JITC Editor Picks
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.
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.
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.
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.
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.
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.