Research Highlights
In this edition of the JITC Digest, there are four noteworthy articles in the Clinical/Translational Cancer Immunotherapy section. The first article, “Effect of neoadjuvant chemotherapy on the immune microenvironment in non–small cell lung carcinomas as determined by multiplex immunofluorescence and image analysis approaches,” by Edwin R. Parra et al. provides a retrospective analysis of the immunological profile of non-small cell lung carcinoma (NSCLC) treated with neoadjuvant chemotherapy (NCT). Specifically, this study uses multiplex immunofluorescence and image analysis to demonstrate chemotherapy-induced changes in the tumor microenvironment of patients treated with NCT compared to those who underwent primary surgical resection without NCT. The results indicate that, contrary to previous thinking, chemotherapy may act ivate specific immune response mechanisms in NSCLC, priming a positive response to checkpoint immunotherapy.
In the article, “Inhibition of WEE1 kinase and cell cycle checkpoint activation sensitizes head and neck cancers to natural killer cell therapies,” Jay Friedman et al. describes how AZD1775, a small molecule inhibitor of WEE1 kinase, prevents G2/M cell cycle checkpoint activation and sensitizes tumor cells to granzyme B-dependent natural killer (NK) cell lysis using a newly characterized murine NK cell line. Additionally, concomitant treatment of adoptively transferred murine NK cells with WEE1 kinase inhibition in immunocompetent mice with aggressive tumors prolonged survival over either treatment alone. These results provide rationale for the combination of NK cell therapies and targeted therapies that block cell cycle checkpoint activation.
Next, the article, “Pan-cancer adaptive immune resistance as defined by the Tumor Inflammation Signature (TIS): results from The Cancer Genome Atlas (TCGA),” by Patrick Danaher et al. explores the TIS, an investigational use only, 18-gene signature shown to correlate with patients who respond to the PD1 inhibitor, pembrolizumab. The authors applied the TIS algorithm to over 9000 tumor gene expression profiles from the TCGA. They found that, similar to the tumor ranking determined by Spranger et al. (2016), tumors sensitive to PD-1 blockade had higher average TIS scores. Therefore, with an increased understanding of tumor immune profiles, they propose that integration of TIS scores may lead to improved indication selection for testing immunotherapeutics.
Finally, Alexander Shimabukuro-Vornhagen et al.’s article, ‘Cytokine release syndrome,” provides a comprehensive and timely review of the mechanisms underlying cytokine release syndrome pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. The immense progress experienced in the field of cancer immunotherapy bears the need for an enriched understanding of potential treatment-related toxicities in order to make immune oncology interventions safer and more effective.
Recent Articles
Tolga Turan, Deepti Kannan, Maulik Patel, J. Matthew Barnes, Sonia G. Tanlimco, Rongze Lu, Kyle Halliwill, Sarah Kongpachith, Douglas E. Kline, Wouter Hendrickx, Alessandra Cesano, Lisa H. Butterfield, Howard L. Kaufman, Thomas J. Hudson, Davide Bedognetti, Francesco Marincola and Josue Samayoa Journal for ImmunoTherapy of Cancer, 6:50 (5 June 2018)
Hypothesis
From the Authors
"Anti-cancer immunotherapy is facing its own checkpoint. The effectiveness of checkpoint inhibition therapy is restricted to a minority of cancers endowed with a pre-existing immune infiltrate. Several models have been proposed to explain primary or secondary immune resistance to therapy. Missing is a unifying theory that could frame each model within a `satellite view’ of cancer and serve as a navigational tool for the rational selection of mono- or combination-therapies applicable to apposite sub-populations of patients. Here, we propose a strategy to unify individual models into a single unifying `Theory of Everything.’"
Francesco M. Marincola, MD — Refuge Biotechnologies
Masood Sadaat and Sekwon Jang Journal for ImmunoTherapy of Cancer, 6:49 (5 June 2018)
Case Report
From the Authors
"Hemophagocytic lymphohistiocytosis (HLH) and similar immune system hyperactivation syndromes can occur as potentially fatal immune related adverse events (irAEs) with PD-1, PD-L1 and CTLA-4 inhibitors, and CAR T cell and BiTe therapies. Diagnostic and therapeutic guidelines for malignancy- and immunotherapy-associated HLH are lacking, which complicates early diagnosis and management. The article describes cases of HLH, macrophage activation syndrome, and cytokine release syndrome due to various immunotherapeutic agents, and provides information regarding early recognition, diagnostic criteria and treatment approaches."
Masood Sadaat, MD, MSc – Inova Fairfax Hospital
Amber J. Giles, Marsha-Kay N. D. Hutchinson, Heather M. Sonnemann, Jinkyu Jung, Peter E. Fecci, Nivedita M. Ratnam, Wei Zhang, Hua Song, Rolanda Bailey, Dionne Davis, Caitlin M. Reid, Deric M. Park and Mark R. Gilbert Journal for ImmunoTherapy of Cancer, 6:51 (11 June 2018)
Research Article
From the Authors
"Immunosuppressive corticosteroids are first-line agents against immune-related adverse events arising from checkpoint blockade in patients with cancer. However, for patients with intracranial tumors, corticosteroids are often initiated at the time a brain tumor is discovered and continued during surgery and chemoradiation, a period that can span 8-12 weeks. Therefore, patients with intracranial tumors are likely to be exposed to corticosteroids before receiving immunotherapy. This study interrogated the impact of corticosteroids on adaptive anti-tumor immunity and confirmed that corticosteroids markedly impair the immune response if administered prior to immunotherapy. Conversely, corticosteroids do not diminish an established immune response. These results indicate that corticosteroid use should be avoided during the initiation of immunotherapy and that clinical trials should exclude patients requiring corticosteroids in order to increase the likelihood of response."
Amber J. Giles, PhD – National Cancer Institute, National Institutes of Health
Edwin R. Parra, Pamela Villalobos, Carmen Behrens, Mei Jiang, Apar Pataer, Stephen G. Swisher, William N. WilliamJr, Jiexin Zhang, Jack Lee, Tina Cascone, John V. Heymach, Marie-Andrée Forget, Cara Haymaker, Chantale Bernatchez, Neda Kalhor, Annikka Weissferdt, Cesar Moran, Jianjun Zhang, Ara Vaporciyan, Don L. Gibbons, Boris SepesiEmail author and Ignacio I. Wistuba
Journal for ImmunoTherapy of Cancer, 6:48 (6 June 2018)
Research Article
About
Edwin R. Parra et al. provides a retrospective analysis of the immunological profile of non-small cell lung cancer (NSCLC) treated with neoadjuvant chemotherapy (NCT). Specifically, this study uses multiplex immunofluorescence and image analysis to demonstrate chemotherapy-induced changes in PD-L1/PD-1 expression and tumor-associated immune cells of patients treated with NCT compared to those who underwent primary surgical resection without NCT. The results indicate that, contrary to previous thinking, chemotherapy may activate specific immune response mechanisms in NSCLC, priming a positive response to checkpoint immunotherapy.
Léa Paolini, Caroline Poli, Simon Blanchard, Thierry Urban, Anne Croué, Marie-Christine Rousselet, Sarah Le Roux, Nathalie Labarrière, Pascale Jeannin† and José Hureaux†
†Contributed equally
Journal for ImmunoTherapy of Cancer, 6:52 (13 June 2018)
Case Report
About
Immune checkpoint inhibitors (ICI) have transformed the treatment arena and prognosis for lung cancer patients. However, with such immense progress in restoring a patient’s antitumor immune response comes related adverse events, such as sarcoidosis. Lea Paolini et al. report the first case of a thoracic and cutaneous sarcoid-like reaction in a patient with a relapsing, unresectable non-small cell lung cancer (NSCLC) treated with nivolumab, shedding light on the complex regulation of PD-1/PD-L1 expression and the importance of monitoring the immune response during and after treatment with ICI.
Janet Lei, Egon J. Jacobus, William K. Taverner, Kerry D. Fisher, Silvio Hemmi, Katy West, Lorna Slater, Fred Lilley, Alice Brown, Brian Champion, Margaret R. Duffy and Len W. Seymour
Journal for ImmunoTherapy of Cancer, 6:55 (13 June 2018)
Research Article
From the Authors
"Translational development of oncolytic vaccines, based on human-specific viruses, would be greatly enhanced by the availability of immunocompetent animal tumour modules that can study virus infection in the context of a functional immune system. We therefore consider it imperative to define the species-related blocks to virus activity in murine cancer cells, and to develop models that can be used to support the oncolytic activity of human-specific viruses."
Leonard W. Seymour, PhD - Oxford University
*This article is part of JITC’s Microbial-Based Cancer Therapy special series. Articles in this series describe the complex nature of the microbe-tumor interaction and discuss recent advances in the field that take advantage of the unique ability of microbes to invade human cells and induce immune responses in order to create therapeutic approaches that direct microbes to selectively target tumors.
Edward Hammond, Nicole M. Haynes, Carleen Cullinane, Todd V. Brennan, Darryn Bampton, Paul Handley, Tomislav Karoli, Fleur Lanksheer, Liwen Lin, Yiping Yang and Keith Dredge
Journal for ImmunoTherapy of Cancer, 6:54 (14 June 2018)
Research Article
From the Authors
“Pixatimod (PG545) is a clinical-stage immunomodulator currently under investigation with nivolumab in advanced and pancreatic cancers (Clinical Trial ID: ACTRN12617001573347). Though multiple preclinical studies have demonstrated additive or synergistic activity with chemotherapy, this is the first study to show the potential utility of pixatimod with a PD1 inhibitor. Importantly, the paper also explores the nonclinical and clinical exposure and safety data, with in-depth comparisons of key safety parameters across species. We hope that readers will gain a deeper understanding of pixatimod’s nonclinical and clinical safety profile, and its potential utility in combination with other I-O agents”
Keith Dredge, PhD - Zucero Therapeutics
**This article is part of JITC's Emerging Immunotherapeutic Agents special series. All articles in this series cover details beyond standard JITC articles, providing readers with a unique collection of cutting-edge cancer immunotherapy research.
Joseph I. Clark, Shams Bufalino, Shruti Singh and Ewa Borys
Journal for ImmunoTherapy of Cancer, 6:53 (14 June 2018)
Case Report
From the Authors
“Sequencing of immunotherapeutic approaches in the treatment of malignant melanoma, and for a number of other malignancies for that matter, is becoming common place. Understanding potential unique toxicities associated with such sequencing will be an important area of investigation as immunotherapeutic advancements continue.”
Joseph I. Clark, MD – Loyola University Medical Center
Alexander Shimabukuro-Vornhagen†, Philipp Gödel†, Marion Subklewe, Hans Joachim Stemmler, Hans Anton Schlößer, Max Schlaak, Matthias Kochanek, Boris Böll and Michael S. von Bergwelt-Baildon
†Contributed equally
Journal for ImmunoTherapy of Cancer, 6:56 (15 June 2018)
Review
Excerpt
“With growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors.”
Robert D. Leone and Leisha A. Emens
Journal for ImmunoTherapy of Cancer, 6:57 (18 June 2018)
Review Article
From the Authors
"Adenosine signaling creates a cloud in the tumor microenvironment that suppresses immunity. Targeting adenosine signaling may lift that cloud and enhance the response to immunotherapy."
Leisha A. Emens, MD, PhD — Johns Hopkins University
Evidio Domingo-Musibay, Paari Murugan, Alessio Giubellino, Sandeep Sharma, Daniel Steinberger, Jianling Yuan, Matthew A. Hunt, Emil Lou and Jeffrey S. Miller
Journal for ImmunoTherapy of Cancer, 6:58 (19 June 2018)
Case Report
From the Authors
"This is the first report describing objective clinical and radiographic responses following immunotherapy for widely metastatic sebaceous carcinoma. The dramatic therapeutic response to pembrolizumab was associated with peripheral blood circulating memory T cells and mature Natural Killer cells after 6 months (24 weeks) of therapy. This report supports prospective clinical trials of anti-PD1 checkpoint blockade for metastatic sebaceous carcinoma."
Evidio Domingo-Musibay, MD — University of Minnesota Medical School
Donald Bastin†, Amelia S. Aitken†, Adrian Pelin, Larissa A. Pikor, Mathieu J. F. Crupi, Michael S. Huh, Marie-Claude Bourgeois-Daigneault, John C. Bell and Carolina S. Ilkow
†Contributed equally
Journal for ImmunoTherapy of Cancer, 6:62 (19 June 2018)
Short Report
About
Many human cancers do not respond to oncolytic virotherapy. Donald Bastin et al. investigates the basic biology of viral defense mechanisms in cancer and presents data which establishes the improved therapeutic potential of a novel virus which targets the RNAi-mediated antiviral defense in human cancer cells.
*This article is part of JITC’s Microbial-Based Cancer Therapy special series. Articles in this series describe the complex nature of the microbe-tumor interaction and discuss recent advances in the field that take advantage of the unique ability of microbes to invade human cells and induce immune responses in order to create therapeutic approaches that direct microbes to selectively target tumors.
Asha Nayak-Kapoor, Zhonglin Hao, Ramses Sadek, Robin Dobbins, Lisa Marshall, Nicholas N. Vahanian, W. Jay Ramsey, Eugene Kennedy, Mario R. Mautino, Charles J. Link, Ray S. Lin, Stephanie Royer-Joo, Xiaorong Liang, Laurent Salphati, Kari M. Morrissey, Sami Mahrus, Bruce McCall, Andrea Pirzkall, David H. Munn, John E. Janik and Samir N. Khleif
Journal for ImmunoTherapy of Cancer, 6:61 (20 June 2018)
Research Article
About
This open-label Phase Ia study assesses safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of the novel Indoleamine-2,3-dioxygenase 1 (IDO1) small molecule inhibitor, navoximod, in patients with recurrent/advanced solid tumors. As evidenced in the current study, data demonstrate that IDO inhibitors produce minimal antitumor activity when given alone. However, emerging clinical data from Phase I/II studies suggest the potential for increased benefit from a combination approach with IDO inhibitors and targeted immunotherapy drugs.
Paula Nunes-Hasler
Journal for ImmunoTherapy of Cancer, 6:60 (20 June 2018)
Commentary
From the Author
"A recent publication by Veglia et al. shows that oxidized lipids sequester the cytosolic chaperone HSP70, and that this contributes to reduced cross-presentation in dendritic cells from tumour-bearing mice. This commentary discusses these results in the context of the multiple roles of HSP70, lipid droplet function, and MHC-I trafficking, as well as their impact on future cancer therapy designs."
Paula Nunes-Hasler, PhD – University of Geneva
Jay Friedman†, Megan Morisada†, Lillian Sun†, Ellen C. Moore, Michelle Padget, James W. Hodge, Jeffrey Schlom, Sofia R. Gameiro and Clint T. Allen
Journal for ImmunoTherapy of Cancer, 6:59 (21 June 2018)
Research Article
From the Authors
"While mechanisms of tumor cell immune escape based on the immunosuppressive tumor microenvironment are well studied, tumor cell intrinsic mechanisms of resistance to effector immune cell killing are less understood. The ability to reverse tumor G2/M cell cycle pause in response to granzyme B with a small molecule inhibitor of Wee1 kinase is an exciting finding that we hope translates into improved efficacy of a diverse array of immunotherapies in clinical trials."
Clint T. Allen, MD – National Institutes of Health
Patrick Danaher, Sarah WarrenView ORCID ID profile, Rongze Lu, Josue Samayoa, Amy Sullivan, Irena Pekker, Brett Wallden, Francesco M. Marincola and Alessandra Cesano
Journal for ImmunoTherapy of Cancer, 6:63 (22 June 2018)
Research Article
From the Authors
"The Tumor Inflammation Signature (TIS) is an 18 gene analytically validated signature which detects the presence of an adaptive immune response peripherally suppressed in the tumor microenvironment by measuring the expression of genes associated with cytotoxic cells, antigen presentation, and IFNγ activity. The TIS has previously been shown to enrich, in a tumor-type agnostic manner, for a population of patients who responds to immune checkpoint blockade. Since the TIS (reagents, instrumentation, algorithm and software) has been analytically developed as an IUO diagnostic assay, the test can be prospectively deployed for patient selection in clinical trials. In this paper we characterized the level of the TIS across a range of tumor gene expression data downloaded from the TCGA in order to understand the prevalence of the tumor “inflamed” phenotype within and between tumor types. In addition, we evaluate how TIS level correlates with other relevant variables such as mutation load, other gene expression signatures, and clinical outcomes in the absence of specific immune therapeutic intervention (i.e. prognosis). Finally, to screen for novel suppressive mechanisms, this study searched for biological pathways associated with low TIS scores."
Alessandra Cesano, MD, PhD – NanoString, Inc.
*This article is part of JITC's Emerging Immunotherapeutic Agents special series. All articles in this series cover details beyond standard JITC articles, providing readers with a unique collection of cutting-edge cancer immunotherapy research.
Highly Accessed Articles
Ryan J. Sullivan, Michael B. Atkins, John M. Kirkwood, Sanjiv S. Agarwala, Joseph I. Clark, Marc S. Ernstoff, Leslie Fecher, Thomas F. Gajewski, Brian Gastman, David H. Lawson, Jose Lutzky, David F. McDermott, Kim A. Margolin, Janice M. Mehnert, Anna C. Pavlick, Jon M. Richards, Krista M. Rubin, William Sharfman, Steven Silverstein, Craig L. SlingluffJr, Vernon K. Sondak, Ahmad A. Tarhini, John A. Thompson, Walter J. Urba, Richard L. White, Eric D. Whitman, F. Stephen Hodi and Howard L. Kaufman
Journal for ImmunoTherapy of Cancer 2018, 6:44 (30 May 2018)
Carl Morrison†, Sarabjot Pabla†, Jeffrey M. Conroy, Mary K. Nesline, Sean T. Glenn, Devin Dressman, Antonios Papanicolau-Sengos, Blake Burgher, Jonathan Andreas, Vincent Giamo, Moachun Qin, Yirong Wang, Felicia L. Lenzo, Angela Omilian, Wiam Bshara, Matthew Zibelman, Pooja Ghatalia, Konstantin Dragnev, Keisuke Shirai, Katherine G. Madden, Laura J. Tafe, Neel Shah, Deepa Kasuganti, Luis de la Cruz-Merino, Isabel Araujo, Yvonne Saenger, Margaret Bogardus, Miguel Villalona-Calero, Zuanel Diaz, Roger Day, Marcia Eisenberg, Steven M. Anderson, Igor Puzanov, Lorenzo Galluzzi, Mark Gardner and Marc S. Ernstoff
†Contributed equally
Journal for ImmunoTherapy of Cancer 2018, 6:32 (9 May 2018)
Young Kwang ChaeEmail author, Ayush Arya, Wade Iams, Marcelo R. Cruz, Sunandana Chandra, Jaehyuk Choi and Francis Giles
Journal for ImmunoTherapy of Cancer 2018, 6:39 (16 May 2018)