgi
Journal for ImmunoTherapy of Cancer, 7:258 (16 October 2019)

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor

B. Martín-Antonio, G. Suñe, A. Najjar, L. Perez-Amill, A. Antoñana-Vildosola, M. Castella, S. León, M. Velasco-de Andrés, F. Lozano, E. Lozano, C. Bueno, J. M. Estanyol, C. Muñoz-Pinedo, S. N. Robinson & A. Urbano-Ispizua
Journal for ImmunoTherapy of Cancer, 7:259 (16 October 2019)

Tumor-infiltrating B cells affect the progression of oropharyngeal squamous cell carcinoma via cell-to-cell interactions with CD8+ T cells

Kamila Hladíková, Vladimír Koucký, Jan Bouček, Jan Laco, Marek Grega, Miroslav Hodek, Michal Zábrodský, Milan Vošmik, Kateřina Rozkošová, Hana Vošmiková, Petr Čelakovský, Viktor Chrobok, Aleš Ryška, Radek Špíšek & Anna Fialová
Journal for ImmunoTherapy of Cancer, 7:261 (17 October 2019)

Seronegative autoimmune autonomic ganglionopathy from dual immune checkpoint inhibition in a patient with metastatic melanoma

Catherine A. Gao, Urs M. Weber, Aldo J. Peixoto & Sarah A. Weiss
Journal for ImmunoTherapy of Cancer, 7:262 (17 October 2019)
Case Report

Monalizumab: inhibiting the novel immune checkpoint NKG2A*

Thorbald van Hall, Pascale André, Amir Horowitz, Dan Fu Ruan, Linda Borst, Robert Zerbib, Emilie Narni-Mancinelli, Sjoerd H. van der Burg & Eric Vivier
Journal for ImmunoTherapy of Cancer, 7:263 (17 October 2019)

*This article is the first publication from JITC’s Immune Checkpoints Beyond PD-1 review series.

Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers

Hao-Xiang Wu, Yan-Xing Chen, Zi-Xian Wang, Qi Zhao, Ming-Ming He, Ying-Nan Wang, Feng Wang & Rui-Hua Xu
Journal for ImmunoTherapy of Cancer, 7:264 (17 October 2019)

Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors

Li Zhu, Jessica L. Narloch, Sayali Onkar, Marion Joy, Gloria Broadwater, Catherine Luedke, Allison Hall, Rim Kim, Katherine Pogue-Geile, Sarah Sammons, Naema Nayyar, Ugonma Chukwueke, Priscilla K. Brastianos, Carey K. Anders, Adam C. Soloff, Dario A. A. Vignali, George C. Tseng, Leisha A. Emens, Peter C. Lucas, Kimberly L. Blackwell, Steffi Oesterreich & Adrian V. Lee
Journal for ImmunoTherapy of Cancer, 7:265 (18 October 2019)
Short Report

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

Saade Anastasia, Mansuet-Lupo Audrey, Arrondeau Jennifer, Thibault Constance, Mirabel Mariana, Goldwasser François, Oudard Stéphane & Weiss Laurence
Journal for ImmunoTherapy of Cancer, 7:266 (18 October 2019)
Case Report

Comprehensive immune profiling and immune-monitoring using body fluid of patients with metastatic gastric cancer

Hyung Soon Park, Woo Sun Kwon, Sejung Park, Eunji Jo, So Jung Lim, Choong-kun Lee, Jii Bum Lee, Minkyu Jung, Hyo Song Kim, Seung-Hoon Beom, Jun Yong Park, Tae Soo Kim, Hyun Cheol Chung & Sun Young Rha
Journal for ImmunoTherapy of Cancer, 7:268 (21 October 2019)

Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma

Arun Rajan, Christopher R. Heery, Anish Thomas, Andrew L. Mammen, Susan Perry, Geraldine O’Sullivan Coyne, Udayan Guha, Arlene Berman, Eva Szabo, Ravi A. Madan, Leomar Y. Ballester, Stefania Pittaluga, Renee N. Donahue, Yo-Ting Tsai, Lauren M. Lepone, Kevin Chin, Fiona Ginty, Anup Sood, Stephen M. Hewitt, Jeffrey Schlom, Raffit Hassan & James L. Gulley
Journal for ImmunoTherapy of Cancer, 7:269 (21 October 2019)

Discovery of low-molecular weight anti-PD-L1 peptides for cancer immunotherapy

Hao Liu, Zhen Zhao, Li Zhang, Yuanke Li, Akshay Jain, Ashutosh Barve, Wei Jin, Yanli Liu, John Fetse & Kun Cheng
Journal for ImmunoTherapy of Cancer, 7:270 (22 October 2019)

Inflammatory signatures for quick diagnosis of life-threatening infection during the CAR T-cell therapy

Hui Luo, Na Wang, Liang Huang, Xiaoxi Zhou, Jin Jin, Chunrei Li, Di Wang, Bin Xu, Jinhuan Xu, Lijun Jiang, Jue Wang, Yang Cao, Yi Xiao, Qian Zhang, Xia Mao, Songya Liu, Liting Chen, Min Xiao & Jianfeng Zhou
Journal for ImmunoTherapy of Cancer, 7:271 (22 October 2019)

Tumor immune microenvironment and genomic evolution in a patient with metastatic triple negative breast cancer and a complete response to atezolizumab

Luciana Molinero, Yijin Li, Ching-Wei Chang, Sophia Maund, Maureen Berg, Jeanne Harrison, Marcella Fassò, Carol O’Hear, Priti Hegde & Leisha A. Emens
Journal for ImmunoTherapy of Cancer, 7:274 (23 October 2019)
Case Report

Avelumab monotherapy as first-line or second-line treatment in patients with metastatic renal cell carcinoma: phase Ib results from the JAVELIN Solid Tumor trial

Ulka Vaishampayan, Patrick Schöffski, Alain Ravaud, Christian Borel, Julio Peguero, Jorge Chaves, John C. Morris, Nuria Kotecki, Martin Smakal, Dongli Zhou, Silke Guenther, Marcis Bajars & James L. Gulley
Journal for ImmunoTherapy of Cancer, 7:275 (24 October 2019)

Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition

Wendy Mao, Ali Ghasemzadeh, Zachary T. Freeman, Aleksandar Obradovic, Matthew G. Chaimowitz, Thomas R. Nirschl, Emily McKiernan, Srinivasan Yegnasubramanian & Charles G. Drake
Journal for ImmunoTherapy of Cancer, 7:277 (25 October 2019)

The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors

Andrew A. Davis & Vaibhav G. Patel
Journal for ImmunoTherapy of Cancer, 7:278 (26 October 2019)
Short Report

Intratumoral immunoglobulin isotypes predict survival in lung adenocarcinoma subtypes

O. I. Isaeva, G. V. Sharonov, E. O. Serebrovskaya, M. A. Turchaninova, A. R. Zaretsky, M. Shugay & D. M. Chudakov
Journal for ImmunoTherapy of Cancer, 7:279 (29 October 2019)

Antibody drug conjugates against the receptor for advanced glycation end products (RAGE), a novel therapeutic target in endometrial cancer

Gareth D. Healey, Belen Pan-Castillo, Jezabel Garcia-Parra, Julia Davies, Shaun Roberts, Eilir Jones, Kalyan Dhar, Sarika Nandanan, Nasima Tofazzal, Luke Piggott, Richard Clarkson, Gillian Seaton, Asa Frostell, Tim Fagge, Colin McKee, Lavinia Margarit, R. Steven Conlan & Deyarina Gonzalez
Journal for ImmunoTherapy of Cancer, 7:280 (29 October 2019)

Nivolumab in chemotherapy-resistant cervical cancer: report of a vulvitis as a novel immune-related adverse event and molecular analysis of a persistent complete response

Florence Baettig, Tatjana Vlajnic, Marcus Vetter, Katharina Glatz, Jürgen Hench, Stephan Frank, Michel Bihl, Roberto Lopez, Michael Dobbie, Viola Heinzelmann-Schwarz & Céline Montavon
Journal for ImmunoTherapy of Cancer, 7:281 (31 October 2019)
Case Report

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. Membership verification will be required upon post-review acceptance.