JITC Editor Picks
Marijo Bilusic, Christopher R. Heery, Julie M. Collins, Renee N. Donahue, Claudia Palena, Ravi A. Madan, Fatima Karzai, Jennifer L. Marté, Julius Strauss, Margaret E. Gatti-Mays, Jeffrey Schlom & James L. Gulley
Journal for ImmunoTherapy of Cancer, 7:240 (5 September 2019)
High serum IL-8 levels have been shown to correlate with poor prognosis in several cancers, and the cytokine is known to contribute to disease progression by inducing angiogenesis, recruiting neutrophils and myeloid-derived suppressor cells to the tumor microenvironment, enhancing tumor “stem-ness,” and promoting the epithelial-mesenchymal transition. Bilusic et al. investigated IL-8 blockade via a novel fully human monoclonal antibody, HuMax-IL8, in an open-label phase 1 clinical trial encompassing 15 patients with incurable metastatic or unresectable, locally advanced solid tumors. No dose-limiting toxicities were reported and the maximum tolerated dose was not reached during the trial, which used a 3 + 3 dose-escalation study design. Reductions in serum IL-8 levels were observed at all dose levels, and even though no objective responses occurred, 11 patients (around 70%) achieved stable disease with 8 (around 50%) remaining progression-free for at least 5.5 months. This study demonstrates that IL-8 blockade can be safe and well tolerated, and ongoing trials are evaluating potential beneficial effects of combining HuMax-IL8 with checkpoint inhibitors or other therapies.
Swati Gupta, Leena McCann, Yvonne G. Y. Chan, Edwin W. Lai, Wei Wei, Pok Fai Wong, James W. Smithy, Jodi Weidler, Brian Rhees, Michael Bates, Harriet M. Kluger & David L. Rimm
Journal for ImmunoTherapy of Cancer, 7:254 (18 September 2019)
To date, only one in five patients may benefit from programmed cell death (PD-1) axis immune checkpoint inhibitor (ICI) therapy in the adjuvant setting in melanoma, and no reliable biomarkers currently exist to predict response to treatment. Seeking an easily standardizable, sensitive and specific companion diagnostic test, Gupta et al. investigated correlations between clinical outcomes in 116 melanoma patients treated with anti-PD-1 immunotherapy and expression levels of a 4-gene multiplex immunotherapy panel, CD274 (PD-L1), PDCDILG2 (PD-L2), CD8A, and IRF1. Transcript levels in pretreatment formalin-fixed, paraffin embedded specimens were enumerated with research use only mRNA expression profiles on the the GeneXpert closed system using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Transcript levels for all four markers were significantly higher in specimens from responders to anti-PD-1 therapy than those from non-responders, and a combined CD274 (PD-L1) & PDCD1LG2 (PD-L2) expression signature remained significantly associated with progression-free survival and overall survival independent of age, sex, stage, mutation, treatment, and prior ICI. With further development and validation, the closed system mRNA approach introduced in this paper might offer significant advantages over immunohistochemistry-based diagnostics in terms of standardization and rapid turnaround time.
Michael Fehlings, Suchit Jhunjhunwala, Marcin Kowanetz, William E. O’Gorman, Priti S. Hegde, Hermi Sumatoh, Boon Heng Lee, Alessandra Nardin, Etienne Becht, Susan Flynn, Marcus Ballinger, Evan W. Newell & Mahesh Yadav
Journal for ImmunoTherapy of Cancer, 7:249 (12 September 2019)
Despite strong evidence that neoantigen-specific CD8+ T cells drive durable responses to checkpoint inhibition, the quantitative and qualitative characteristics of an effective anti-tumor T cell response during immunotherapy have been difficult to define. Fehlings et al. set out to characterize CD8+ T cell responses to treatment with the anti-PD-L1 antibody atezolizumab in 14 patients with non-small cell lung cancer from the the phase 2 POPLAR trial. Although no differences were measured in the bulk CD8+ T cell populations from patients with an objective response to therapy and those with progressive disease, neoantigen-specific T cells were detected more frequently in samples from responders and those cells displayed a distinct differentiated effector phenotype, characterized by high expression of KLRG-1, 2B4, CD57, CD161, TGIT and CD25. In contrast, neoantigen specific T cells from nonresponders were characterized by a more memory-like phenotype, with a trend toward elevated expression of CD127, CD28, CD27 and CCR7. Importantly, the ex vivo whole-exome sequencing, mass cytometry and barcoding approach deployed in this study enabled the detection of rare neoantigen-specific cells without expansion or restimulation. These observations offer new insight into the development of neoantigen-specific responses in immunotherapy, suggesting that the differentiation status of circulating tumor-reactive T cells could be relevant to predicting clinical outcomes.
Shiran Hoogi, Vasyl Eisenberg, Shimrit Mayer, Astar Shamul, Tilda Barliya & Cyrille J. Cohen
Journal for ImmunoTherapy of Cancer, 7:243 (9 September 2019)
Tumors often overexpress ligands for the TIGIT receptor, a co-inhibitory molecule that is capable of downregulating T cell cytokine production and effector function. To circumvent inhibitory signals, and, at the same time, deliver stimulatory ones, Hoogi et al. devised a T cell engineering strategy based on a novel costimulatory switch receptor (CSR), by fusing the extracellular domain of TIGIT to the intracellular signaling domain of CD28. In xenograft models of established melanoma, T cells transduced with the CSR delayed tumor growth and substantially prolonged survival. In vitro, T cells transduced with the CSR displayed enhanced tumor necrosis factor alpha secretion during co-culture with melanoma cell lines, and maintained elevated IL-2 production even in the presence of the immunosuppressive cytokine transforming growth factor beta. The CSR also enhanced cytokine production in CD19-directed chimeric antigen receptor (CAR) T cells. Additionally, in an original model of T-cell exhaustion based on repetitive antigen exposure, the CSR rescued cytokine production to on average 90.1% of control levels, independent of TCR expression. This study suggests that a TGIT-based CSR can augment T cell function, potentially adding a valuable tool to the arsenal of engineered T cell immunotherapies.