JITC Digest March 2018

Inside this Issue:

Letter from the Editor March ARTICLES February HIGHLY ACCESSED ARTICLES

Letter from the Editor

Dear JITC Readers:

The Journal for ImmunoTherapy of Cancer (JITC) is proud to present nine, high-impact articles in this month's digest. Highlighted in the Clinical/Translational Cancer Immunotherapy section, "A randomized, controlled trial evaluating the efficacy and safety of BTH1677 in combination with bevacizumab, carboplatin, and paclitaxel in first-line treatment of advanced non-small cell lung cancer (NSCLC)," conducted by Walburga Engel-Riedel et al., describes results from a phase II study investigating the efficacy of the beta-glucan pathogen-associated molecular patter molecule (PAMP) BTH1677 in combination with bevacizumab/carboplatin/paclitaxel in patients with untreated, advanced NSCLC. Despite not reaching statistical significance, data revealed that patients who received BTH1677 had an increased objective response rate compared to patients receiving bevacizumab/carboplatin/paclitaxel only (60.4% vs 43.5%; p = 0.21). Overall survival and disease control rate were also increased in the BTH1677 cohort, but again did not reach statistical significance (p = 0.27 and p = 0.66, respectively). Importantly, BTH1677 addition to the treatment regimen did not increase adverse event frequency compared to the control arm. These data suggest the potential of combining PAMPs, such as some TLR agonists or a beta-glucan in this case, with chemotherapies as a front line treatment for patients with advanced NSCLC, a potentially novel immune engagement strategy outside of immune checkpoint inhibitors.

Also featured this month, Priyanka Subrahmanyam, Zhiwan Dong et al. in "Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients" identified novel predictive biomarkers of anti-CTLA-4 and/or anti-PD-1 therapeutic response by analyzing peripheral blood samples from melanoma patients using mass cytometry. In regard to anti-PD-1 therapy, researchers observed that non-responders had reduced abundance of CD69+ and MIP-1ß+ NK cells (p < 0.05, each). Additionally, data indicate that CD4+ and CD8+ memory/effector cell distribution may predict response to anti-CTLA-4 treatment. Interestingly, these identified biomarkers were only predictive for their respective therapies. Using this data, researchers conducted multivariate analyses and generated a prediction model for response to anti-CTLA-4 therapy based on four cellular features (AUC = 0.729). Together, these data elucidate potentially useful and exclusive predictive biomarkers for patients with melanoma treated with either anti-CTLA-4 or anti-PD-1 agents.

With best regards,

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

JITC Welcomes Sandra Demaria, MD to the Editorial Board Leadership

JITC is pleased to welcome Dr. Sandra Demaria, Professor of Radiation Oncology and Pathology and Laboratory Medicine at Weill Cornell Medical College, as the new Section Co-Editor for JITC's Reviews Section. Following three years of service as a SITC Board Director and an Associate Editor for JITC's Commentary/Editorials section, Dr. Demaria will lead one of the journal's most highly-cited sections with Co-Editor Dr. Thomas F. Gajewski during a time of exponential growth in cancer immunotherapy research.

Dr. Demaria is internationally known for her studies demonstrating the synergy of local radiation therapy with different immunotherapeutic agents in preclinical models of cancer. She was the first to show that radiotherapy can convert tumors unresponsive to immune checkpoint inhibitors into responsive ones, a finding being translated in several clinical trials at multiple institutions. Her current work is aimed at identifying the molecular mechanisms that regulate ionizing radiation's ability to generate an in situ tumor vaccine in preclinical tumor models as well as cancer patients treated in clinical trials testing combinations of radiation and immunotherapy. As a breast cancer pathologist Dr. Demaria has also studied the immunological microenvironment of breast cancer in patients, and therapeutic strategies to modulate the immune infiltrate in preclinical breast cancer models

Please take a moment to congratulate and welcome Dr. Demaria through SITC CONNECT.

Ipilimumab induced digital vasculitis

Amrita Padda, Elena Schiopu, Justin Sovich, Vincent Ma, Ajjai Alva and Leslie Fecher

Journal for ImmunoTherapy of Cancer, 6:12 (12 February 2018)
Case Report

From the Authors
"Rheumatologists and oncologists are working together to manage immunotherapy induced inflammatory reactions and improve the quality of life of our patients. This paper highlights a successful treatment plan in a case of Ipilimumab induced small vessel digital vasculitis."

Amrita Padda, MD — University of Michigan, Ann Arbor

Metastatic uveal melanoma showing durable response to anti-CTLA-4 and anti-PD-1 combination therapy after experiencing progression on anti-PD-1 therapy alone

Muhammad Zubair Afzal, Rodwell Mabaera and Keisuke Shirai

Journal for ImmunoTherapy of Cancer, 6:13 (12 February 2018)
Case Report

From the Authors
"Metastatic uveal melanoma (MUM) is a rare form of melanoma that has a different clinical course and poorer prognosis when compared to cutaneous melanoma. Several case reports and case series have shown varying results with the use of immune checkpoint inhibitors in MUM. We present a case of a MUM patient, with poor prognostic features such as GNA11 mutation, older age, male gender, short metastatic-free interval, and extraocular extension, that was able to achieve a durable and ongoing response (22 months since last treatment) to combination anti-PD1/anti-CTLA4 therapy."

Keisuke Shirai, MD — Dartmouth-Hitchcock Medical Center

Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors: a marker of therapy response in a subset of melanoma patients

Michael T. Tetzlaff, Kelly C. Nelson, Adi Diab, Gregg A. Staerkel, Priyadharsini Nagarajan, Carlos A. Torres-Cabala, Beth A. Chasen, Jennifer A. Wargo, Victor G. Prieto, Rodabe N. Amaria and Jonathan L. Curry

Journal for ImmunoTherapy of Cancer, 6:14 (12 February 2018)
Case Report

From the Authors
"Granulomatous/sarcoid-like lesions associated with checkpoint inhibitor therapy represent an immune related adverse event (irAE) that can present in several tissue types, including skin, lymph nodes and lung. This irAE can mimic disease recurrence clinically and radiographically; however, it may actually represent a favorable immune reaction that might be predictive of treatment response in a subset of melanoma patients."

Jonathan L. Curry, MD and Michael T. Tetzlaff MD, PhD — MD Anderson Cancer Center

The impact of PD-L1 on survival and value of the immune check point inhibitors in non-small-cell lung cancer; proposal, policies and perspective

Helmy M. Guirgis

Journal for ImmunoTherapy of Cancer, 6:15 (20 February 2018)
Research Article

From the Author
"Cost and value would render docetaxel useful and universally usable despite its adverse events. The immune checkpoint inhibitor safety and markedly enhanced value could probably justify their costs ."

Helmy M. Guirgis, MD — University of California, Irvine

A randomized, controlled trial evaluating the efficacy and safety of BTH1677 in combination with bevacizumab, carboplatin, and paclitaxel in first-line treatment of advanced non-small cell lung cancer

Walburga Engel-Riedel, Jamie Lowe, Paulette Mattson, J. Richard Trout, Richard D. Huhn, Michele Gargano, Myra L. Patchen, Richard Walsh, My My Trinh, Mariève Dupuis and Folker Schneller

Journal for ImmunoTherapy of Cancer, 6:16 (27 February 2018)
Research Article

About
BTH1677, a beta-glucan pathogen-associated molecular pattern molecule, drives an anti-cancer immune response in combination with oncology antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with bevacizumab/carboplatin/paclitaxel in patients with untreated advanced non-small cell lung cancer (NSCLC).

Radiation and PD-(L)1 treatment combinations: immune response and dose optimization via a predictive systems model

Yuri Kosinsky, Simon J. Dovedi, Kirill Peskov, Veronika Voronova, Lulu Chu, Helen Tomkinson, Nidal Al-Huniti, Donald R. Stanski and Gabriel Helmlinger

Journal for ImmunoTherapy of Cancer, 6:17 (27 February 2018)
Research Article

From the Authors
"A mathematical model is presented. It integrates key mechanistic features of immuno-oncology biology, radiation and anti-PD-L1 pharmacokinetics, to accurately predict optimal radiation and anti-PD-L1 dose sequencing for maximal antitumor efficacy. Owing to its mechanistic nature, the model features mechanistic insights into the immune-suppressive vs. immuno-activating forces underlying dose sequencing optimization."

Gabriel Helmlinger — AstraZeneca

Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients

Priyanka B. Subrahmanyam, Zhiwan Dong, Daniel Gusenleitner, Anita Giobbie-Hurder, Mariano Severgnini, Jun Zhou, Michael Manos, Lauren M. Eastman, Holden T. Maecker and F. Stephen Hodi

Journal for ImmunoTherapy of Cancer, 6:18 (6 March 2018)
Research Article

From the Authors
"Using cytof for analyses of the peripheral blood, distinct predictive biomarker candidates were identified for anti-CTLA-4 and anti-PD-1. While CD4⁺ and CD8⁺ memory T cell subsets may play an important role in response to anti-CTLA-4, NK cell subsets may influence the results for anti-PD-1 therapy."

F. Stephen Hodi, MD — Dana-Farber Cancer Institute

Randomized phase II trial of autologous dendritic cell vaccines versus autologous tumor cell vaccines in metastatic melanoma: 5-year follow up and additional analyses

Robert O. Dillman, Andrew N. Cornforth, Gabriel I. Nistor, Edward F. McClay, Thomas T. Amatruda and Carol Depriest

Journal for ImmunoTherapy of Cancer, 6:19 (6 March 2018)
Research Article

From the Authors
"In a small randomized trial, presentation of autologous tumor antigens by subcutaneous injections of autologous dendritic cells was associated with better survival compared to injections of irradiated autologous tumor cells. This patient-specific dendritic cell vaccine approach, which was associated with minimal toxicity, resulted in 3-year and 5-year survival rates of 61% and 33% which are quite comparable to those seen for patients with recurrent metastatic melanoma treated with checkpoint inhibitors, even though the mechanisms of action are different--the former inducing new immune responses or enhancing weak ones, while the latter removes the inhibition of existing strong immune responses."

Robert O. Dillman, MD, FACP — AiVita Biomedical, Inc.

Measuring multiple parameters of CD8+ tumor-infiltrating lymphocytes in human cancers by image analysis

Keith E. Steele, Tze Heng Tan, René Korn, Karma Dacosta, Charles Brown, Michael Kuziora, Johannes Zimmermann, Brian Laffin, Moritz Widmaier, Lorenz Rognoni, Ruben Cardenes, Katrin Schneider, Anmarie Boutrin, Philip Martin, Jiping Zha and Tobias Wiestler

Journal for ImmunoTherapy of Cancer, 6:20 (6 March 2018)
Research Article

From the Authors
"Keith Steele and colleagues in 'Measuring Multiple Parameters of CD8⁺ Tumor-Infiltrating Lymphocytes in Human Cancers by Image Analysis' report the development of digital image analysis methods to directly compare CD8 parameters across 9 types of major human cancers. The authors provide for the first time a landscape view of the immune response to cancer based on CD8 immunohistochemistry and highlight differences between tumor regions, among individuals and between cancer types. This report should serve as a model for the kind of methodological harmonization and validation needed to compare tissue data across sample sets analyzed by various labs and serve to promote the application of more sophisticated image analysis required to tease apart the immunological complexity of the tumor microenvironment."

Keith E. Steele, DVM, PhD — MedImmune, LLC

Highly Accessed Articles

Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

Jun Gong, Alexander Chehrazi-Raffle, Srikanth Reddi and Ravi Salgia

Journal for ImmunoTherapy of Cancer 2018, 6:8 (23 January 2018)

Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond

Jason Zhu, Andrew J. Armstrong, Terence W. Friedlander, Won Kim, Sumanta K. Pal, Daniel J. George and Tian Zhang

Journal for ImmunoTherapy of Cancer 2018, 6:4 (25 January 2018)

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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 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.

SITC Members Receive Complimentary Article Processing Charges in 2018

As a thank you to our members, SITC is offering complimentary article processing charges throughout 2018 (a $2,500 USD savings). For your discount code, contact the SITC office at +1 (414) 271-2456.

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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