JITC Digest June 2018


Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero(1)(1).jpg

In this edition of the JITC Digest, we are proud to include the latest update to SITC’s Cancer Immunotherapy Guidelines for cutaneous melanoma as well as a SITC-led review on the significance and implications of pembrolizumab for biomarker-defined disease. Together, these articles further demonstrate how SITC is at the forefront of cancer immunotherapy, providing valuable insights and resources to the greater cancer immunotherapy community.

Additionally, we are pleased to feature three articles in the Clinical/Translational Cancer Immunotherapy section.  The first article, “Targeting the TGFß pathway with galunisertib, a TGFßRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade,” by Rikke Holmgaard et al. provides in vitro and in vivo data suggesting that galunisertib may reverse TGFß/regulatory T cell suppression of CD8+ T cell proliferation to mediate anti-tumor activity. Additionally, the authors demonstrate that galunisertib in combination with PD-L1 blockade significantly reduces tumor growth in pre-clinical colon carcinoma models, consistent with two other articles published in Nature earlier this year suggesting enhancement of checkpoint blockade efficacy through TGFß inhibition. These pre-clinical data indicate that galunisertib has significant anti-tumor activity as a monotherapy and in combination with immune checkpoint inhibitors.

Michael Lattanzi et al. in “Adjuvant NY-ESO-1 vaccine immunotherapy in high-risk resected melanoma: a retrospective cohort analysis” conducted a pooled, retrospective analysis of patients with high-risk resected melanoma vaccinated with the recombinant NY-ESO-1 protein, or peptides thereof, a highly immunogenic cancer testis antigen, in the adjuvant setting. In all, data from 67 patients with stage III disease indicate that adjuvant NY-ESO-1 vaccination significantly reduced both risk of recurrence (HR = 0.51, p < 0.01) and risk of death (HR = 0.45, p = 0.01) compared to historical control patients who did not received adjuvant therapy (n = 123). Furthermore, analyses of specific substages also revealed reduced risk of recurrence and death in patients treated with adjuvant NY-ESO-1 vaccine compared to the control cohort. Together, these data support further investigation of NY-ESO-1 vaccine immunotherapy for the treatment of patients with high-risk, resectable melanoma in the adjuvant setting.

Finally, “CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation,” by Pradip Bajgain et al. illustrates that co-expression of a chimeric cytokine receptor, combining the IL-4 binding domain with the IL-7 receptor signaling domain (4/7ICR) together with a second generation MUC-1 specific CAR provides increased efficacy against breast cancer tumor models secreting IL-4, compared to single CAR T cells. This innovative design suggests the potential benefit of equipping engineered T cells with a signal 3 provided by cytokines, in this case the usually immunosuppressive cytokine IL-4. The data indeed shows a clever way of harnessing immunosuppressive cues prevailing in the tumor microenvironment and converting them into T cell enhancing signals and supports future translation into clinical trials.

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

Recent Articles

A robust response to combination immune checkpoint inhibitor therapy in HPV-related small cell cancer: a case report

Won Jin Ho, Lisa Rooper, Sarah Sagorsky and Hyunseok Kang
Journal for ImmunoTherapy of Cancer, 6:33 (9 May 2018)
Case Report

From the Authors

"HPV positive small cell carcinoma of head and neck is a rare, aggressive variant of HPV positive malignancy of head and neck with no established standard of care. We illustrated a case with progressive disease who had a robust response to combination of anti-CTLA4 Ab and anti-PD1 Ab."

Hyunseok Kang, MD, MPH — Johns Hopkins University

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden

Carl Morrison†, Sarabjot Pabla†, Jeffrey M. Conroy, Mary K. Nesline, Sean T. Glenn, Devin Dressman, Antonios Papanicolau-Sengos, Blake Burgher, Jonathan Andreas, Vincent Giamo, Moachun Qin, Yirong Wang, Felicia L. Lenzo, Angela Omilian, Wiam Bshara, Matthew Zibelman, Pooja Ghatalia, Konstantin Dragnev, Keisuke Shirai, Katherine G. Madden, Laura J. Tafe, Neel Shah, Deepa Kasuganti, Luis de la Cruz-Merino, Isabel Araujo, Yvonne Saenger, Margaret Bogardus, Miguel Villalona-Calero, Zuanel Diaz, Roger Day, Marcia Eisenberg, Steven M. Anderson, Igor Puzanov, Lorenzo Galluzzi, Mark Gardner and Marc S. Ernstoff
†Contributed equally
Journal for ImmunoTherapy of Cancer, 6:32 (9 May 2018)
Research Article

From the Authors

"Clinical management of melanoma with immune checkpoint inhibitors (ICIs) has changed standard of care practice and there is a pressing need to identify biomarkers of response. The majority of work in predicting response to ICIs has taken a focused approach of a single biomarker such as tumor mutation burden (TMB) or PD-L1 IHC. In our study we evaluated multiple biomarkers, including not only TMB and PD-L1 IHC, but also cold versus hot tumors, pattern of lymphocytic infiltration, and expression of key immune-related factors. All of these variable were combined into an algorithm to provide an improved performance to predicting response to ICIs in melanoma. Certainly we understand that additional studies we will be needed for further validation of this approach, but this does represent the first step to a more sophisticated approach to a somewhat complicated problem."

Carl Morrison, MD, DVM – Baylor College of Medicine

CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation

Pradip Bajgain†, Supannikar Tawinwung†, Lindsey D’Elia, Sujita Sukumaran, Norihiro Watanabe, Valentina Hoyos, Premal Lulla, Malcolm K. Brenner, Ann M. Leen and Juan F. Vera
†Contributed equally
Journal for ImmunoTherapy of Cancer, 6:34 (10 May 2018)
Research Article

From the Authors

"This study demonstrates the feasibility of genetically engineering CAR T cells to function at the immunosuppressive tumor micro-environment (TME) by the expression of an inverted cytokine receptor (ICR) which reacts to the presence of IL4 cytokine present in the breast TME. The expression of the ICR on the surface of CAR-MUC1 T cells resulted in the protection of T cells from the immunosuppressive effects of IL4 by instead delivering a stimulatory Th1 signal derived from IL7 cytokine to the T cells. This combination of CAR and ICR resulted in an improved T cell proliferation, persistence, and enhanced anti-tumor activity in-vitro and in-vivo."

Pradip Bajgain, BS – Baylor College of Medicine

Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson

Yinghong Wang, Hamzah Abu-Sbeih, Emily Mao, Noman Ali, Faisal Shaukat Ali, Wei Qiao, Phillip Lum, Gottumukkala Raju, Gladis Shuttlesworth, John Stroehlein and Adi Diab
Journal for ImmunoTherapy of Cancer, 6:37 (11 May 2018)
Research Article

From the Authors

"Patients with ICPI-induced diarrhea or colitis have improved survival outcomes. Diarrhea is an independent predictor of an improved survival regardless of treatment requirement. Immunosuppressive treatment for diarrhea did not significantly affect overall survival, however, infection rates were numerically higher among patients who received steroids for a long duration. Therefore, early non-steroid immunosuppressive therapy may ensure a more favorable overall outcome."

Yinghong Wang, MD, PhD — University of Texas, MD Anderson Cancer Center

Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease

Michael M. Boyiadzis, John M. Kirkwood, John L. Marshall, Colin C. Pritchard, Nilofer S. Azad and James L. Gulley
Journal for ImmunoTherapy of Cancer, 6:35 (14 May 2018)
Review Article

From the Authors

"The regulatory approval of pembrolizumab for patients whose tumors express microsatellite instability and those deficient in DNA mismatch repair (who have an increased likelihood of immunologically relevant neoepitopes caused by an increased tumor mutation burden) represents a paradigm shift. It is not surprising that this first tissue agnostic indication for any anti-cancer therapy is conferred in immunotherapy where the appropriate effector cells are often already primed against the respective tumor cells but held in check by an immune checkpoint."

James. L. Gulley, MD, PhD, FACP — National Cancer Institute

Talimogene Laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III-IV melanoma: a case series**

Lillian Sun, Pauline Funchain, Jung Min Song, Patricia Rayman, Charles Tannenbaum, Jennifer Ko, Michael Mcnamara, C. Marcela Diaz-Montero and Brian Gastman
Journal for ImmunoTherapy of Cancer, 6:36 (16 May 2018)
Research Article


Talimogene Laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of patients with unresectable stage IIIB-IV metastatic melanoma. The mechanisms of action for T-VEC and immune checkpoint inhibitors are highly complementary. The authors present a series of 10 cases of melanoma patients treated with combination T-VEC + checkpoint inhibitors to better understand synergy between these two therapies.

**This article is part of JITC’s Microbial-Based Cancer Therapy special series. Articles in this series describe the complex nature of the microbe-tumor interaction and discuss recent advances in the field that take advantage of the unique ability of microbes to invade human cells and induce immune responses in order to create therapeutic approaches that direct microbes to selectively target tumors.

Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC)

Young Kwang Chae, Ayush Arya, Wade Iams, Marcelo R. Cruz, Sunandana Chandra, Jaehyuk Choi and Francis Giles
Journal for ImmunoTherapy of Cancer, 6:39 (16 May 2018)


Combination therapies using both anti-PD-1/PD-L1 and anti-CTLA-4 monoclonal antibodies are being evaluated for efficacy in many diseases. This review summarizes use of combination anti-CTLA-4 and anti-PD-1/PD-L1 agents in patients with melanoma and non-small cell lung cancer, and discusses the potential of this combinatorial approach moving into other disease settings.

Adjuvant NY-ESO-1 vaccine immunotherapy in high-risk resected melanoma: a retrospective cohort analysis*

Michael Lattanzi, Joseph Han, Una Moran, Kierstin Utter, Jeremy Tchack, Rachel Lubong Sabado, Russell Berman, Richard Shapiro, Hsin-Hui Huang, Iman Osman, Nina Bhardwaj and Anna C. Pavlick
Journal for ImmunoTherapy of Cancer6:38 (18 May 2018)
Research Article


Cancer-testis antigen NY-ESO-1 is a highly immunogenic melanoma antigen which has been incorporated into adjuvant vaccine clinical trials. Three such early-phase trials were conducted at our center among patients with high-risk resected melanoma. We herein report on the pooled long-term survival outcomes of these patients in comparison to historical controls.

*This article is part of JITC's Emerging Immunotherapeutic Agents special series. All articles in this series cover details beyond standard JITC articles, providing readers with a unique collection of cutting-edge cancer immunotherapy research.

Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events

Heinz Läubli, Catharina Balmelli, Lukas Kaufmann, Michal Stanczak, Mohammedyaseen Syedbasha, Dominik Vogt, Astrid Hertig, Beat Müller, Oliver Gautschi, Frank Stenner, Alfred Zippelius, Adrian Egli and Sacha I. Rothschild
Journal for ImmunoTherapy of Cancer, 6:40 (22 May 2018)
Research Article

From the Authors

"Immune checkpoint inhibitors are nowadays frequently used to treat patients with various solid tumors. Immune checkpoint blockade has led to durable remissions in some patients, but may also induce immune-related adverse events. Cancer patients, especially those with lung cancer have a higher risk for complications when infected with influenza viruses. Safety and activity of influenza vaccination in patients undergoing immune checkpoint inhibitor therapy has not been investigated so far. In our study, we did not observe significant differences between patients and healthy controls in vaccine-induced antibody titers against all three viral antigens. However, we observed an unexpected rate of immune-related adverse events that was higher than frequencies published in the literature in a non-study population at our institution. Although this is a non-randomized trial with a limited number of patients, the increased rate of immunological toxicity is concerning. This finding should be studied in a larger patient population."

Sacha I. Rothschild, MD — Universitätsspital Basel

Immunohistochemical expression and prognostic value of PD-L1 in Extrapulmonary small cell carcinoma: a single institution experience

Mohammed Salhab, Yazan Migdady, Melanie Donahue, Yiqin Xiong, Karen Dresser, William Walsh, Benjamin J. Chen and James Liebmann
Journal for ImmunoTherapy of Cancer, 6:42 (29 May 2018)
Research Article

From the Authors

"Extrapulmonay small cell carcinomas remain a challenging aggressive malignancy. Our study demonstrated that at least one third of our ESCC tissue samples expressed PD-L1 thus check point inhibitors pathway could be of interest to investigate and explore for such rare entity of small cell carcinomas."

Mohammed Salhab, MD — University of Massachusetts Medical School

Co-transfer of tumor-specific effector and memory CD8+ T cells enhances the efficacy of adoptive melanoma immunotherapy in a mouse model

Amanda Contreras†, Megan V. Beems†, Andrew J. Tatar, Siddhartha Sen, Prakrithi Srinand, M. Suresh, Tahra K. Luther and Clifford S. Cho
†Contributed equally
Journal for ImmunoTherapy of Cancer, 6:41 (29 May 2018)
Research Article

From the Authors

"There is mounting evidence that memory T cells have unique oncological advantages over effector T cells when used for adoptive cell transfer immunotherapy. This preclinical study uses a mouse model to show that combined transfer of tumor-specific T cells of both effector plus memory phenotype results in an additive improvement in efficacy. This improvement appears to be mediated by both IL-2-mediated paracrine cross-talk between effector and memory T cells, as well as by a temporal “two-hit” combination of early effector T cell-mediated cell killing followed by delayed but durable memory T cell-mediated activity. "

Clifford S. Cho, MD, FACS — University of Michigan Medical School

An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0

Ryan J. Sullivan, Michael B. Atkins, John M. Kirkwood, Sanjiv S. Agarwala, Joseph I. Clark, Marc S. Ernstoff, Leslie Fecher, Thomas F. Gajewski, Brian Gastman, David H. Lawson, Jose Lutzky, David F. McDermott, Kim A. Margolin, Janice M. Mehnert, Anna C. Pavlick, Jon M. Richards, Krista M. Rubin, William Sharfman, Steven Silverstein, Craig L. SlingluffJr, Vernon K. Sondak, Ahmad A. Tarhini, John A. Thompson, Walter J. Urba, Richard L. White, Eric D. Whitman, F. Stephen Hodi and Howard L. Kaufman
Journal for ImmunoTherapy of Cancer, 6:44 (30 May 2018)
Position Article and Guidelines

From the Authors

"The rapidly emerging landscape in immunotherapy for patients with melanoma can be confusing for oncologists and other healthcare providers. The new SITC Clinical Immunotherapy Guidelines for melanoma provides current expert consensus thinking along with updated evidence-based data to inform and guide clinicians in how to optimize treatment for patients with melanoma considering treatment with immunotherapy."

Howard L. Kaufman, MD, FACS — Replimune Group Inc.

In-field and abscopal response after short-course radiation therapy in patients with metastatic Merkel cell carcinoma progressing on PD-1 checkpoint blockade: a case series

Melody J. Xu, Susan Wu, Adil I. Daud, Siegrid S. Yu and Sue S. Yom
Journal for ImmunoTherapy of Cancer, 6:43 (30 May 2018)
Case Report

From the Authors

"The radiation-triggered abscopal effect remains controversial and has been difficult to document. However in our Merkel cell carcinoma patients, we saw this consistently striking observation that even very focused small amounts of radiation really seemed to be helping them to stay disease-free. We thought it was important to provide a detailed illustration of these two very dramatic cases, hopefully with the thought of supporting and stimulating more research into the immune-related effects of radiation for this specific disease. Although specific sequencing and mechanistic details need to be worked out, we are confident that radiation and immune checkpoint inhibitors have a positive interaction in Merkel cell carcinoma that deserves more investigation."

Sue S. Yom, MD, PhD, MAS — University of California San Francisco

Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination

Jun Gong, Thang Q. Le, Erminia Massarelli, Andrew E. Hendifar and Richard Tuli
Journal for ImmunoTherapy of Cancer, 6:46 (4 June 2018)

From the Authors

"Radiation therapy (RT) has been shown to enhance the priming and effector phases of the antitumor T-cell response rendering it an attractive therapy to combine with inhibitors of programmed cell death-1 (PD-1) and programmed death ligand-1 (PD-L1). In this report, the authors comprehensively review the preclinical data supporting the rational combination of the 2 modalities as well as the clinical development of combined RT and PD-1/PD-L1 blockade in cancer. The authors also discuss putative mechanisms by which the combination enhances antitumor immune responses and considerations for clinical trial design including timing of RT, dosing of RT, and toxicities associated with various combinations."

Richard Tuli, MD, PhD — Cedars-Sinai Medical Center

Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade*

Rikke B. Holmgaard†, David A. Schaer†, Yanxia Li, Stephen P. Castaneda, Mary Y. Murphy, Xiaohong Xu, Ivan Inigo, Julie Dobkin, Jason R. Manro, Philip W. Iversen, David Surguladze, Gerald E. Hall, Ruslan D. Novosiadly, Karim A. Benhadji, Gregory D. Plowman, Michael Kalos and Kyla E. Driscoll
†Contributed equally
Journal for ImmunoTherapy of Cancer, 6:47 (4 June 2018)
Research Article


TGF ß signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGF ß ’s immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGF ß pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses.

*This article is part of JITC's Emerging Immunotherapeutic Agents special series. All articles in this series cover details beyond standard JITC articles, providing readers with a unique collection of cutting-edge cancer immunotherapy research.

Highly Accessed Articles


Microsatellite instability in prostate cancer by PCR or next-generation sequencing

Jennifer A. Hempelmann, Christina M. Lockwood, Eric Q. Konnick, Michael T. Schweizer, Emmanuel S. Antonarakis, Tamara L. Lotan, Bruce Montgomery, Peter S. Nelson, Nola Klemfuss, Stephen J. Salipante and Colin C. Pritchard
Journal for ImmunoTherapy of Cancer 2018, 6:28 (17 April 2018)


An innovative immunotherapeutic strategy for ovarian cancer: CLEC10A and glycomimetic peptides

Laura L. Eggink, Katherine F. Roby, Robert Cote and J. Kenneth Hoober
Journal for ImmunoTherapy of Cancer 2018, 6:28 (17 April 2018)

Submit Your Research to JITC

SITC Members Receive Complimentary Article Processing Charges in 2018*
SITC members and non-members are invited to submit manuscripts to the society's official journal.
Article Types
JITC Editor-in-Chief
Pedro J. Romero, MD – University of Lausanne

Section Editors

  • Basic Tumor Immunology: Cornelis J.M. Melief, MD, PhD – ISA Therapeutics BV
  • Case Reports: Alfred Zippelius, MD – University Hospital Basel
  • Clinical/Translational Cancer Immunology: James L. Gulley, MD, PhD, FACP  National Cancer Institute, National Institutes of Health
  • Clinical Trials Monitor: Leisha A. Emens, MD, PhD – Johns Hopkins University
  • Commentary/Editorials: Christian Capitini, MD – University of Wisconsin - Madison
  • Guidelines and Consensus Statements: Robert L. Ferris, MD, PhD – University of Pittsburgh Cancer Institute
  • Immunotherapy Biomarkers: Lisa H. Butterfield, PhD – University of Pittsburgh Cancer Institute
  • Reviews: Sandra Demaria, MD – Weill Cornell Medical College; Thomas F. Gajewski, MD, PhD – University of Chicago

To view the full editorial board, please click here.

*As a way to thank the dedicated society members who tirelessly work to advance the science and ultimately to improve the lives of patients with cancer, one article per SITC member is eligible for waived article processing charges through 2018. To take advantage of this benefit valued at more than $2,400, authors must contact JITC Managing Editor Andrea Rindo at JITCEditor@sitcancer.org or 1-414-271-2456 prior to submission to obtain a discount code and instructions.

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Journal for ImmunoTherapy of Cancer (JITC) is the official, online, open access journal of the Society for Immunotherapy of Cancer (SITC) and considered BMC’s premier cancer immunotherapy journal. JITC welcomes basic, translational and clinical research and literature reviews on any aspect of tumor immunology and cancer immunotherapy. Topics of interest include tumor-host interactions, immune biomarkers, novel therapeutics, and immune-related toxicity.  The journal’s full collection, including its seminal guidelines and consensus statements, advances the rapidly evolving field of cancer immunotherapy through dissemination of rigorous peer-reviewed research.