JITC Digest March 2017


Inside this Issue:

Letter from the Editor

pedro-romero_1__1_.jpgDear JITC Readers:

I am pleased to highlight three interesting articles in this month’s issue of the Journal for ImmunoTherapy of Cancer (JITC). These articles evaluate immune regulation and modulation, review challenges associated with the use of CAR T cell therapy in treating solid tumors, and take a closer look at IRF-1 as a biomarker to predict response to anti-PD-1 immunotherapy in melanoma.

The review entitled “Systematic evaluation of immune regulation and modulation” by David Stroncek et al. is the latest review from the Society for Immunotherapy of Cancer (SITC) Immune Biomarkers Task Force. Comprised of experts tasked with exploring the systematic assessment of immune regulation and modulation, Working Group 3 of the Task Force used the tumor microenvironment, microbiome, bone marrow and adoptively transferred T cells as examples to discuss the optimal type and timing of sample collection. Potential measurements, assays and analyses are also discussed. Among their conclusions, the authors stress the importance of routine, direct evaluation of tumor samples and the necessity of a structured plan for sample collection, biomarker analysis and data analysis in all cancer immunotherapy clinical trials.

Marcela Maus and Irene Scarfo’s article, “Current approaches to increase CAR T cell potency in solid tumors: targeting the tumor microenvironment,” focuses on the immunosuppressive nature of tumor microenvironment. The authors discuss strategies developed to enhance the efficacy of CAR T cell therapy, such as coadministration of CAR T cells with checkpoint inhibitors, or with other therapies. They conclude that many further clinical trials will be required to refine the optimal strategies and determine the safest and most effective treatment for patients with solid tumors.

This issue also includes the highlighted original research article, “Nuclear IRF-1 expression as an assay to predict capability to express PD-L1 and response to PD-1 therapy in metastatic melanoma,” by David Rimm et al. This first report of IRF-1 as a tissue-based biomarker to predict response to anti-PD-1 immunotherapy in melanoma boldly suggests that, compared to PD-L1 status, nuclear IRF-1 staining of melanoma samples is a better predictor of objective radiographic response and progression-free survival. These results were even greater in patients treated with combination ipilimumab and nivolumab, a treatment that is rapidly being adopted in this disease setting.

Last, but certainly not least, please join me in thanking the 200+ reviewers who volunteered their time in 2016 to provide insightful comments that led to the successful publication of many diverse, high-quality manuscripts in JITC. The journal would not be thriving as it is without their thoughtful reviews and dedication. For this, I am sincerely grateful.

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

Case Report

Ipilimumab-induced thrombotic thrombocytopenic purpura (TTP)

Jeanelle King, Javier de la Cruz and Jose Lutzky
Journal for ImmunoTherapy of Cancer 2017, 5:19 (21 March 2017)

From the Authors

"Since the introduction of therapeutic checkpoint inhibitors in the treatment of advanced melanoma only a few years ago, there has been an unprecedented expansion of the indications for the use of these immunotherapeutic agents. As a result, all providers involved in the care of cancer patients should become familiar with the spectrum of immune-related adverse events associated with these drugs. This case report documents for the first time the occurrence of thrombotic thrombocytopenic purpura in a patient treated with Ipilimumab, a blocking antibody to CT LA 4. This report further widens the gamut of hematologic immune-related adverse events associated with checkpoint inhibitors."

Jose Lutzky, MD, FACP — Mount Sinai Medical Center


Sudden hearing loss in a melanoma patient on pembrolizumab: an etiology not to be omitted in the differential diagnosis

Marc-Elie Nader, Jeffrey N. Myers and Paul W. Gidley
Journal for ImmunoTherapy of Cancer 2017, 5:24 (21 March 2017)

From the Authors

"This commentary discusses the importance of considering the diagnosis of leptomeningeal metastasis in patients with metastatic melanoma who present with new cranial nerve deficits."

Kamyar Nader, MD — MD Anderson Cancer Center at Cooper

Meeting Report

Immunotherapy biomarkers 2016: overcoming the barriers

James L. Gulley, Jay A. Berzofsky, Marcus O. Butler, Alessandra Cesano, Bernard A. Fox, Sacha Gnjatic, Sylvia Janetzki, Shyam Kalavar, Vaios Karanikas, Samir N. Khleif, Ilan Kirsch, Peter P. Lee, Cristina Maccalli, Holden Maecker, Jeffrey Schlom, Barbara Seliger, Janet Siebert, David F. Stroncek, Magdalena Thurin, Jianda Yuan and Lisa H. Butterfield
Journal for ImmunoTherapy of Cancer 2017, 5:29 (21 March 2017)

From the Authors

"This paper summarizes the SITC Biomarkers Task Force meeting, co-organized by SITC and the National Cancer Institute (NCI), held at the NCI on April 1, 2016. Each working group presented data on their areas of focus, and the NCI investigators presented new data on their work on immunotherapy biomarkers. This interactive meeting served to complement the formal white papers with recommendations to the field produced by each working group, which are also appearing in JITC."

Lisa H. Butterfield, PhD — University of Pittsburgh

Research Article

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer

Kristen M. Hege, Emily K. Bergsland, George A. Fisher, John J. Nemunaitis, Robert S. Warren, James G. McArthur, Andy A. Lin, Jeffrey Schlom, Carl H. June and Stephen A. Sherwin
Journal for ImmunoTherapy of Cancer 2017, 5:22 (21 March 2017)

From the Authors

"This manuscript provides a historical account of the first two clinical trials in the field of chimeric antigen receptor (CAR) modified T cells for the treatment of solid tumors conducted in the 1990s. Important observations included clinical symptoms consistent with cytokine release syndrome, but a lack of “on-target-off-tumor” toxicity; trafficking of CAR T cells to tumor tissue; and immunogenicity of the humanized CAR construct targeting TAG-72 in the absence of lymphodepletion."

Kristen Hege, MD — Celgene/UCSF

Ex vivo Akt inhibition promotes the generation of potent CD19CAR T cells for adoptive immunotherapy

Ryan Urak, Miriam Walter, Laura Lim, ChingLam W. Wong, Lihua E. Budde, Sandra Thomas, Stephen J. Forman and Xiuli Wang
Journal for ImmunoTherapy of Cancer 2017, 5:26 (21 March 2017)

From the Authors

"Generating chimeric antigen receptor CAR T cells with enhanced persistence and effector function to improve potency is of increasing importance in the field. The simple process of supplementation with an Akt inhibitor to existing methods during ex vivo priming and expansion could significantly increase the effectiveness of adoptive CAR T cell therapy."

Xiuli Wang, PhD — City of Hope National Medical Center

Nuclear IRF-1 expression as a mechanism to assess “Capability” to express PD-L1 and response to PD-1 therapy in metastatic melanoma

James W. Smithy, Lauren M. Moore, Vasiliki Pelekanou, Jamaal Rehman, Patricia Gaule, Pok Fai Wong, Veronique M. Neumeister, Mario Sznol, Harriet M. Kluger and David L. Rimm
Journal for ImmunoTherapy of Cancer 2017, 5:25 (21 March 2017)

From the Authors

"PD-L1 expression appears to be highly heterogeneous and this may be why some patients that are PD-L1 negative respond to PD-1 axis therapy. Here we show the first evidence that assessment of regulators of PD-L1 expression (IRF1) may be more informative than PD-L1 itself."

David L. Rimm, MD, PhD — Yale University


Systematic evaluation of immune regulation and modulation

David F. Stroncek, Lisa H. Butterfield, Michael A. Cannarile, Madhav V. Dhodapkar, Tim F. Greten, Jean Charles Grivel, David R. Kaufman, Heidi H. Kong, Firouzeh Korangy, Peter P. Lee, Francesco Marincola, Sergio Rutella, Janet C. Siebert, Giorgio Trinchieri and Barbara Seliger
Journal for ImmunoTherapy of Cancer 2017, 5:21 (21 March 2017)

From the Authors

"Despite the recent success of immunotherapies the response rates of patients still need to be increased and therefore predictive as well as prognostic markers have to be identified in order to select patients undergoing these therapies. Based on a collaborative, multidisciplinary effort, strategies to systematically assess immune regulation and modulation from sample collection to measurement of immune parameters including the (high throughput) technologies and their pitfalls will be addressed in this review."

Barbara Seliger, MD, PhD — Martin Luther University Halle-Wittenberg

Current approaches to increase CAR T cell potency in solid tumors: targeting the tumor microenvironment

Irene Scarfò and Marcela V. Maus
Journal for ImmunoTherapy of Cancer 2017, 5:28 (21 March 2017)

From the Authors

"This manuscript is a review which highlights some of the challenges of engineered T cell therapy in solid tumor. We also discuss potential approaches to overcome these challenges, particularly the hostile tumor microenvironment, which plays a key role in dampening immune responses."

Marcela V. Maus, MD, PhD — Massachusetts General Hospital

Short Report

Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade

Evan J. Lipson, Mohammed T. Lilo, Aleksandra Ogurtsova, Jessica Esandrio, Haiying Xu, Patricia Brothers, Megan Schollenberger, William H. Sharfman and Janis M. Taube
Journal for ImmunoTherapy of Cancer 2017, 5:23 (21 March 2017)

From the Authors

"Might PD-1 blockade trigger antitumor immunity in patients with advanced basal cell carcinoma (BCC)? We interrogated the tumor microenvironments of 40 BCC specimens and found high levels of PD-L1 expression which, in other tumor types, has been associated with response to anti-PD-1. Additionally, we describe a patient with metastatic BCC whose partial response to pembrolizumab (anti-PD-1) is ongoing at 14 months. Our findings provide a rationale for further testing of PD-1-directed therapies in patients with advanced BCC."

Evan J. Lipson — Johns Hopkins University

February Highly Accessed Articles


Combination immunotherapy: a road map

Patrick A. Ott, F. Stephen Hodi, Howard L. Kaufman, Jon M. Wigginton and Jedd D. Wolchok
Journal for ImmunoTherapy of Cancer 2017 5:16 (21 February 2017)


Gene expression markers of Tumor Infiltrating Leukocytes

Patrick Danaher, Sarah Warren, Lucas Dennis, Leonard D’Amico, Andrew White, Mary L. Disis, Melissa A. Geller, Kunle Odunsi, Joseph Beechem and Steven P. Fling
Journal for ImmunoTherapy of Cancer 2017 5:18 (21 February 2017)