JITC Digest June 2019

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Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

In the June edition of the JITC Digest, I would like to draw special attention to the following articles. First, “Carboplatin/paclitaxel, E7-vaccination and intravaginal CpG as tri-therapy towards efficient regression of genital HPV16 tumors” by Sonia Domingos-Pereira et al. investigates the effects of systemic administration of a chemotherapy doublet in combination with HPV16-E7 synthetic long peptide (E7LP) vaccination, followed by intravaginal immunostimulation in the genital orthotopic TC-1 mouse model. Results from this study suggest that combining novel vaccine formulations with local immunostimulation and standard-of-care chemotherapy have the potential to benefit patients with HPV-associated cancer.

Next, the research article “Selectively hampered activation of lymph node-resident dendritic cells precedes profound T cell suppression and metastatic spread in the breast cancer sentinel lymph node,” by Kim M. van Pul et al. describes the immune status of breast draining lymph nodes (LN) in a quantitative and functional manner using multi-parameter flow cytometry and ex-vivo cultures, and compares it with that of breast-draining axillary LN from healthy donors. This study provides new insights into the mechanisms underlying loco-regional immune suppression in breast cancer and how this relates to clinical parameters and suggests that LN-resident-conventional dendritic cells are potential therapeutic targets.

Furthermore, the article, “Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies,” by Victoria M. Kim et al. shows for the first time, that a Listeria vaccine-based immunotherapy was able to induce a tumor antigen-specific T cell response within the tumor microenvironment of a “cold” tumor such as PDAC and further sensitizes the tumor to checkpoint inhibitor therapy. This combination immunotherapy led to objective tumor responses and survival benefit in mice with spontaneously developed PDAC tumors, supporting Lm-ANXA2 as a therapeutic agent in combination with anti-PD-1 antibody for PDAC treatment.

“Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study,” by Douglas B. Johnson et al. leverages Vigibase, the World Health Organization pharmacovigilance database, to further define neurologic toxicities in the largest characterization of neurologic immune-related adverse events (irAEs) associated with ICIs. Results of this analysis pinpointed several categories of neurologic toxicities strongly associated with CNS inflammation or peripheral neuromuscular autoimmune disorders of which clinicians should be aware of in administering checkpoint blockade.

Finally, Hyun Gul Yang et al.’s article, “Discovery of a novel natural killer cell line with distinct immunostimulatory and proliferative potential as an alternative platform for cancer immunotherapy,” presents a novel NK cell line, NK101, from a patient with extra-nodal NK/T cell lymphoma and an assessment of its phenotypic, genomic and functional characteristics, with results suggestive of its therapeutic application as a CAR T-alternative anti-cancer cellular platform with improved efficacy and superior scalability.

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


JITC Editor Picks

Carboplatin/paclitaxel, E7-vaccination and intravaginal CpG as tri-therapy towards efficient regression of genital HPV16 tumors

Sonia Domingos-Pereira, Gabriele Galliverti, Douglas Hanahan and Denise Nardelli-Haefliger
Journal for ImmunoTherapy of Cancer, 7:122 (6 May 2019)
Short Report

Summary:

Widespread application of prophylactic human papilloma virus (HPV) vaccines used to prevent HPV-associated cancers provide no benefit for individuals already infected with HPV. Pre-clinical results of recent genital orthotopic TC-1 mouse studies have demonstrated that conjugation of HPV16-E7LP to ultra-small polymeric nanoparticles (NP) enhances the antitumor efficacy of therapeutic vaccination. Domingos-Pereira et al. report on the development and assessment of a novel regimen combining chemotherapies currently used to treat cervical cancer patients with an optimized therapeutic E7LP vaccine and a localized immune-stimulant treatment. This study combines systemic administration of the carboplatin/paclitaxel chemotherapy doublet with HPV-E7LP or NP-E7LP vaccination followed by intravaginal immunostimulation with the synthetic toll-like receptor-9 agonist CpG. Results of this novel strategy suggest that combining vaccine formulations with local immune stimulation and standard of care chemotherapy may provide clinical benefit in patients with HPV-associated cancer.

Selectively hampered activation of lymph node-resident dendritic cells precedes profound T cell suppression and metastatic spread in the breast cancer sentinel lymph node

Kim M. van Pul, Ronald J.C.L.M. Vuylsteke, Rieneke van de Ven, Elisabeth A. te Velde, Emiel J. Th. Rutgers, Petrousjka M. van den Tol, Hein B.A.C. Stockmann and Tanja D. de Gruijl
Journal for ImmunoTherapy of Cancer, 7:133 (22 May 2019)
Research Article

Summary:

Immunogenicity in breast cancer has recently been confirmed by studies demonstrating the prevalence of tumor infiltrating lymphocytes (TIL). Such TILs have been associated with favorable prognosis and higher complete response rates as a result of antitumor responses generated in the regional tumor-draining lymph nodes (TDLN). van Pul et al. monitored the immune status of metastasis-free versus metastasis-involved breast cancer sentinel lymph nodes (SLN) using multi-parameter flow cytometry and ex-vivo cultures of viable breast cancer LN cell suspensions. Differences in SLN immune status with regard to primary tumor size and hormone receptor (HR) expression were identified. Moreover, a comparative analysis with breast-draining axillary LNs from healthy donors undergoing a prophylactic mastectomy reflective of steady state conditions was performed. Results from this study identify the LN-resident-conventional dendritic cell (cDC) subset as a promising therapeutic target related to high-risk breast cancer subtypes lacking expression of HRs and may be as a negative predictor of disease-free survival.

Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies

Victoria M. Kim, Alex B. Blair, Peter Lauer, Kelly Foley, Xu Che, Kevin Soares, Tao Xia, Stephen T. Muth, Jennifer Kleponis, Todd D. Armstrong, Christopher L. Wolfgang, Elizabeth M. Jaffee, Dirk Brockstedt and Lei Zheng
Journal for ImmunoTherapy of Cancer, 7:132 (22 May 2019)
Research Article

Summary:

Despite limited efficacy of single agent checkpoint blockade in pancreatic cancer, preclinical and clinical research has suggested that vaccine therapy, particularly the GM-CSF-secreting pancreatic tumor whole cell vaccine (GVAX), may function to re-program the tumor microenvironment, sensitizing pancreatic ductal adenocarcinoma (PDAC) to anti-PD-1 or PD-L1 therapies. Kim et al. describe the development of the first human Annexin A2 (ANXA2)-targeted, vaccine-type immunotherapy and its anti-tumor effects as a combination immunotherapy for PDAC. This study reveals a tumor antigen-specific T cell response within the tumor microenvironment of PDAC, an infamously “cold” tumor. Vaccination sensitizes this tumor to checkpoint inhibitor therapy, leading to objective tumor responses and survival benefit in the mice with spontaneously developed PDAC tumors. These results warrant further investigation into ANXA2-expressing Listeria-based immunotherapy in combination with anti-PD-1 antibody for treatment of PDAC.

Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study

Douglas B. Johnson, Ali Manouchehri, Alexandra M. Haugh, Henry T. Quach, Justin M. Balko, Benedicte Lebrun-Vignes, Andrew Mammen, Javid J. Moslehi and Joe-Elie Salem
Journal for ImmunoTherapy of Cancer, 7:134 (22 May 2019)
Research Article

Summary:

Although immune checkpoint inhibitor-related neurologic toxicities are usually manageable with administration of corticosteroids, such complications can potentially lead to clinically severe events, morbidity and even mortality. Until now, a systematic analysis of the timing, spectrum, clinical associations, and outcomes of neurological adverse events has not been performed in a large number of patients. Johnson et al. addressed this knowledge gap by leveraging Vigibase, a large WHO database which has been used to characterize other ICI-induced toxicities, to further define neurologic toxicities in the largest characterization of neurologic immune-related adverse events (irAEs) associated with ICIs. Results of this analysis pinpointed a robust set of categories of neurologic toxicities relating to CNS inflammation (encephalitis/myelitis, meningitis, and CNS vasculitis) and peripheral neuromuscular autoimmune disorders (Guillain-Barre and myasthenia gravis). These specific toxicities may help clinicians in monitoring patients receiving ICI therapy.

Discovery of a novel natural killer cell line with distinct immunostimulatory and proliferative potential as an alternative platform for cancer immunotherapy

Hyun Gul Yang, Moon Cheol Kang, Tae Yoon Kim, Injung Hwang, Hyun Tak Jin, Young Chul Sung, Ki-Seong Eom and Sae Won Kim
Journal for ImmunoTherapy of Cancer, 7:138 (24 May 2019)
Research Article

Summary:

Natural killer (NK) cells are regarded as an alternative platform for adoptive cell transfer (ACT) immunotherapy that might allow overcoming the numerous challenges faced by engineering T cells. However, NK cell-based therapies have their own limitations and challenges, including the need of developing stable NK cell lines for clinical application. Yang et al. introduce here a novel NK cell line (NK101) obtained from a patient with extra-nodal NK/T cell lymphoma and present an assessment of its phenotypic, genomic and functional characteristics, as well as its potential for therapeutic application as an anti-cancer cellular platform. Results from this study indicate that NK101 is superior in providing in vivo antitumor efficacy compared to the clinically assessed NK cell line NK-92, potentially via the activation of systemic antitumor immunity. Thus, NK101 may serve as an alternative platform with improved efficacy and superior scalability.

STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models

Weiqing Jing, Donna McAllister, Emily P. Vonderhaar, Katie Palen, Matthew J. Riese, Jill Gershan, Bryon D. Johnson and Michael B. Dwinell
Journal for ImmunoTherapy of Cancer, 7:115 (29 April 2019)
Research Article

Immunotherapeutic effects of intratumoral nanoplexed poly I:C

M. Angela Aznar, Lourdes Planelles, Mercedes Perez-Olivares, Carmen Molina, Saray Garasa, Iñaki Etxeberría, Guiomar Perez, Inmaculada Rodriguez, Elixabet Bolaños, Pedro Lopez-Casas, Maria E. Rodriguez-Ruiz, Jose L. Perez-Gracia, Ivan Marquez-Rodas, Alvaro Teijeira, Marisol Quintero and Ignacio Melero
Journal for ImmunoTherapy of Cancer, 7:116 (2 May 2019)
Research Article

Haemophagocytic lymphohistiocytosis in patients treated with immune checkpoint inhibitors: analysis of WHO global database of individual case safety reports

Roberta Noseda, Raffaela Bertoli, Laura Müller and Alessandro Ceschi
Journal for ImmunoTherapy of Cancer, 7:117 (2 May 2019)
Short Report

Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment

Hamzah Abu-Sbeih, Cynthia Nguyen Tran, Phillip S. Ge, Manoop S. Bhutani, Mazen Alasadi, Aung Naing, Amir A. Jazaeri and Yinghong Wang
Journal for ImmunoTherapy of Cancer, 7:118 (3 May 2019)
Research Article

Safety and clinical activity of PD-L1 blockade in patients with aggressive recurrent respiratory papillomatosis

Clint T. Allen, Sunmin Lee, Scott M. Norberg, Damian Kovalovsky, Hong Ye, Paul E. Clavijo, Siwen Hu-Lieskovan, Richard Schlegel, Jeffrey Schlom, Julius Strauss, James L. Gulley, Jane Trepel and Christian S. Hinrichs
Journal for ImmunoTherapy of Cancer, 7:119 (3 May 2019)
Research Article

First-line treatment for patients with advanced non-small cell lung carcinoma and high PD-L1 expression: pembrolizumab or pembrolizumab plus chemotherapy

Yixin Zhou, Zuan Lin, Xuanye Zhang, Chen Chen, Hongyun Zhao, Shaodong Hong and Li Zhang
Journal for ImmunoTherapy of Cancer, 7:120 (3 May 2019)
Commentary

Automated image analysis of NSCLC biopsies to predict response to anti-PD-L1 therapy

Sonja Althammer, Tze Heng Tan, Andreas Spitzmüller, Lorenz Rognoni, Tobias Wiestler, Thomas Herz, Moritz Widmaier, Marlon C. Rebelatto, Helene Kaplon, Diane Damotte, Marco Alifano, Scott A. Hammond, Marie-Caroline Dieu-Nosjean, Koustubh Ranade, Guenter Schmidt, Brandon W. Higgs and Keith E. Steele
Journal for ImmunoTherapy of Cancer, 7:121 (6 May 2019)
Research Article

Tumor genomic alterations in severe-combined immunodeficiency bare-lymphocyte syndrome genes are associated with high mutational burden and disproportional neo-antigen rates

Yu Wang, Douglas B. Johnson, Steve Lu, Luis A. Diaz Jr, Yaomin Xu and Justin M. Balko
Journal for ImmunoTherapy of Cancer, 7:123 (7 May 2019)
Short Report

Two cases of intrahepatic cholangiocellular carcinoma with high insertion-deletion ratios that achieved a complete response following chemotherapy combined with PD-1 blockade

Minghao Sui, Yu Li, Hongguang Wang, Ying Luo, Tao Wan, Xun Wang, Bingyang Hu, Yanshuang Cheng, Xianrong Lv, Xianlei Xin, Qiang Xu, Guan Wang and Shichun Lu
Journal for ImmunoTherapy of Cancer, 7:125 (7 May 2019)
Case Report

Recurrent pseudogout after therapy with immune checkpoint inhibitors: a case report with immunoprofiling of synovial fluid at each flare

Sang T. Kim, Mohamad Bittar, Hyun J. Kim, Sattva S. Neelapu, Amado J. Zurita, Roza Nurieva and Maria E. Suarez-Almazor
Journal for ImmunoTherapy of Cancer, 7:126 (14 May 2019)
Case Report

A phase II trial of intermittent nivolumab in patients with metastatic renal cell carcinoma (mRCC) who have received prior anti-angiogenic therapy

Moshe C. Ornstein, Laura S. Wood, Brian P. Hobbs, Kimberly D. Allman, Allison Martin, Michael Bevan, Timothy D. Gilligan, Jorge A. Garcia and Brian I. Rini
Journal for ImmunoTherapy of Cancer, 7:127 (16 May 2019)
Short Report

Paired whole exome and transcriptome analyses for the Immunogenomic changes during concurrent chemoradiotherapy in esophageal squamous cell carcinoma

Sehhoon Park, Je-Gun Joung, Yang Won Min, Jae-Yong Nam, Daeun Ryu, Dongryul Oh, Woong-Yang Park, Se-Hoon Lee, Yoon La Choi, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park and Jong-Mu Sun
Journal for ImmunoTherapy of Cancer, 7:128 (16 May 2019)
Research Article

The promise of Immuno-oncology: implications for defining the value of cancer treatment

Howard L. Kaufman, Michael B. Atkins, Prasun Subedi, James Wu, James Chambers, T. Joseph Mattingly II, Jonathan D. Campbell, Jeff Allen, Andrea E. Ferris, Richard L. Schilsky, Daniel Danielson, J. Leonard Lichtenfeld, Linda House and Wendy K. D. Selig
Journal for ImmunoTherapy of Cancer, 7:129 (17 May 2019)
Position Article and Guidelines

Remembering the forgotten child: the role of immune checkpoint inhibition in patients with human immunod eficiency virus and cancer

Jacob J. Adashek, Pedro Nazareth Aguiar Junior, Natalie Galanina and Razelle Kurzrock
Journal for ImmunoTherapy of Cancer, 7:130 (22 May 2019)
Commentary

Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop

Davide Bedognetti, Michele Ceccarelli, Lorenzo Galluzzi, Rongze Lu, Karolina Palucka, Josue Samayoa, Stefani Spranger, Sarah Warren, Kwok-Kin Wong, Elad Ziv, Diego Chowell, Lisa M. Coussens, Daniel D. De Carvalho, David G. DeNardo, Jérôme Galon, Howard L. Kaufman, Tomas Kirchhoff, Michael T. Lotze, Jason J. Luke, Andy J. Minn, Katerina Politi, Leonard D. Shultz, Richard Simon, Vésteinn Thórsson, Joanne B. Weidhaas, Maria Libera Ascierto, Paolo Antonio Ascierto, James M. Barnes, Valentin Barsan, Praveen K. Bommareddy, Adrian Bot, Sarah E. Church, Gennaro Ciliberto, Andrea De Maria, Dobrin Draganov, Winson S. Ho, Heather M. McGee, Anne Monette, Joseph F. Murphy, Paola Nisticò, Wungki Park, Maulik Patel, Michael Quigley, Laszlo Radvanyi, Harry Raftopoulos, Nils-Petter Rudqvist, Alexandra Snyder, Randy F. Sweis, Sara Valpione, Lisa H. Butterfield, Mary L. Disis, Bernard A. Fox, Alessandra Cesano, Francesco M. MarincolaEmail author and Society for Immunotherapy of Cancer (SITC) Cancer Immune Responsiveness Task Force and Working Groups
Journal for ImmunoTherapy of Cancer, 7:131 (22 May 2019)
Review

Level of neo-epitope predecessor and mutation type determine T cell activation of MHC binding peptides

Hanan Besser, Sharon Yunger, Efrat Merhavi-Shoham, Cyrille J. Cohen and Yoram Louzoun
Journal for ImmunoTherapy of Cancer, 7:135 (22 May 2019)
Research Article

Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration

Mark N. Stein, Jyoti Malhotra, Rohinton S. Tarapore, Usha Malhotra, Ann W. Silk, Nancy Chan, Lorna Rodriguez, Joseph Aisner, Robert D. Aiken, Tina Mayer, Bruce G. Haffty, Jenna H. Newman, Salvatore M. Aspromonte, Praveen K. Bommareddy, Ricardo Estupinian, Charles B. Chesson, Evita T. Sadimin, Shengguo Li, Daniel J. Medina, Tracie Saunders, Melissa Frankel, Aparna Kareddula, Sherrie Damare, Elayne Wesolowsky, Christian Gabel, Wafik S. El-Deiry, Varun V. Prabhu, Joshua E. Allen, Martin Stogniew, Wolfgang Oster, Joseph R. Bertino, Steven K. Libutti, Janice M. Mehnert and Andrew Zloza
Journal for ImmunoTherapy of Cancer, 7:136 (22 May 2019)
Research Article

Prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma

Pooja Ghatalia, Jennifer Gordetsky, Fengshen Kuo, Essel Dulaimi, Kathy Q. Cai, Karthik Devarajan, Sejong Bae, Gurudatta Naik, Timothy A. Chan, Robert Uzzo, A. Ari Hakimi, Guru Sonpavde and Elizabeth Plimack
Journal for ImmunoTherapy of Cancer, 7:139 (28 May 2019)
Research Article

Generation of monocyte-derived tumor-associated macrophages using tumor-conditioned media provides a novel method to study tumor-associated macrophages in vitro

Brooke Benner, Luke Scarberry, Lorena P. Suarez-Kelly, Megan C. Duggan, Amanda R. Campbell, Emily Smith, Gabriella Lapurga, Kallie Jiang, Jonathan P. Butchar, Susheela Tridandapani, John Harrison Howard, Robert A. Baiocchi, Thomas A. Mace and William E. Carson III
Journal for ImmunoTherapy of Cancer, 7:140 (28 May 2019)
Research Article

Metastatic Merkel cell carcinoma and myasthenia gravis: contraindication for therapy with immune checkpoint inhibitors?

Anne Zaremba, Eleftheria Chorti, Finja Jockenhöfer, Saskia Bolz, Selma Sirin, Martin Glas, Jürgen C. Becker, Selma Ugurel, Alexander Roesch, Dirk Schadendorf, Elisabeth Livingstone, Tim Hagenacker and Lisa Zimmer
Journal for ImmunoTherapy of Cancer, 7:141 (29 May 2019)
Case Report

Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations

Vidyalakshmi Chandramohan, Xuhui Bao, Xin Yu, Scott Parker, Charlotte McDowall, Yen-Rei Yu, Patrick Healy, Annick Desjardins, Michael D. Gunn, Matthias Gromeier, Smita K. Nair, Ira H. Pastan and Darell D. Bigner
Journal for ImmunoTherapy of Cancer, 7:142 (29 May 2019)
Research Article

Bispecific NKG2D-CD3 and NKG2D-CD16 fusion proteins for induction of NK and T cell reactivity against acute myeloid leukemia

Melanie Märklin, Ilona Hagelstein, Samuel P. Koerner, Kathrin Rothfelder, Martin S. Pfluegler, Andreas Schumacher, Ludger Grosse-Hovest, Gundram Jung and Helmut R. Salih
Journal for ImmunoTherapy of Cancer, 7:143 (29 May 2019)
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.