JITC Digest February 2017

Inside this Issue:

Letter from the Editor

Dear JITC Readers:

Among the articles in this February issue of the Journal for ImmunoTherapy of Cancer (JITC), three stand to be highlighted, beginning with a white paper from the Society for Immunotherapy of Cancer (SITC) that explores the rational design and clinical use of combination immunotherapies. The progress in the field is such that there is now great potential to improve on the benefits obtained with monotherapy by combining agents with complementary mechanisms of action. Moreover, the increasing opportunities for collaboration between pharmaceutical, academic and government organizations provide a supportive framework for such development. The SITC Combination Immunotherapy Task Force white paper, entitled “Combination immunotherapy: a road map” (Ott et al.), aims to identify the most promising prospects for combination therapy and address challenges associated with combinatorial approaches. Building on previous work on combination immunotherapy, this article is the first to address the use of mouse models, safety considerations in early clinical testing, the need for innovative early phase clinical trial designs, and appropriate safety and efficacy endpoints for early phase clinical trials, all in the specific setting of combination immunotherapy.

In “Analyses of the peripheral immunome following multiple administrations of a human IgGI anti-PD-L1 monoclonal antibody (Avelumab)”, Lepone et al. used flow cytometry to analyze the effects of multiple administrations of the fully human IgG1 MAb, avelumab, on 123 immune cell subsets in the peripheral blood of 28 cancer patients. While this is the only anti-PD-L1 monoclonal antibody in the clinic capable of mediating antibody-dependent cytotoxicity (ADCC), there was no statistically significant change in any immune cell subset, at any avelumab dose or dose frequency. The increased ratio of sCD27:sCD40L observed suggested potential immune activation. Intriguingly, controlled in vitro studies showed lysis of tumor cells but not donor PBMC. These studies suggest that concerns about MAb-driven PD-L1 positive immune cell lysis via ADCC may be unfounded and provide the rationale to further explore the potential ADCC mechanism of action of avelumab and other human IgG1 checkpoint inhibitors.

Lastly, although analysis of gene expression in purified immune cells suggests that hundreds of genes are enriched in a single cell type, the utility of these gene sets in the context of tumor samples remains unclear. In “Gene expression markers of tumor infiltrating leukocytes”, Danaher et al. report the results of a study that examined co-expression patterns in nearly 10,000 samples from The Cancer Genome Atlas (TCGA) database. Their goal was to identify a subset of “high confidence” marker genes with sufficient cell type specificity that their expression levels could be used to measure immune cell subpopulations in the tumor microenvironment. Immune cell scores inferred from these high confidence gene sets were concordant with immune cell measurements by flow cytometry and immunohistochemistry. These cell scores would represent a convenient technique for extracting information about the tumor immune contexture when flow cytometry is unavailable, using – for instance – RNA extracted from formalin fixed paraffin-embedded tissues. In an immunotherapy context, the scores could potentially provide early separation of responders and non-responders and help predict or monitor response to immunotherapy.

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

Case Report

Nivolumab induced myxedema crisis

Uqba Khan, Humaira Rizvi, Dahlia Sano, Jane Chiu and Tarik Hadid
Journal for ImmunoTherapy of Cancer 2017, 5:13 (21 February 2017)

From the Authors

"Checkpoint inhibitors have a unique adverse event profile. Although endocrinopathies are relatively common with nivolumab, myxedema crisis is a rare and life-threatening complication associated with use of nivolumab. Close monitoring of thyroid function is required during the course of treatment with checkpoint inhibitors to prevent such serious toxicities."

Uqba Khan, MD — St. John Hospital and Medical Center

PD-1 blockade induces remissions in relapsed classical Hodgkin lymphoma following allogeneic hematopoietic stem cell transplantation

James Godfrey, Michael R. Bishop, Sahr Syed, Elizabeth Hyjek and Justin Kline
Journal for ImmunoTherapy of Cancer 2017, 5:11 (21 February 2017)

From the Authors

"Limited treatment options are available for patients with Hodgkin lymphoma who relapse after allogeneic stem cell transplantation. We show that PD-1 blockade is highly effective in this context, leading to durable responses in all of the patients described. Anti-PD-1 antibody therapy appears to be a promising approach for patients with Hodgkin lymphoma (and potentially other hematological cancers) who experience disease relapse after allogeneic transplantation."

Justin P. Kline, MD — University of Chicago

Thrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy

Eileen Shiuan, Kathryn E. Beckermann, Alpaslan Ozgun, Ciara Kelly, Meredith McKean, Jennifer McQuade, Mary Ann Thompson, Igor Puzanov, John P. Greer, Suthee Rapisuwon, Michael Postow, Michael A. Davies, Zeynep Eroglu and Douglas Johnson
Journal for ImmunoTherapy of Cancer 2017, 5:8 (21 February 2017)

From the Authors

"Thrombocytopenia in patients with melanoma treated with checkpoint inhibition is an uncommon complication and frequently resolves spontaneously. However, in two cases it required standard treatments for idiopathic thrombocytopenic purpura. Clinical vigilance should be used when rechallenging with checkpoint inhibitors following resolution of thrombocytopenia."

Kathryn E. Beckermann, MD, PhD — Vanderbilt University Medical Center

Immunotherapy-associated autoimmune hemolytic anemia

Uqba Khan, Farman Ali, Muhammad Siddique Khurram, Awais Zaka and Tarik Hadid
Journal for ImmunoTherapy of Cancer 2017, 5:15 (21 February 2017)

From the Authors

"Autoimmune hemolytic anemia (AIHA) is a rare and unusual adverse effect of checkpoint inhibitors. Both CTLA-4 and PD-1 inhibitors have been associated with AIHA. Steroids are usually the cornerstone for management of AIHA induced by checkpoint inhibitors, although rituximab may be needed in refractory or resistant cases."

Uqba Khan, MD — St. John Hospital and Medical Center

Commentary

FAK-inhibition opens the door to checkpoint immunotherapy in pancreatic cancer

Stefan N. Symeonides, Stephen M. Anderton and Alan Serrels
Journal for ImmunoTherapy of Cancer 2017, 5:17 (21 February 2017)

From the Author

"This work builds on our previous observations identifying a role for Focal Adhesion Kinase (FAK) in regulation of the antitumor immune response, and beautifully illustrates the potential for FAK kinase inhibitors in combination with immunotherapy in the treatment of pancreatic cancer. With clinical trials testing these combinations now underway, it will be interesting to see whether promising pre-clinical research will translate to the clinic."

Alan Serrels, PhD — The University of Edinburgh

Immunotherapy resistance: the answers lie ahead – not in front – of us

Miles C. Andrews and Jennifer A. Wargo
Journal for ImmunoTherapy of Cancer 2017, 5:10 (21 February 2017)

From the Authors

"Despite elegant descriptions of molecular mechanisms underpinning cases of resistance to immune checkpoint blockade, such as defective interferon pathway signaling, our understanding remains in its infancy. In order to maximize the clinical impact of immunotherapy, continued attention must be given to comprehensive immune monitoring and sample collection, striving for an integrated understanding of the adaptive changes both within and outside the tumor microenvironment."

Miles C. Andrews, PhD — University of Texas MD Anderson Cancer Center

Research Article

ENHANCING ADOPTIVE CANCER IMMUNOTHERAPY WITH Vγ2Vδ2 T CELLS THROUGH PULSE ZOLEDRONATE STIMULATION

Mohanad H. Nada, Hong Wang, Grefachew Workalemahu, Yoshimasa Tanaka and Craig T. Morita
Journal for ImmunoTherapy of Cancer 2017, 5:9 (21 February 2017)

From the Authors

"Adoptive immunotherapy with Vγ2Vδ2 T cells has been used to treat patients with a variety of cancers, with partial and complete remissions in a few cases and relatively little toxicity. Most clinical trials have used continuous zoledronate exposure to expand Vγ2Vδ2 T cells. We find that pulse zoledronate stimulation maximizes the purity, quantity and quality of expanded Vγ2Vδ2 T cells when tested in vitro and in NSG mice against human prostate cancer cells. This simple modification to existing protocols could significantly increase the effectiveness of adoptive immunotherapy with γδ T cells."

Craig T. Morita, MD, PhD — The University of Iowa Carver College of Medicine

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)

From the Authors

"We derived 14 gene expression signatures quantifying immune cell populations in tumor samples. These 14 cell type signatures hold prognostic information in a wide range of cancer types, predict response to checkpoint inhibition in a melanoma dataset, and describe single patients’ tumor-immune interactions in rich detail."

Patrick Danaher, PhD — NanoString Technologies

CCR7⁺ selected gene-modified T cells maintain a central memory phenotype and display enhanced persistence in peripheral blood in vivo

Gray Kueberuwa, Hannah Gornall, Erik Marcelo Alcantar-Orozco, Deborah Bouvier, Zainul Abedin Kapacee, Robert Edward Hawkins and David Edward Gilham
Journal for ImmunoTherapy of Cancer 2017, 5:14 (21 February 2017)

From the Authors

"Adoptively transferred T cells of early differentiation status have increased persistence and enhanced ability to eliminate tumors in vivo. This study presents a method of selecting early differentiated T cells that is translatable to the clinic and could lead to enhanced persistence of adoptively transferred T cells and improved clinical outcomes."

Gray Kueberuwa, PhD — The University of Manchester

Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody

Renee N. Donahue, Lauren M. Lepone, Italia Grenga, Caroline Jochems, Massimo Fantini, Ravi A. Madan, Christopher R. Heery, James L. Gulley and Jeffrey Schlom
Journal for ImmunoTherapy of Cancer 2017, 5:20 (21 February 2017)

From the Authors

"Avelumab is a fully human IgG1 anti-PD-L1 monoclonal antibody, which has been shown to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) of human tumor cells. These studies demonstrate that the administration of multiple cycles of avelumab to cancer patients has no adverse effect on 123 distinct immune cell subsets, nor does avelumab have the ability to lyse PBMC from multiple donors in vitro. These studies thus provide the rationale to further exploit the potential ADCC mechanism of avelumab and other IgG1 checkpoint inhibitor monoclonals in future clinical studies."

Jeffrey Schlom, PhD — National Cancer Institute, National Institutes of Health

Review

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)

From the Authors

"Although PD-1 pathway blockade has broad clinical activity in a wide spectrum of malignancies, combination therapies will be needed to increase efficacy. The article provides an overview of the different therapeutic approaches that have potential to act synergistically with PD1/PD-L1 inhibition and seeks to give guidance on clinical trial design, toxicity considerations and endpoints for the clinical development of combination immunotherapies."

Patrick A. Ott, MD, PhD — Dana-Farber Cancer Institute, Harvard Medical School

January Highly Accessed Articles

Radiotherapy and MVA-MUC1-IL-2 vaccine act synergistically for inducing specific immunity to MUC-1 tumor antigen

Gilda G. Hillman, Lyndsey A. Reich, Shoshana E. Rothstein, Lisa M. Abernathy, Matthew D. Fountain, Kali Hankerd, Christopher K. Yunker, Joseph T. Rakowski, Eric Quemeneur and Philippe Slos
Journal for ImmunoTherapy of Cancer 2017 5:4 (17 January 2017)

Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer

Juan R. Cubillos-Ruiz, Eslam Mohamed and Paulo C. Rodriguez
Journal for ImmunoTherapy of Cancer 2017 5:5 (17 January 2017)