JITC Digest October 2019

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Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

I am pleased to share news of the launching of JITC’s very own Twitter handle (@JITCancer). Managed by JITC’s very own editors, this new platform will provide followers with access to JITC’s latest publications as well as cutting-edge news from throughout the fields of tumor immunology and cancer immunotherapy. Furthermore, it will give authors, readers, and editors a place to connect more directly on a global level.

If you use Twitter, please take a moment to follow @JITCancer and explore its social content. The October edition of the JITC digest also contains several highlighted articles that may be of interest for you to share with your followers. In particular, these highlighted articles show how insight into the interplay between malignant cells and the immune system can unlock new therapeutic strategies and diagnostic tools.

Two papers reveal new insight into which patients may benefit from checkpoint inhibition. The first, “Closed system RT-qPCR as a potential companion diagnostic test for immunotherapy outcome in metastatic melanoma” by Swati Gupta et al., develops a profile based on mRNA expression signatures of four genes (CD274 (PD-L1), PDCDILG2 (PD-L2), CD8A, and IRF1) that correlates with clinical outcomes in melanoma patients treated with anti-PD-1 immunotherapy. With further development, the approach they describe could offer a rapid-turnaround companion diagnostic, without standardization and threshold issues inherent in immunohistochemistry-based diagnostics.

The second article addresses the ongoing question of how T cell responses determine outcomes of checkpoint inhibition. Fehlings et al. shine some light on this issue by identifying a distinctive population of neoantigen-specific CD8+ effector-like T cells in PBMCs from patients with non-small cell lung cancer who responded to anti-PD-L1 treatment. Their findings are described in, “Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment.”

T cell engineering has emerged as an exciting new clinical frontier, with the marked success of chimeric antigen receptor (CAR)-based therapies. In, “A TIGIT-based chimeric co-stimulatory switch receptor improves T cell anti-tumor function,” Hoogi et al. deploy a novel T cell engineering strategy, generating a chimeric costimulatory switch receptor (CSR) that circumvents inhibitory signaling in the cancer milieu by fusing the extracellular ligand-binding domain of the co-inhibitory receptor TIGIT to the intracellular stimulatory domain of CD28. T cells co-transduced with both an antigen receptor and the CSR displayed enhanced cytokine production in vitro and prolonged survival in xenograft models of established melanoma.

The final paper highlighted in this month’s digest describes encouraging results from a phase 1 trial of a humanized anti-IL-8 monoclonal antibody in 15 patients with incurable metastatic or unresectable, locally advanced solid tumors. Bilusic et al. demonstrate that IL-8 blockade is safe and well-tolerated in, “Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors.” What’s more, 11 out of 15 patients achieved stable disease, an encouraging result for ongoing studies investigating IL-8 blockade in combination with checkpoint inhibition.

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


JITC Editor Picks

Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors

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)
Research

Summary:

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.

Closed system RT-qPCR as a potential companion diagnostic test for immunotherapy outcome in metastatic melanoma

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)
Research

Summary:

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.

Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment

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)
Research

Summary:

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.

A TIGIT-based chimeric co-stimulatory switch receptor improves T cell anti-tumor function

Shiran Hoogi, Vasyl Eisenberg, Shimrit Mayer, Astar Shamul, Tilda Barliya & Cyrille J. Cohen
Journal for ImmunoTherapy of Cancer, 7:243 (9 September 2019)
Research

Summary:

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.

Challenges in assessing the clinical utility and economic value of immune checkpoint inhibitor therapies of Cancer

Peter Paul Yu, Omar Eton & Louis P. Garrison
Journal for ImmunoTherapy of Cancer, 7:235 (3 September 2019)
Commentary

High numbers of activated helper T cells are associated with better clinical outcome in early stage vulvar cancer, irrespective of HPV or p53 status

Kim E. Kortekaas, Saskia J. Santegoets, Ziena Abdulrahman, Vanessa J. van Ham, Marij van der Tol, Ilina Ehsan, Helena C. van Doorn, Tjalling Bosse, Mariëtte I. E. van Poelgeest & Sjoerd H. van der Burg
Journal for ImmunoTherapy of Cancer, 7:236 (3 September 2019)
Research

Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy

Hari Menon, Dawei Chen, Rishab Ramapriyan, Vivek Verma, Hampartsoum B. Barsoumian, Taylor R. Cushman, Ahmed I. Younes, Maria A. Cortez, Jeremy J. Erasmus, Patricia de Groot, Brett W. Carter, David S. Hong, Isabella C. Glitza, Renata Ferrarotto, Mehmet Altan, Adi Diab, Stephen G. Chun, John V. Heymach, Chad Tang, Quynh N. Nguyen & James W. Welsh
Journal for ImmunoTherapy of Cancer, 7:237 (4 September 2019)
Research

Biomaterial-based platforms for in situ dendritic cell programming and their use in antitumor immunotherapy

João Calmeiro, Mylène Carrascal, Célia Gomes, Amílcar Falcão, Maria Teresa Cruz & Bruno Miguel Neves
Journal for ImmunoTherapy of Cancer, 7:238 (4 September 2019)
Review

Reactivation of tuberculosis in cancer patients following administration of immune checkpoint inhibitors: current evidence and clinical practice recommendations

Amalia Anastasopoulou, Dimitrios C. Ziogas, Michael Samarkos, John M. Kirkwood & Helen Gogas
Journal for ImmunoTherapy of Cancer, 7:239 (4 September 2019)
Review

Anti-programmed cell death protein 1 (anti-PD1) immunotherapy induced autoimmune polyendocrine syndrome type II (APS-2): a case report and review of the literature

Ashray Gunjur, Oliver Klein, Damien Kee & Jonathan Cebon
Journal for ImmunoTherapy of Cancer, 7:241 (5 September 2019)
Case Report

Impact of antibiotic therapy on the development and response to treatment of immune checkpoint inhibitor-mediated diarrhea and colitis

Hamzah Abu-Sbeih, Lauren Nicholas Herrera, Tenglong Tang, Mehmet Altan, Anne-Maria P. Chaftari, Pablo C. Okhuysen, Robert R. Jenq & Yinghong Wang
Journal for ImmunoTherapy of Cancer, 7:242 (5 September 2019)
Research

Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies

Stefanie R. Mullins, John P. Vasilakos, Katharina Deschler, Iwen Grigsby, Pete Gillis, Julius John, Matthew J. Elder, John Swales, Elina Timosenko, Zachary Cooper, Simon J. Dovedi, Andrew J. Leishman, Nadia Luheshi, James Elvecrog, Ashenafi Tilahun, Richard Goodwin, Ronald Herbst, Mark A. Tomai & Robert W. Wilkinson
Journal for ImmunoTherapy of Cancer, 7:244 (11 September 2019)
Research

Niclosamide, an antihelmintic drug, enhances efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer

Fan Luo, Min Luo, Qi-Xiang Rong, Hong Zhang, Zhen Chen, Fang Wang, Hong-Yun Zhao & Li-Wu Fu
Journal for ImmunoTherapy of Cancer, 7:245 (11 September 2019)
Research

Carboxyamidotriazole combined with IDO1-Kyn-AhR pathway inhibitors profoundly enhances cancer immunotherapy

Jing Shi, Chen Chen, Rui Ju, Qingzhu Wang, Juan Li, Lei Guo, Caiying Ye & Dechang Zhang
Journal for ImmunoTherapy of Cancer, 7:246 (11 September 2019)
Research

Unchecked immunity: a unique case of sequential immune-related adverse events with Pembrolizumab

N. Shah, J. Jacob, Z. Househ, E. Shiner, L. Baird & H. Soudy
Journal for ImmunoTherapy of Cancer, 7:247 (12 September 2019)
Case Report

Recovery from secondary adrenal insufficiency in a patient with immune checkpoint inhibitor therapy induced hypophysitis

Sahityasri Thapi, Amanda Leiter, Matthew Galsky & Emily J. Gallagher
Journal for ImmunoTherapy of Cancer, 7:248 (12 September 2019)
Case Report

Therapeutic efficacy of a novel humanized antibody-drug conjugate recognizing plexin-semaphorin-integrin domain in the RON receptor for targeted cancer therapy

Xiang-Min Tong, Liang Feng, Sreedhar Reddy Suthe, Tian-Hao Weng, Chen-Yu Hu, Yi-Zhi Liu, Zhi-Gang Wu, Ming-Hai Wang & Hang-Ping Yao
Journal for ImmunoTherapy of Cancer, 7:250 (13 September 2019)
Research

Clinical and immune profiling for cancer of unknown primary site

Koji Haratani, Hidetoshi Hayashi, Takayuki Takahama, Yasushi Nakamura, Shuta Tomida, Takeshi Yoshida, Yasutaka Chiba, Takahiro Sawada, Kazuko Sakai, Yoshihiko Fujita, Yosuke Togashi, Junko Tanizaki, Hisato Kawakami, Akihiko Ito, Kazuto Nishio & Kazuhiko Nakagawa
Journal for ImmunoTherapy of Cancer, 7:251 (13 September 2019)
Research

Targeting interferon signaling and CTLA-4 enhance the therapeutic efficacy of anti-PD-1 immunotherapy in preclinical model of HPV+ oral cancer

Stephanie Dorta-Estremera, Venkatesh L. Hegde, Ravaen B. Slay, Rachel Sun, Ananta V. Yanamandra, Courtney Nicholas, Sita Nookala, Gloria Sierra, Michael A. Curran & K. Jagannadha Sastry
Journal for ImmunoTherapy of Cancer, 7:252 (18 September 2019)
Research

Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma

Mouhammed Amir Habra, Bettzy Stephen, Matthew Campbell, Kenneth Hess, Coya Tapia, Mingxuan Xu, Jordi Rodon Ahnert, Camilo Jimenez, Jeffrey E. Lee, Nancy D. Perrier, Russell R. Boraddus, Shubham Pant, Vivek Subbiah, David S. Hong, Abdulrazzak Zarifa, Siqing Fu, Daniel D. Karp, Funda Meric-Bernstam & Aung Naing
Journal for ImmunoTherapy of Cancer, 7:253 (18 September 2019)
Research

Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3

Rosalinda Trovato, Alessandra Fiore, Sara Sartori, Stefania Canè, Rosalba Giugno, Luciano Cascione, Salvatore Paiella, Roberto Salvia, Francesco De Sanctis, Ornella Poffe, Cristina Anselmi, Francesca Hofer, Silvia Sartoris, Geny Piro, Carmine Carbone, Vincenzo Corbo, Rita Lawlor, Samantha Solito, Laura Pinton, Susanna Mandruzzato, Claudio Bassi, Aldo Scarpa, Vincenzo Bronte & Stefano Ugel
Journal for ImmunoTherapy of Cancer, 7:255 (18 September 2019)
Research

Tertiary lymphoid organs in the inflammatory myopathy associated with PD-1 inhibitors

Shiro Matsubara, Morinobu Seki, Shigeaki Suzuki, Takashi Komori & Mikio Takamori
Journal for ImmunoTherapy of Cancer, 7:256 (18 September 2019)
Short Report

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. Membership verification will be required upon post-review acceptance.