JITC Digest August 2017

Inside this Issue:

Letter from the Editor

Dear JITC Readers:

Among the articles in this August issue of the Journal for ImmunoTherapy of Cancer (JITC), three stand to be highlighted, beginning with the newest publication from the Society for Immunotherapy of Cancer (SITC) Cancer Immunotherapy Guidelines (CIG) initiative. "The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma” is the fourth disease-specific treatment guideline developed by SITC. With the approval of immune checkpoint blockade for patients with platinum-resistant metastatic urothelial carcinoma, this consensus statement addresses important questions related to patient selection, and choice and sequencing of approved immunotherapies. As a collaboration between leaders in cancer immunotherapy and bladder cancer specialists, this paper provides an expert consensus on the optimal use of immunotherapy to treat patients with bladder cancer.

“Whole-blood RNA transcript-based models can predict clinical response in two large independent clinical studies of patients with advanced melanoma treated with the checkpoint inhibitor, tremelimumab” by Friedlander, et al. This article reports data from what may be the largest blood-based biomarker study of a checkpoint inhibitor to date. In addition, this work proposes a validated 15-gene classifier model that may predict clinical response to treatment of advanced metastatic melanoma with the anti-CTLA-4 monoclonal antibody tremelimumab. Provocatively, this blood based-gene signature may help to discriminate responders from non-responders to anti-CTLA-4 treatment, removing the need to examine tumor biopsies. This is in contrast to the emerging consensus that pre- or ontumor biopsies should be examined in order to identify much-needed predictive biomarkers of response to immune checkpoint blockade therapies.

The third spotlight article in this issue, from Wilkinson, et al., is entitled “The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment”. This article explores the immunomodulatory effects of MEK inhibition using selumetinib as monotherapy and in combination with an anti-CTLA-4 monoclonal antibody (mAb). Using a range of in vitro and in vivo models, the authors demonstrate that pre-treatment with a MEK inhibitor can enhance the efficacy of anti-CTLA-4 in a CT26 preclinical tumor model. The mechanisms underpinning this effect include conditioning the tumor microenvironment to be more permissive to checkpoint inhibition through reduction of the immunosuppressive myeloid compartment while minimally affecting the enhancement of specific T cell immunity brought about by anti-CTLA-4. Appropriate sequencing of the MEK inhibitor and anti- CTLA-4 was also important in optimizing anti-tumor activity. These findings suggest that dose scheduling may be an important consideration for delivering optimal therapeutic activity when MEK inhibitors are combined with checkpoint inhibitor therapy.

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

Case Report

Predictive role of PD-L1 expression in the response of renal medullary carcinoma to PD-1 inhibition

Quaovi Sodji, Kandy Klein, Kavuri Sravan and Jigarkumar Parikh
Journal for ImmunoTherapy of Cancer 2017, 5:62 (15 August 2017)

From the Authors

"This article addresses the question of whether PD-L1 expression is prognostic or predictive of response to PD-1 inhibition in renal medullary carcinoma."

Jigarkumar Parikh, MD — Medical College of Georgia

Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1 inhibitors: A case series

Dylan J. Martini, Aly-Khan A. Lalani, Dominick Bossé, John A. Steinharter, Lauren C. Harshman, F. Stephen Hodi, Patrick A. Ott and Toni K. Choueiri
Journal for ImmunoTherapy of Cancer 2017, 5:66 (15 August 2017)

From the Authors

"Our case series highlights that there is insufficient data to support treatment with a different PD-1/PD-L1 inhibitor after progression on PD-1 pathway blockade. Identifying mechanisms of resistance to immunotherapy will be informative and may ultimately assist physicians in selecting a rational approach to initial, and sequential, treatment options for these patients."

Dylan Martini, MD Candidate — Emory University School of Medicine

Research Article

Tumor-derived exosomes induce CD8⁺ T cell suppressors

Brian T. Maybruck, Lukas W. Pfannenstiel, Marcela Diaz-Montero and Brian R. Gastman
Journal for ImmunoTherapy of Cancer 2017, 5:65 (15 August 2017)

From the Authors

"Tumor immune evasion can be both passive and active, and the latter is often related to secreted factors and factors traveling in tumor-derived exosomes (TDEs). Our study advances our knowledge of this active process by providing evidence that these TDEs transfer protein and genetic material that can convert otherwise anti-tumor T cells to pro-tumoral immune cells with suppressive functions."

Brian R. Gastman — Cleveland Clinic

Multi-target chimaeric VLP as a therapeutic vaccine in a model of colorectal cancer

Braeden Donaldson, Farah Al-Barwani, Simon J. Pelham, Katie Young, Vernon K. Ward and Sarah L. Young
Journal for ImmunoTherapy of Cancer 2017, 5:69 (15 August 2017)

From the Authors

"We have developed chimaeric virus-like particles (VLP) containing epitopes derived from murine colorectal cancer-associated antigens as a candidate immunotherapeutic vaccine. In this manuscript, we demonstrate that these chimaeric VLP can induce epitope-specific immune responses, delay tumour growth and improve survival in a murine model of colorectal cancer."

Braeden Donaldson, BMLSc, PGDipMLSc — University of Otago

Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma

Ashish M. Kamat, Joaquim Bellmunt, Matthew D. Galsky, Badrinath R. Konety, Donald L. Lamm, David Langham, Cheryl T. Lee, Matthew I. Milowsky, Michael A. O’Donnell, Peter H. O’Donnell, Daniel P. Petrylak, Padmanee Sharma, Eila C. Skinner, Guru Sonpavde, John A. Taylor III, Prasanth Abraham and Jonathan E. Rosenberg
Journal for ImmunoTherapy of Cancer 2017, 5:68 (15 August 2017)

From the Authors

"Immunotherapy for urologic cancers was first used in the 1970s with intravesical BCG for early stage bladder cancer. Over the years, certain myths and misconceptions have crept in regarding intravesical immunotherapy that have kept it from realizing its full benefit to many patients. Now, four decades later, there has been an explosion in options available for patients with advanced disease. In this review, a task force commission by SITC and lead by Drs. Kamat and Rosenberg puts forth recommendations on the optimal use of immunotherapy for bladder cancer with the goal of clarifying issues related to delivery and optimal use of bladder cancer immunotherapy."

Ashish M. Kamat, MD, MBBS, FACS — MD Anderson Cancer Center

The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment

Edmund Poon, Stefanie Mullins, Amanda Watkins, Geoffrey S. Williams, Jens-Oliver Koopmann, Gianfranco Di Genova, Marie Cumberbatch, Margaret Veldman-Jones, Shaun E. Grosskurth, Vasu Sah, Alwin Schuller, Corrine Reimer, Simon J. Dovedi, Paul D. Smith, Ross Stewart and Robert W. Wilkinson
Journal for ImmunoTherapy of Cancer 2017, 5:63 (15 August 2017)

From the Authors

"Inhibition of MEK using selumetinib modulates the tumor microenvironment to enhance the anti-tumor response to CTLA-4 blockade in preclinical models. Conditioning of the tumor microenvironment through MEK inhibition may improve immunologic response when combined with immune checkpoint inhibitors and warrants evaluation in clinical trials."

Simon J. Dovedi, PhD — MedImmune

Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy

Rajeev Shrimali, Shamim Ahmad, Zuzana Berrong, Grigori Okoev, Adelaida Matevosyan, Ghazaleh Shoja E. Razavi, Robert Petit, Seema Gupta, Mikayel Mkrtichyan and Samir N. Khleif
Journal for ImmunoTherapy of Cancer 2017, 5:64 (15 August 2017)

From the Authors

"Combination immunotherapy has to be developed based on rational biologic design. We demonstrate that combining a Listeria monocytogenes-based vaccine, shown to decrease the T-regulatory (Treg) cell ratio to CD4+ T cells, with an anti-GITR agonist, which has been shown to work better in a Treg-depleted environment, generates highly significant synergistic anti-tumor response. Accordingly, this provides a rational basis on which to design a promising combination immunotherapy, an extremely important area in the current development of the field."

Seema Gupta, PhD — Augusta University

Whole-blood RNA transcript-based models can predict clinical response in two large independent clinical studies of patients with advanced melanoma treated with the checkpoint inhibitor, tremelimumab

Philip Friedlander, Karl Wassmann, Alan M. Christenfeld, David Fisher, Chrisann Kyi, John M. Kirkwood, Nina Bhardwaj and William K. Oh
Journal for ImmunoTherapy of Cancer 2017, 5:67 (15 August 2017)

From the Authors

"We have identified and validated a 15-gene signature predictive for response to the CTLA-4 inhibitor tremelimumab using pre-treatment blood samples obtained from stage IV melanoma patients treated on two large international studies. Identification of a pre-treatment blood-based biomarker can help optimize treatment planning, minimize toxicity risk, and decrease health care expenditure. The approach used serves as proof of concept for identification of blood-based pre-treatment biomarkers to assess efficacy of anti-PD-1 and other immune-based therapies."

Philip Friedlander, MD, PhD — Icahn School of Medicine at Mount Sinai

July Highly Accessed Articles

Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy

Michael A. Cannarile, Martin Weisser, Wolfgang Jacob, Anna-Maria Jegg, Carola H. Ries and Dominik Rüttinger
Journal for ImmunoTherapy of Cancer 2017, 5:53 (18 July 2017)

Angiosarcoma treated successfully with anti-PD-1 therapy - a case report

Simran Sindhu, Lana H. Gimber, Lee Cranmer, Ali McBride and Andrew S. Kraft
Journal for ImmunoTherapy of Cancer 2017, 5:58 (18 July 2017)