JITC Digest May 2020


Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

Welcome to the latest edition of the JITC digest—perhaps you share the sentiment that the month of April seemed exceptionally short. Like every other aspect of life, the journal is still adapting to the 'new normal' imposed by the COVID-19 pandemic and we are exceptionally grateful to the editors and reviewers who work tirelessly behind the scenes to enable JITC to continue to publish top-quality immunotherapy research even during these exceptional times.
SITC is proud to stand alongside and support our colleagues on the frontlines of the pandemic, and you can read the society editorial advocating for expanded access to IL-6-targeting therapies for COVID-19 in this issue of JITC.
You may notice that the digest is extra-long this month, featuring three original research articles, two reviews and the aforementioned editorial. It is a testament to the dedication of our immunotherapy community, and we're excited to share these articles with you, our readers.
April saw two reviews publish that are part of the ongoing JITC "Immune Checkpoints Beyond PD-1" review series. Be sure to read a thought-provoking discussion of the increasing reliance on non-conventional trial protocols in immune-oncology by Luca Mazarella et al. as well as a fascinating overview of some potential unusual suspects for checkpoint blockade in the innate cells that function to initiate and guide T cell activity from Carla V Rothlin and Sourav Ghosh.
The original research articles in this month's digest provide important insight into responses to immunotherapy in real-world patients both in terms of basic tumor immunology and evaluable clinical outcomes. On the clinical side, Yukihiro Umeda et al. leverage integrated FDG-PET/MRI-based methods to predict PFS in nivolumab-treated non-small cell lung cancer based on scans after the first dose.
Delving into immunological responses, Houssein Abdul Sater et al. demonstrate that the therapeutic prostate cancer vaccine PROSTVAC induces systemic immune responses and corresponding increases in lymphocyte infiltration around the tumor despite failing to demonstrate survival benefits in randomized trials. Finally, Tatsuya Yoshida and colleagues provide mechanistic underpinnings behind the link with high C-reactive protein (CRP) and poor outcomes through a variety of in vitro assays showing that CRP inhibits T cell proliferation and effector function as well as dendritic cell phenotypes.
Best regards,

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

JITC Editor Picks

Insights from immuno-oncology: the Society for Immunotherapy of Cancer Statement on access to IL-6-targeting therapies for COVID-19

Paolo Antonio Ascierto, Bernard A Fox, Walter J Urba, Ana Carrizosa Anderson, Michael B Atkins, Ernest C Borden, Julie R Brahmer, Lisa H Butterfield, Alessandra Cesano, Daniel S Chen, Tanja D de Gruijl, Robert O Dillman, Charles G Drake, Leisha A Emens, Thomas F Gajewski, James L Gulley, F Stephen Hodi Jr, Patrick Hwu, David Kaufman, Howard L Kaufman, Michael T Lotze, Douglas G McNeel, Kim A Margolin, Francesco M Marincola, Michael J Mastrangelo, Marcela V Maus, David R Parkinson, Pedro J Romero, Paul M Sondel, Stefani Spranger, Mario Sznol, George J Weiner, Jon M Wigginton and Jeffrey S Weber
Journal for ImmunoTherapy of Cancer 2020;8:e000878 (16 April 2020)


Based on anecdotal data from the frontlines of the COVID-19 pandemic that the anti-IL-6 agent tocilizumab may offer lifesaving benefit, the Society for Immunotherapy of Cancer is calling on pharmaceutical sponsors, health authorities and institutional review boards to move swiftly and creatively to remove barriers and increase access to IL-6 modulatory therapies.

Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer

Houssein Abdul Sater, Jennifer L Marté, Renee N Donahue, Beatriz Walter-Rodriguez, Christopher R Heery, Seth M Steinberg, Lisa M Cordes, Guinevere Chun, Fatima Karzai, Marijo Bilusic, Stephanie A Harmon, Ismail Baris Turkbey, Peter L Choyke, Jeffrey Schlom, William L Dahut, Ravi A Madan, Peter A Pinto and James L Gulley
Journal for ImmunoTherapy of Cancer 2020;8:e000655  (7 April 2020)



Tumor mutational burden (TMB) values can predict responses to immune checkpoint inhibitor therapy, but calculation methods including the content of gene panels sequenced (the denominator of TMB) and the inclusion of synonymous variants (the numerator of TMB) are not standardized between institutions. To understand the impact of altering these parameters, Nicholas Bevins et al. used publicly available data for more than 9000 tumors from The Cancer Genome Atlas (TCGA) to perform in silico simulations of TMB calculations by six commonly used molecular profiling products. The correlation between panel-based and whole-exome sequencing-based method was linear and the correlations between individual panel-based TMB calculations showed slopes of 0.9-1.1, indicating that the absolute value is comparable between panels. For TMB calculations derived from whole-exome sequencing, inclusion of synonymous variants led to differences of roughly 5-10 variants/Mb specifically in the approximate clinical decision range of TMB <20. By contrast, inclusion of synonymous variants in panel-based TMB calculations did not cause any differences in values for panels of similar size. Although most of the datasets in TCGA were deposited before the widespread use and FDA approval of checkpoint inhibitors, analysis of pan-tumor data showed an inverse correlation between TMB and overall survival, though this relationship varied for individual subgroups of cancers. The analysis provides reassuring confirmation that TMB calculations between the gene panels examined are analytically and prognostically equivalent.

Predictive value of integrated 18F-FDG PET/MRI in the early response to nivolumab in patients with previously treated non-small cell lung cancer

Yukihiro Umeda, Miwa Morikawa, Masaki Anzai, Shingo Ameshima, Maiko Kadowaki, Yuko Waseda, Hiroko Shigemi, Tetsuya Tsujikawa, Yasushi Kiyono, Hidehiko Okazawa and Tamotsu Ishizuka
Journal for ImmunoTherapy of Cancer 2020;8:e000349 (28 April 2020)


Pseudoprogression, the transient growth of malignant masses after treatment with immune checkpoint inhibitors is one reason why early responses to therapy are difficult to evaluate. Yukihiro Umeda and colleagues developed a predictor of response to nivolumab treatment in non-small cell lung cancer based on integrated 18F-fluoro-2-deoxy-D-glucose positron emission tomography/MRI (18F-FDG PET/MRI) parameters after two weeks of therapy. In multivariate analysis of pre- and post-treatment imaging from 25 patients with previously treated NSCLC, a combined metric based on total lesion glycolysis (delta TLG) by PET and apparent diffusion coefficient (delta ADC) by MRI between the two scans was an independent predictor of PFS. A cut-off value of 16.5 for delta TLG+ delta ADC had 92% accuracy (92%) for distinguishing between patients with non-progressive and progressive disease and values less than 16.5 were significantly associated with a longer median progression-free survival  of 9.0 versus 1.8 months (p<0.00001). The findings indicate that changes in integrated 18F-FDG PET/MRI parameters can successfully capture the response to nivolumab after a single dose.

C reactive protein impairs adaptive immunity in immune cells of patients with melanoma

Tatsuya Yoshida, Junya Ichikawa, Iulia Giuroiu, Andressa S Laino, Yuhan Hao, Michelle Krogsgaard, Melinda Vassallo, David M Woods, F Stephen Hodi and Jeffrey Weber
Journal for ImmunoTherapy of Cancer 2020;8:e000234 (16 April 2020)



High levels of C-reactive protein (CRP) have been linked to increased cancer risk as well as worse outcomes in established tumors across a variety of disease settings, though the mechanism is unclear. Evidence for an inhibitory effect on adaptive immunity of CRP is provided by Tatsuya Yoshida and colleagues who show through a variety of in vitro assays that it inhibits T cell proliferation and effector function as well as dendritic cell differentiation. CRP treatment led to impaired cytokine production, decreased actin localization at immune synapses and reduced peroxide-induced T cell receptor signaling, as assayed by phosphorylation of LCK, ZAP70, LAT and ERK in CD4+ and CD8+ T cells. Expansion of Melan-A tetramer-positive CD8+ T cells isolated from patients with melanoma was suppressed by CRP in a dose-dependent manner. Additionally, elevated serum CRP at baseline was associated with significantly worse overall survival in patients with advanced melanoma from the CheckMate-064 trial. The data suggest that CRP may contribute to a state of systemic immune suppression in patients with cancer.

Master protocols in immuno-oncology: do novel drugs deserve novel designs?

Luca Mazzarella, Stefania Morganti, Antonio Marra, Dario Trapani, Giulia Tini, Piergiuseppe Pelicci and Giuseppe Curigliano
Journal for ImmunoTherapy of Cancer 2020;8:e000475 (1 April 2020)



Some experts have argued that the canonical three-phase model of clinical trials is poorly suited for developing immunotherapy agents, especially in the case of combination therapies. Luca Mazarella and colleagues introduce the concept and rationale for a master trial protocol for immune-oncology agents based on the inadequacy of classical toxicity and efficacy endpoints, the increasing reliance on biomarkers, and the rapid pace at which the treatment indications and disease classification are changing. Master protocols overcome these limitations and encompass trials designed to evaluate single drugs across multiple populations (‘basket trials’), multiple drugs on a single population (‘umbrella trials’), or complex multi-arm, multi-stage designs that evaluate multiple treatments simultaneously (‘platform trials’). Although master protocols sacrifice some statistical strength and can increase the risk of inconclusive findings, the likelihood of exposing patients to the best therapy is increased. The review provides a balanced framework to consider how master protocols influence the classic ‘access versus evidence’ dilemma.

Lifting the innate immune barriers to antitumor immunity

Carla V Rothlin and Sourav Ghosh
Journal for ImmunoTherapy of Cancer 2020;8:e000695 (8 April 2020)



Despite approvals for immune checkpoint inhibitor therapies in 16 indications and a global market exceeding US $7 billion, the majority of cancer patients do not qualify for these agents and even among those that do, response rates are as meager as roughly 12%. In a comprehensive review, Carla V Rothlin and Sourav Ghosh look beyond the “usual suspects” of additional T cell checkpoints to identify potentially therapeutic targets in innate immune cells and tumor microenvironment-derived ligands to drive the next frontiers in immunotherapy. Detailed descriptions are provided of ongoing early phase trials and preclinical models evaluating such approaches as NK cell-mediated therapeutics, strategies to neutralize myeloid-derived suppressor cells to enhance antitumor immunity and molecules that license T cell entry into tumor microenvironment as targets to improve antitumor immunity. Additionally, Rothlin and Gourash posit that cell death can function as a novel checkpoint. The review sets the stage for future studies to vastly expand the landscape of cancer immunotherapy.

Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce

Harriet M. KlugerHussein A. TawbiMaria L. AsciertoMichaela BowdenMargaret K. CallahanEdward ChaHelen X. ChenCharles G. DrakeDavid M. FeltquateRobert L. FerrisJames L. GulleyShilpa GuptaRachel W. HumphreyTheresa M. LaValleeDung T. LeVanessa M. Hubbard-LuceyVassiliki A. PapadimitrakopoulouMichael A. PostowEric H. RubinElad SharonJanis M. TaubeSuzanne L. TopalianRoberta ZappasodiMario SznolRyan J. Sullivan
Journal for ImmunoTherapy of Cancer 
2020;8:e000398 (1 April 2020)

PRKDC: new biomarker and drug target for checkpoint blockade immunotherapy

Kien Thiam TanChun-Nan YehYu-Chan ChangJen-Hao ChengWen-Liang FangYi-Chen YehYu-Chao WangDennis Shin-Shian HsuChiao-En WuJiun-I LaiPeter Mu-Hsin ChangMing-Han ChenMeng-Lun LuShu-Jen ChenYee ChaoMichael HsiaoMing-Huang Chen
Journal for ImmunoTherapy of Cancer 
2020;8:e000485 (1 April 2020)

Low-dose interferon-alpha preconditioning and adoptive cell therapy in patients with metastatic melanoma refractory to standard (immune) therapies: a phase I/II study

Els Verdegaal, Monique K van der Kooij, Marten Visser, Caroline van der Minne, Linda de Bruin, Pauline Meij, Anton Terwisscha van Scheltinga, Marij J Welters, Saskia Santegoets, Noel de Miranda, Inge Roozen, Gerrit Jan Liefers, Ellen Kapiteijn, Sjoerd H van der Burg
Journal for ImmunoTherapy of Cancer 
2020;8:e000166 (1 April 2020)

Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3–dependent spread immunity against endogenous tumor antigens

Paula Jaime-Sanchez, Iratxe Uranga-Murillo, Nacho Aguilo, Sofia C Khouili, Maykel A Arias, David Sancho and Julian Pardo
Journal for ImmunoTherapy of Cancer 2020;8:e000528  (1 April 2020)

Immunogenicity of cell death driven by immune effectors

Lorenzo GalluzziGiulia PetroniGuido Kroemer
Journal for ImmunoTherapy of Cancer 2020;8:e000802  (5 April 2020)

Melanoma-specific bcl-2 promotes a protumoral M2-like phenotype by tumor-associated macrophages

Marta Di Martile, Valentina Farini, Francesca Maria Consonni, Daniela Trisciuoglio, Marianna Desideri, Elisabetta Valentini, Simona D'Aguanno, Maria Grazia Tupone, Simonetta Buglioni, Cristiana Ercolani, Enzo Gallo, Bruno Amadio, Irene Terrenato, Maria Laura Foddai, Antonio Sica and Donatella Del Bufalo
Journal for ImmunoTherapy of Cancer 2020;8:e000489 (7 April 2020)

Vaccine efficacy against primary and metastatic cancer with in vitro-generated CD103+ conventional dendritic cells

Yifan Zhou, Natalie Slone, Taylor T Chrisikos, Oleksandr Kyrysyuk, Rachel L Babcock, Yusra B Medik, Haiyan S Li, Eugenie S Kleinerman and Stephanie S Watowich
Journal for ImmunoTherapy of Cancer 2020;8:e000474  (8 April 2020)

Efficacy and safety of avelumab treatment in patients with metastatic Merkel cell carcinoma: experience from a global expanded access program

John W Walker, Celeste Lebbé, Giovanni Grignani, Paul Nathan, Luc Dirix, Eyal Fenig, Paolo Antonio Ascierto, Shahneen Sandhu, Rodrigo Munhoz, Elena Benincasa, Sarah Flaskett, Josh Reed, Arne Engelsberg, Subramanian Hariharan and Vijay Kasturi
Journal for ImmunoTherapy of Cancer 2020;8:e000313  (8 April 2020)

Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy

Brett A SchroederRalph Graeme BlackSydney SpadingerShihong ZhangKaran KohliJianhong CaoJose G MantillaErnest U ConradStanley R RiddellRobin L JonesCassian YeeSeth M Pollack
Journal for ImmunoTherapy of Cancer 
2020;8:e000247 (8 April 2020)
Case Report

First in human dose calculation of a single-chain bispecific antibody targeting glioma using the MABEL approach

Teilo H Schaller, David J Snyder, Ivan Spasojevic, Patrick C Gedeon, Luis Sanchez-Perez, John H Sampson
Journal for ImmunoTherapy of Cancer 2020;8:e000213  (8 April 2020)

Immune involvement of the contralateral hemisphere in a glioblastoma mouse model

Matheus H W Crommentuijn, Sjoerd T T Schetters, Sophie A Dusoswa, Laura J W Kruijssen, Juan J Garcia-Vallejo and Yvette van Kooyk
Journal for ImmunoTherapy of Cancer 2020;8:e000323  (16 April 2020)

Targeting ANXA1 abrogates Treg-mediated immune suppression in triple-negative breast cancer

Fang Bai, Peng Zhang, Yipeng Fu, Hongliang Chen, Mingdi Zhang, Qianru Huang, Dan Li, Bin Li and Kejin Wu
Journal for ImmunoTherapy of Cancer 2020;8:e000169  (16 April 2020)

Decrease in tumor content assessed in biopsies is associated with improved treatment outcome response to pembrolizumab in patients with rare tumors

Coya Tapia, Phyu P. Aung, Sinchita Roy-Chowdhuri, Mingxuan Xu, Fengying Ouyang, Anas Alshawa, Joud Hajjar, Gopal Singh, Vincent Yang, Lilibeth Castillo, Hung Le, Ravi Murthy, Bettzy Stephen, Kenneth R Hess, Ignacio Wistuba, Aung Naing
Journal for ImmunoTherapy of Cancer 2020;8:e000665  (16 April 2020)

Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist

Karin M Knudson, Kristin C Hicks, Yohei Ozawa, Jeffrey Schlom, Sofia R Gameiro
Journal for ImmunoTherapy of Cancer 2020;8:e000493  (16 April 2020)

Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma

Won Jin HoLudmila DanilovaSu Jin LimRohan VermaStephanie XavierJames M LeathermanMarcelo B SzteinElana J FertigHao WangElizabeth JaffeeMark Yarchoan
Journal for ImmunoTherapy of Cancer 
2020;8:e000394  (16 April 2020)

Development and validation of the immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma

Sai-Lan Liu, Li-Juan Bian, Ze-Xian Liu, Qiu-Yan Chen, Xue-Song Sun, Rui Sun, Dong-Hua Luo, Xiao-Yun Li, Bei-Bei Xiao, Jin-Jie Yan, Zi-Jian Lu, Shu-Mei Yan, Li Yuan, Lin-Quan Tang, Jian-Ming Li, Hai-Qiang Mai
Journal for ImmunoTherapy of Cancer 
2020;8:e000205 (16 April 2020)

Immunotherapy to treat malignancy in patients with pre-existing autoimmunity

Patrick BolandAnna C PavlickJeffrey WeberSabina Sandigursky
Journal for ImmunoTherapy of Cancer 
2020;8:e000356 (16 April 2020)

Inhibition of TGF-β-receptor signaling augments the antitumor function of ROR1-specific CAR T-cells against triple-negative breast cancer

Tanja StüberRazieh MonjeziLars WallstabeJohanna KühnemundtSarah Louise NietzerGudrun DandekarAchim WöckelHermann EinseleJörg WischhusenMichael Hudecek
Journal for ImmunoTherapy of Cancer 
2020;8:e000676 (16 April 2020)
Short Report

Cancer cell-intrinsic expression of MHC II in lung cancer cell lines is actively restricted by MEK/ERK signaling and epigenetic mechanisms

Alexander J Neuwelt, Abigail K Kimball, Amber M Johnson, Benjamin W Arnold, Bonnie L Bullock, Rachael E Kaspar, Emily K Kleczko, Jeff W Kwak, Meng-Han Wu, Lynn E Heasley, Robert C Doebele, Howard Y Li, Raphael A Nemenoff and Eric T Clambey
Journal for ImmunoTherapy of Cancer
2020;8:e000441  (19 April 2020)

Results of a randomized, double-blind phase II clinical trial of NY-ESO-1 vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in participants with high-risk resected melanoma

Jonathan S Cebon, Martin Gore, John F Thompson, Ian D Davis, Grant A McArthur, Euan Walpole, Mark Smithers, Vincenzo Cerundolo, P Rod Dunbar, Duncan MacGregor, Cyril Fisher, Michael Millward, Paul Nathan, Michael P N Findlay, Peter Hersey, T R Jeffry Evans, Christian Hermann Ottensmeier, Jeremy Marsden, Angus G Dalgleish, Pippa G Corrie, Marples Maria, Margaret Brimble, Geoff Williams, Sintia Winkler, Heather M Jackson, Liliana Endo-Munoz, Candani S A Tutuka, Ralph Venhaus, Lloyd J Old, Dennis Haack, Eugene Maraskovsky, Andreas Behren, Weisan Chen
Journal for ImmunoTherapy of Cancer 2020;8:e000410  (20 April 2020)

ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy

Jared E Lopes, Jan L Fisher, Heather L Flick, Chunhua Wang, Lei Sun, Marc S Ernstoff, Juan C Alvarez and Heather C Losey
Journal for ImmunoTherapy of Cancer 2020;8:e000673  (21 April 2020)

CAR T-cell therapy for a relapsed/refractory acute B-cell lymphoblastic lymphoma patient in the context of Li-Fraumeni syndrome

Liting ChenBin XuXiaolu LongJia GuYaoyao LouDi WangYang CaoNa WangChunrui LiGaoxiang WangYing WangLi ZhuJin WangHaiyun AnMin XiaoYi XiaoJianfeng Zhou
Journal for ImmunoTherapy of Cancer 2020;8:e000364  (28 April 2020)
Case Report

Incomplete Freund’s adjuvant reduces arginase and enhances Th1 dominance, TLR signaling and CD40 ligand expression in the vaccine site microenvironment

Karlyn E PollackMax O MeneveauMarit M MelssenKevin T LynchAlexander F KoeppelSamuel J YoungStephen TurnerPankaj KumarKatia Sol-ChurchIleana S MauldinCraig L Slingluff Jr
Journal for ImmunoTherapy of Cancer 2020;8:e000544  (28 April 2020)

Overcoming hypoxia-induced functional suppression of NK cells

Kristen Solocinski, Michelle R Padget, Kellsye P Fabian, Benjamin Wolfson, Fabiola Cecchi, Todd Hembrough, Stephen C Benz, Shahrooz Rabizadeh, Patrick Soon-Shiong, Jeffrey Schlom, James W Hodge
Journal for ImmunoTherapy of Cancer 
2020;8:e000246 (28 April 2020)

Neutrophil expansion defines an immunoinhibitory peripheral and intratumoral inflammatory milieu in resected non-small cell lung cancer: a descriptive analysis of a prospectively immunoprofiled cohort

Kyle G Mitchell, Lixia Diao, Tatiana Karpinets, Marcelo V Negrao, Hai T Tran, Edwin R Parra, Erin M Corsini, Alexandre Reuben, Lorenzo Federico, Chantale Bernatchez, Hitoshi Dejima, Alejandro Francisco-Cruz, Jing Wang, Mara B Antonoff, Ara A Vaporciyan, Stephen G Swisher, Tina Cascone, Ignacio I Wistuba, John V Heymach, Don L Gibbons, Jianjun Zhang, Cara L Haymaker, Boris Sepesi
Journal for ImmunoTherapy of Cancer 
2020;8:e000405 (28 April 2020)

The Fully human anti-CD47 antibody SRF231 exerts dual-mechanism antitumor activity via engagement of the activating receptor CD32a

Marisa O PelusoAmmar AdamCaroline M ArmetLi ZhangRachel W O’ConnorBenjamin H LeeAndrew C LakeEmmanuel NormantScott C ChappelJonathan A HillVito J PalombellaPamela M HollandAlison M Paterson
Journal for ImmunoTherapy of Cancer 2020;8:e000413 (28 April 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.