JITC Digest October 2018

Letter from the Editor

Dear JITC Readers,

The Journal for ImmunoTherapy of Cancer (JITC) congratulates James P. Allison, PhD, and Tasuku Honjo, MD, PhD, on their recognition as 2018 recipients of the Nobel Prize for their scientific contributions to the emerging field of immune checkpoint blockade therapy. Their work in the lab has become a foundational component of cancer treatment across the globe. The honor draws light on the innovation and collaboration of cancer researchers allowing the science to advance rapidly in the lab and into the clinic where many patients are now benefiting from these breakthroughs. I look forward to seeing where this continued momentum takes us as we work toward making the word “cure” a reality for patients everywhere.

In the October edition of the JITC Digest, there are four articles of special significance of which I wish to draw special attention. First, “Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy,” by Guozhu Xie et al. demonstrates the role of local angiotensin II (AngII) in establishing an immunosuppressive tumor microenvironment. In this research article, Dr. Xie’s team describes a novel mechanism for enhancing tumor response to checkpoint blockade immunotherapy through blockage of AngII signaling.

Next, Jason M. Redman et al.’s clinical trials monitor article, “Quick efficacy seeking trial (QuEST1): a novel combination immunotherapy study designed for rapid clinical signal assessment metastatic castration-resistant prostate cancer,” presents the QuEST1 study, an open and accruing adaptive-design clinical trial evaluating various combination therapies in metastatic castration-resistant prostate cancer (mCRPC). QuEST1 aims to expedite investigation of multimodal immunotherapy in mCRPC, a disease with low response rates to single agent immune checkpoint inhibitors.

Maartje W. Rohaan et al.’s review, “Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option,” provides an authoritative overview of the current state of adoptive cell therapy with tumor infiltrating lymphocytes (TILs) in melanoma patients. Specifically, this article provides a detailed account of the applicability and hurdles of developing TIL immunotherapy, including clinical response, production and treatment strategies, toxicity, and the future potential of TIL therapy as part of both monotherapy and combination therapy anti-tumor treatment regimens.

Finally, the article, “A nomogram-based immunoprofile predicts overall survival for previously untreated patients with esophageal squamous cell carcinoma after esophagectomy,” by Jingjing Duan et al. presents a novel model for predicting prognosis in esophageal squamous cell carcinoma (ESCC) patients based on independent prognostic immune variables. This comprehensive, nomogram-based immunoprofile developed by Dr. Duan’s team appears apt to complement the TNM system for survival prediction in operable ESCC patients.

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

Recent Articles

Alpha-fetoprotein (AFP) as tumor marker in a patient with urothelial cancer with exceptional response to anti-PD-1 therapy and an escape lesion mimic

Johannes C. Melms, Rohit Thummalapalli, Kristin Shaw, Huihui Ye, Leo Tsai, Rupal S. Bhatt and Benjamin Izar
Journal for ImmunoTherapy of Cancer, 6:89 (12 September 2018)
Case Report

Excerpt:

"This case indicates that in some patients, biomarkers aberrantly expressed by their tumors, such as AFP in this patient, may be used as a tumor marker for response to anti-PD-1 therapy and emphasizes the importance of confirming potential escape lesions by pathologic examination."

Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy

Guozhu Xie, Tan Cheng, Jie Lin, Lanfang Zhang, Jieling Zheng, Ying Liu, Guobo Xie, Baiyao Wang and Yawei Yuan
Journal for ImmunoTherapy of Cancer, 6:88 (12 September 2018)
Research Article

From the Authors

"Most of tumors still display resistance to current checkpoint immunotherapy. An immunosuppressive microenvironment is an important factor mediating the resistance of tumors to immunotherapy. Local angiotensin II (AngII) predominantly existed in the hypoxic tumor microenvironment where hypoxic tumor cells are able to produce AngII by a hypoxia-lactate-chymase-dependent mechanism. Here we found that local AngII in the tumor microenvironment was involved in immune escape of tumor cells and inhibition of AngII signaling triggered an immune-activating cytokine profile and sensitized tumors to checkpoint immunotherapy. More importantly, AGT silencing combined with checkpoint blockage generated an abscopal effect to resistant tumors. Thus, the study demonstrates an important role of local AngII in the formation of the tumor immunosuppressive microenvironment and the combination of AngII signaling inhibition with immune-checkpoint blockage would be a promising strategy to improve tumors’ response to current checkpoint immunotherapy. "

Guozhu Xie, MD, PhD — Southern Medical University Nanfang Hospital

Quick efficacy seeking trial (QuEST1): a novel combination immunotherapy study designed for rapid clinical signal assessment metastatic castration-resistant prostate cancer

Jason M. Redman, Seth M. Steinberg and James L. Gulley
Journal for ImmunoTherapy of Cancer, 6:91 (18 September 2018)
Clinical Trials Monitor

Excerpt:

"Here we present an open and accruing adaptive-design clinical trial of combination immunotherapy in mCRPC…This novel “fail early or win early” strategy can identify inactive combinations early in the treatment process and allow for immediate interrogation of the next combination."

A whole-blood RNA transcript-based gene signature is associated with the development of CTLA-4 blockade-related diarrhea in patients with advanced melanoma treated with the checkpoint inhibitor tremelimumab

Philip Friedlander, Kevin Wood, Karl Wassmann, Alan M. Christenfeld, Nina Bhardwaj and William K. Oh
Journal for ImmunoTherapy of Cancer, 6:90 (18 September 2018)
Research Article

From the Authors

"CTLA-4 inhibition is associated with the development of immune mediated toxicity that can lead to significant morbidity and treatment interruption. Identifying biomarkers for high grade toxicity can help optimize treatment selection and reduce toxicity risk. Patients identified as at high risk for diarrhea/colitis should be educated as to symptoms to watch for and more closely monitored for the onset of severe diarrhea. In “A whole-blood RNA transcript-based gene signature is associated with the development of CTLA-4 blockade-related diarrhea in patients with advanced melanoma treated with the checkpoint inhibitor tremelimumab” Friedlander et al. demonstrate that changes in gene expression can be detected 30 days after initiation of tremelimumab treatment in patients with advanced melanoma and the changes can differentiate patients who will or will not develop grade 2 or higher diarrhea. Assessment of changes in peripheral blood gene expression is a minimally invasive approach that can be investigated to try to identify biomarkers of immune mediated toxicity following anti-CTLA-4 or anti-PD-1/L1 blockade. "

Philip Friedlander, MD, PhD — Mount Sinai Beth Israel

Response to PD1 inhibition in conventional chondrosarcoma

Michael J. Wagner, Robert W. Ricciotti, Jose Mantilla, Elizabeth T. Loggers, Seth M. Pollack and Lee D. Cranmer
Journal for ImmunoTherapy of Cancer, 6:94 (25 September 2018)
Case Report

From the Authors

"This case demonstrates the promise of immunotherapy in chondrosarcoma, a cancer that is notoriously difficult to treat with chemotherapy. Molecular testing revealed no clear mechanism to explain this remarkable response, highlighting the need for improved biomarkers to identify who might benefit from immunotherapies. The possibility of pseudoprogression, as was seen in this patient, should be taken into account in future immunotherapy trials that include chondrosarcoma patients."

Michael J. Wagner, MD — University of Washington School of Medicine

Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis

Hamzah Abu-Sbeih, Faisal S. Ali, Wenyi Luo, Wei Qiao, Gottumukkala S. Raju and Yinghong Wang
Journal for ImmunoTherapy of Cancer, 6:95 (25 September 2018)
Research Article

From the Authors

"In patients with immune checkpoint inhibitor-induced colitis, endoscopic and histologic findings provide important markers of disease severity and predictors of long-term outcomes. Timely endoscopic and histological evaluation therefore should be used to devise focused treatment algorithms that incorporate a more intricate degree of specificity. "

Yinghong Wang, MD, PhD — MD Anderson Cancer Center

Dose escalation results from a first-in-human, phase 1 study of glucocorticoid-induced TNF receptor–related protein agonist AMG 228 in patients with advanced solid tumors

Ben Tran, Richard D. Carvajal, Aurelien Marabelle, Sandip Pravin Patel, Patricia M. LoRusso, Erik Rasmussen, Gloria Juan, Vijay V. Upreti, Courtney Beers, Gataree Ngarmchamnanrith and Patrick Schöffski
Journal for ImmunoTherapy of Cancer, 6:93 (25 September 2018)
Research Article

From the Authors

"Traditionally, phase I trials have only aimed to define safety and recommended phase 2 dose. More recently, results from phase I trials have been used to make go/no-go decisions for ongoing drug development. Not only does this approach reduce the costs associated with drug development, but it also ensures novel agents in later phase studies are more likely to be efficacious. One way to help go/no-go decisions in early drug development of novel cancer agents, is increased investment in pharmacodynamic (PD) studies. The importance of PD studies is well demonstrated in our phase I trial of AMG228, a novel GITR agonist. Our trial included several PD studies, including peripheral blood assays and paired tumour biopsies. While the trial demonstrated AMG228 had an acceptable safety profile, it was the PD studies that contributed the most important information. Our PD studies showed that while AMG228 bound to GITR, as it did in preclinical studies, as monotherapy, this did not lead to notable changes in peripheral blood lymphocyte populations, and generally did not result in CD8 T cell infiltration or granzyme B activation within the tumour itself. Our study demonstrates the importance and value of PD studies, particularly paired biopsies, in the early drug development of novel immunoncology agents."

Ben Tran, MBBS, FRACP — Peter MacCallum Cancer Centre

Durable response to anti-PD-1 immunotherapy in epithelioid angiomyolipoma: a report on the successful treatment of a rare malignancy

Michael Lattanzi, Fang-Ming Deng, Luis A. Chiriboga, Alisa N. Femia, Shane A. Meehan, Gopa Iyer, Martin H. Voss, Yuliya Sundatova, William C. Huang and Arjun V. Balar
Journal for ImmunoTherapy of Cancer, 6:97 (1 October 2018)
Case Report

From the Authors

"Metastatic epithelioid angiomyolipoma is an exceedingly rare malignancy characteristically responsive mTOR inhibition, however benefit is typically transient. We report a case of durable activity of immune-checkpoint blockade in patient who progressed on everolimus, highlighting the broad application of immunotherapy even in uncommon malignancies."

Arjun V. Balar, MD — Perlmutter Cancer Center - New York University Langone Medical Center

Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab

Nicolas A. Giraldo, Peter Nguyen, Elizabeth L. Engle, Genevieve J. Kaunitz, Tricia R. Cottrell, Sneha Berry, Benjamin Green, Abha Soni, Jonathan D. Cuda, Julie E. Stein, Joel C. Sunshine, Farah Succaria, Haiying Xu, Aleksandra Ogurtsova, Ludmila Danilova, Candice D. Church, Natalie J. Miller, Steve Fling, Lisa Lundgren, Nirasha Ramchurren, Jennifer H. Yearley, Evan J. Lipson, Mac Cheever, Robert A. Anders, Paul T. Nghiem, Suzanne L. Topalian and Janis M. Taube
Journal for ImmunoTherapy of Cancer, 6:99 (1 October 2018)
Research Article

Excerpt:

"Our study supports the evolving concept that lymphocytic populations beyond CD8+ cytotoxic T-cells may promote tumor regression following anti-PD-1 administration."

Ibuprofen supports macrophage differentiation, T cell recruitment, and tumor suppression in a model of postpartum breast cancer

Nathan D. Pennock, Holly A. Martinson, Qiuchen Guo, Courtney B. Betts, Sonali Jindal, Takahiro Tsujikawa, Lisa M. Coussens, Virginia F. Borges and Pepper Schedin
Journal for ImmunoTherapy of Cancer, 6:98 (1 October 2018)
Research Article

From the Authors

"Mammary gland involution is a normal developmental process whereby 90% of the lactating epithelium dies post weaning to return the gland to a pre-pregnant like state. In rodent models, this dramatic tissue remodeling process promotes tumor growth and metastasis and is thought to account for the poor prognosis of post-partum breast cancer. In this study, mouse mammary tumors experiencing the involution microenvironment are enriched for tumor promoting myeloid cells and impaired for T cell activity. Ibuprofen treatment enhances anti-tumor macrophage differentiation, promotes cytotoxic T cell presence and reduces tumor burden. Barriers to the broad adoption of ibuprofen use in postpartum women, including autoantibody production, T cell activation and lactation failure, were not observed. These data support future clinical investigation of NSAIDs as chemopreventive agents in nursing women."

Nathan D. Pennock, PhD — Oregon Health and Science University

Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option

Maartje W. Rohaan, Joost H. van den Berg, Pia Kvistborg and John B. A. G. Haanen
Journal for ImmunoTherapy of Cancer, 6:102 (3 October 2018)
Review

From the Authors

"Treatment with Tumor Infiltrating Lymphocytes has shown clear activity in patients with metastatic melanoma and was one of the first immunotherapies to be successful. Despite the great revolution with immune checkpoint inhibitors, adoptive cell therapy with TIL remains a highly interesting treatment option for metastatic melanoma, especially in patients failing anti-PD1/PDL1 therapy. This review summarizes the TIL treatment of melanoma to date and discusses how TIL therapy added to our understanding of modern immunotherapy."

John B.A.G. Haanen, MD, PhD — Netherlands Cancer Institute

A nomogram-based immunoprofile predicts overall survival for previously untreated patients with esophageal squamous cell carcinoma after esophagectomy

Jingjing Duan, Yongwei Xie, Lijuan Qu, Lingxiong Wang, Shunkai Zhou, Yu Wang, Zhongyi Fan, Shengsheng Yang and Shunchang Jiao
Journal for ImmunoTherapy of Cancer, 6:100 (3 October 2018)
Research Article

About:

Research demonstrates that immune cells and immunomodulatory molecules in the tumor microenvironment play a key role in determining the prognosis of cancer patients. Jingjing Duan et al. presents a novel model for predicting prognosis in esophageal squamous cell carcinoma (ESCC) patients based on independent prognostic immune variables which appears apt to complement the TNM system for survival prediction in operable ESCC patients.

Serious adverse events and fatal adverse events associated with nivolumab treatment in cancer patients

Bin Zhao, Hong Zhao and Jiaxin Zhao
Journal for ImmunoTherapy of Cancer, 6:101 (3 October 2018)
Research Article

From the Authors

"The introduction of nivolumab into clinical practice has a revolutionary effect on the outlook in numerous cancers. However, the incidence and risk of developing serious adverse events (SAEs) or fatal adverse events (FAEs) following nivolumab administration are unclear. This study revealed that, compared with conventional agents, nivolumab did not increase the risk of SAEs (incidence, 11.2%) or FAEs (incidence, 0.3%). SAEs occurred in the major organ systems dispersedly, with the most common toxicities appearing in the respiratory (21.4%), gastrointestinal (7.7%), and hepatic systems (6.6%). Non-oncologists should be aware these rare but clinically important organ specific adverse events."

Bin Zhao, PhD — The Second Affiliated Hospital & Yuying Children's Hospital

Highly Accessed Articles

Resident memory T cells, critical components in tumor immunology

Fathia Mami-Chouaib, Charlotte Blanc, Stéphanie Corgnac, Sophie Hans, Ines Malenica, Clémence Granier, Isabelle Tihy and Eric Tartour
Journal for ImmunoTherapy of Cancer 2018, 6:87 (4 September 2018)

Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity

Orneala Bakos, Christine Lawson, Samuel Rouleau and Lee-Hwa Tai
Journal for ImmunoTherapy of Cancer 2018, 6:86 (3 September 2018)

White paper on microbial anti-cancer therapy and prevention

Neil S. Forbes, Robert S. Coffin, Liang Deng, Laura Evgin, Steve Fiering, Matthew Giacalone, Claudia Gravekamp, James L. Gulley, Hal Gunn, Robert M. Hoffman, Balveen Kaur, Ke Liu, Herbert Kim Lyerly, Ariel E. Marciscano, Eddie Moradian, Sheryl Ruppel, Daniel A. Saltzman, Peter J. Tattersall, Steve Thorne, Richard G. Vile, Halle Huihong Zhang, Shibin Zhou and Grant McFadden
Journal for ImmunoTherapy of Cancer 2018, 6:78 (6 August 2018)