JITC Digest November 2017

Inside this Issue:

Letter from the Editor

Dear JITC Readers:

Earlier this month, at the Society for Immunotherapy of Cancer's (SITC) 32^nd Annual Meeting and Pre-Conference Programs, a clear goal among researchers and clinicians was to increase understanding of the mechanisms and management of immune-related toxicities stemming from cancer immunotherapy. Taking an important step to advance understanding in this area, SITC's highly-anticipated consensus recommendations on recognition and management of toxicities associated with immune checkpoint inhibitors were published this month in JITC. "Managing toxicities associated with immune checkpoint inhibitors: Consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group" draws on the expertise of more than 80 oncology researchers, clinical practitioners, disease area specialists and industry representatives who convened at a dedicated one-day workshop, organized by SITC, in spring 2017. These multidisciplinary guidelines, offering expert recommendations on how to recognize, report and manage common and rare toxicities across multiple organ systems, will provide clinical practitioners with the guidance necessary to address this emerging and discrete group of adverse events until evidence-based data are available to inform clinical decision-making.

Also in this issue, Adam Ajina and John Maher discuss the potential for using recombinant oncolytic viruses to augment chimeric antigen receptor (CAR)-T cell therapeutic efficacy in "Prospects for combined use of oncolytic viruses and CAR T-cells". Although CAR-T cell monotherapy has displayed unprecedented success in treating refractory B-cell malignancies, evidence of efficacy in solid tumors is lacking. The authors hypothesize that the inclusion of an oncolytic virus in a novel CAR-T cell combination therapy may help facilitate CAR-T cell trafficking into the tumor microenvironment, mitigate or reverse local immunosuppression, and/or enhance CAR-T cell functionality and persistence to increase efficacy in patients with solid tumors. This thorough review provides an excellent foundation to help identify opportunities for synergistic oncolytic virus/CAR-T cell deployment.

On the same theme, JITC's latest issue also includes a timely research article from Qiong Xue et al. that assesses functional profiles of CAR-T cell products. "Single-cell multiplexed cytokine profiling of CD19 CAR-T cells reveals a diverse landscape of polyfunctional antigen-specific response" explores utilization of single-cell profiling of CD19 CAR-T cell pre-infusion products to characterize functional attributes related to potency and immunotoxicity. In this study, individual cell cytokine secretion profiles were assessed using a novel single-cell barcode chip with ~12000 microchambers. CAR ligation induced a wide-array of CAR-T cell responses  including anti-tumor, stimulatory, regulatory, and inflammatory processes. This highly multiplexed single-cell capture and analysis system provides a sensitive and comprehensive functional assessment of CAR-T cell pre-infusion products that can offer further insight into the safety and efficacy of this extremely promising therapy and might help in the search for useful predictive biomarkers.

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

Case Report

Impressive response to immunotherapy in a metastatic gastric cancer patient: could somatic copy number alterations help patient selection?

Gustavo dos Santos Fernandes, Daniel da Motta Girardi, Luiza Dib Batista Bugiato Faria, João Paulo Giacomini Bernardes and Renata de Almeida Coudry
Journal for ImmunoTherapy of Cancer 2017, 5:84 (21 November 2017)

From the Authors

"Immunotherapies certainly have an important role in the management of patients with gastric cancer. We described a patient who presented complete response with immunotherapy even in the absence of the typical biomarkers PD-L1 expression or microsatellite instability. We hypothesized that other molecular characteristics that we described may also predict response to treatment."

Gustavo dos Santos Fernandes, MD — Hospital Sírio-Libanês, Brazil

Smoldering myocarditis following immune checkpoint blockade

Timothy G. Norwood, Brian C. Westbrook, Douglas B. Johnson, Silvio H. Litovsky, Nina L. Terry, Svetlana B. McKee, Alan S. Gertler, Javid J. Moslehi and Robert M. Conry
Journal for ImmunoTherapy of Cancer 2017, 5:91 (21 November 2017)

From the Authors

"Subclinical, smoldering myocarditis may occur following immune checkpoint blockade, with evidence of both humoral and cell-mediated immunity responsive to corticosteroid therapy. This experience supports early monitoring for myocarditis with serial electrocardiograms and serum troponin I determinations in large, prospective cohorts of patients receiving combination immune checkpoint blockade as early detection and initiation of immunosuppression may forestall fulminant presentation of this disease and limit myocardial damage."

Robert M. Conry, MD — The University of Alabama at Birmingham, United States

Consensus Recommendation

Managing toxicities associated with immune checkpoint inhibitors: Consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group

I. Puzanov, A. Diab, K. Abdallah, C. O. BinghamIII, C. Brogdon, R. Dadu, L. Hamad, S. Kim, M. E. Lacouture, N. R. LeBoeuf, D. Lenihan, C. Onofrei, V. Shannon, R. Sharma, A. W. Silk, D. Skondra, M. E. Suarez-Almazor, Y. Wang, K. Wiley, H. L. Kaufman, M. S. Ernstoff and on behalf of the Society for Immunotherapy of Cancer Toxicity Management Working Group
Journal for ImmunoTherapy of Cancer 2017, 5:95 (21 November 2017)

About

It's extremely encouraging that patients have new treatment options, but patterns of toxicity are beginning to emerge. We're seeing effects on the skin, gut, gastrointestinal and endocrine systems, joints, heart and other organs, some of which we haven't seen before. Clinicians need guidance on how to recognize early signs and manage these toxicities. These guidelines, which were developed with strategic partners ASCO and NCCN to ensure harmonization, represent the best consensus thinking in this rapidly developing area of tumor immunotherapy. This is a dynamic effort and recommendations will be updated as new data, and new drugs and combinations, become available.

Research Article

A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer

Patrick M. Dillon, Gina R. Petroni, Mark E. Smolkin, David R. Brenin, Kimberly A. Chianese-Bullock, Kelly T. Smith, Walter C. Olson, Ibrahim S. Fanous, Carmel J. Nail, Christiana M. Brenin, Emily H. Hall and Craig L. Slingluff Jr
Journal for ImmunoTherapy of Cancer 2017, 5:92 (21 November 2017)

From the Authors

"A clinical trial of a 9 peptide vaccine plus tetanus helper peptide and poly-ICLC was safe in early and advanced breast cancer patients. Some patients generated ELIspot responses to the vaccine."

Patrick M. Dillon, MD — University of Virginia, United States

Safety in treatment of hepatocellular carcinoma with immune checkpoint inhibitors as compared to melanoma and non-small cell lung cancer

Zachary J. Brown, Bernd Heinrich, Seth M. Steinberg, Su Jong Yu and Tim F. Greten
Journal for ImmunoTherapy of Cancer 2017, 5:93 (21 November 2017)

From the Authors

"Immunotherapy is quickly evolving as a treatment for hepatocellular carcinoma (HCC) with multiple studies showing efficacy of immune checkpoint inhibitors. In the article 'Safety in treatment of hepatocellular carcinoma with immune checkpoint inhibitors as compared to melanoma and non-small cell lung cancer', we demonstrate that although patients with HCC have underlying liver dysfunction, immune checkpoint inhibitors are safe to pursue in the treatment of HCC as compared to melanoma and non-small cell lung cancer."

Zachary Brown, DO — National Institutes of Health, United States

Peripheral and local predictive immune signatures identified in a phase II trial of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV melanoma

Rahima Jamal, Réjean Lapointe, Eftihia Cocolakis, Paméla Thébault, Shirin Kazemi, Jennifer E. Friedmann, Jeanne Dionne, Jean-François Cailhier, Karl Bélanger, Jean-Pierre Ayoub, Huy Le, Caroline Lambert, Jida El-Hajjar, Léon C. van Kempen, Alan Spatz and Wilson H. Miller Jr
Journal for ImmunoTherapy of Cancer 2017, 5:83 (21 November 2017)

From the Authors

"Identification of biomarkers predicting outcome in patients treated with immunotherapy continues to be an unmet medical need. We found that circulating biomarkers associated with a pre-existing inflammatory state predicted markedly inferior outcomes in metastatic melanoma patients treated with the combination of ipilimumab and carboplatin/paclitaxel."

Eftihia Cocolakis, PhD — Jewish General Hospital, McGill University, Canada

Single-cell multiplexed cytokine profiling of CD19 CAR-T cells reveals a diverse landscape of polyfunctional antigen-specific response

Qiong Xue, Emily Bettini, Patrick Paczkowski, Colin Ng, Alaina Kaiser, Timothy McConnell, Olja Kodrasi, Máire F. Quigley, James Heath, Rong Fan, Sean Mackay, Mark E. Dudley, Sadik H. Kassim and Jing Zhou
Journal for ImmunoTherapy of Cancer 2017, 5:85 (21 November 2017)

From the Authors

"In this report, our single-cell analyses reveal a diverse landscape of immune effector responses of CD19 CAR-T cell products to antigen-specific stimulation. The presented biomarker capture and analysis system provides a more sensitive and comprehensive functional assessment of CAR-T pre-infusion products and supports a road map for correlative discoveries on the role of polyfunctional CAR-T cells in clinical responses."

Qiong (Chelsea) Xue, PhD — Novartis, United States

Review

Prospects for combined use of oncolytic viruses and CAR T-cells

Adam Ajina and John Maher
Journal for ImmunoTherapy of Cancer 2017, 5:90 (21 November 2017)

From the Authors

"CAR T-cell therapy is transforming the lives of patients with chemotherapy-refractory B-cell malignancies but has proven far less successful in managing solid tumours. Here, we highlight a number of strategies designed to augment CAR T-cell function by exploiting potential synergies with oncolytic virotherapy."

John Maher, MSc, PhD — King's College London, United Kingdom

Biomarkers for immunotherapy in bladder cancer: a moving target

David H. Aggen and Charles G. Drake
Journal for ImmunoTherapy of Cancer 2017, 5:94 (21 November 2017)

From the Authors

"With 5 new approved immunotherapies in metastatic bladder cancer, the challenge now lies in developing a reliable, standardized biomarker to guide treatment. Promising candidates include tumor mutation burden and an inflammatory immune gene signature. Validation of these modalities as predictive biomarkers will rely on pivotal results from on-going prospective trials."

David H. Aggen, MD, PhD — Columbia University Medical Center/NYPH, United States

October Highly Accessed Articles

The immune system in cancer metastasis: friend or foe?

Louise M.E. Janssen, Emma E. Ramsay, Craig D. Logsdon and Willem W. Overwijk
Journal for ImmunoTherapy of Cancer 2017, 5:79 (17 October 2017)

Immuno-thermal ablations – boosting the anticancer immune response

Ryan Slovak, Johannes M. Ludwig, Scott N. Gettinger, Roy S. Herbst and Hyun S. Kim
Journal for ImmunoTherapy of Cancer 2017, 5:78 (17 October 2017)