JITC Digest December 2017

Inside this Issue:

Letter from the Editor

Dear JITC Readers:

As 2017 comes to a close, JITC is pleased to present eight new articles. Featured in this month’s Basic Tumor Immunology section is “Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment” by Susanne M. Steggerda et al. Myeloid cell arginase 1 (Arg1) depletes the amino acid L-arginine, which is necessary for T cell and NK cell proliferation. In this study, the authors assess efficacy of the Arg1 small-molecule inhibitor, CB-1158, in reversing myeloid-cell Arg1-derived inhibitory mechanisms. Using pre-clinical mouse cancer models, investigators revealed that CB-1158 therapy reduced tumor growth when used as monotherapy, and in combination with gemcitabine, anti-PD-L1, adoptive T cell therapy, or adoptive NK cell therapy. These data suggest that myeloid-cell Arg1 inhibition may be a viable anti-tumor strategy in clinical settings. This piece sheds light on an inhibitor recently tested in a first-in-human clinical study reported at ASCO 2017.

Using a pre-clinical canine sarcoma model in addition to a ‘first-in-dog’ clinical trial, Robert Canter et al. demonstrate in “Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial” that radiation therapy enhances natural killer (NK) cell activity against canine osteosarcoma. In pre-clinical models, NK cell expansion and cytotoxicity increased in response to tumor irradiation in a dose-dependent fashion, and NK cells delayed radiation-treated xenograft tumor growth (p < 0.01). In the first-in-dog clinical trial, ten dogs with spontaneous osteosarcoma were treated with focal radiation and autologous NK transfer. Five dogs remained metastasis-free six months-post therapy, and increased NK cell circulation and persistence were observed. This study provides valuable insights towards advancing human NK cell therapeutic options and establishes a novel dog clinical trial model for drug development.

Immune-related adverse events (irAEs) are a consequence of immunotherapy, but also correlate with overall survival (OS) and tumor control (CR+PR+SD). In “Improved survival and tumor control with interleukin-2 associated with the development of immune-related adverse events: data from the PROCLAIM (SM) registry," Brendan Curti et al. assessed the long-term relationship between irAE incidence and OS/tumor control by analyzing 1535 patient reports from the 2008-2016 PROCLAIM (SM) registry. Analysis of reports from 130 patients with metastatic melanoma or renal cell carcinoma (RCC) and irAES related to high dose interleukin-2 (IL-2) revealed increased tumor control and median OS compared to patients who did not experience irAEs (p = 0.0008). These data indicate that irAEs following IL-2 therapy are closely associated with clinical benefit, and suggest this relationship should be investigated further in other therapeutic contexts.

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

Case Report

Combined checkpoint inhibitor therapy causing diabetic ketoacidosis in metastatic melanoma

Pouyan N. Changizzadeh, Shiva Kumar R. Mukkamalla and Vincent A. Armenio
Journal for ImmunoTherapy of Cancer 2017, 5:97 (19 December 2017)

From the Authors

"The impact of checkpoint inhibitors in treatment of melanoma is nothing short of a revolution, which has since spread its territory to encompass multiple other malignancies. These come with a unique spectrum of side effects as compared to traditional chemotherapy related adverse events. We described a young patient with no prior history of diabetes mellitus, presenting with diabetic ketoacidosis during treatment with combined checkpoint inhibitor therapy using nivolumab and ipilimumab. This case highlights the importance of watching out for these novel side effects and incorporation of appropriate early detection tools in the national guidelines."

Shiva Kumar R. Mukkamalla, MD, MPH — Roger Williams Medical Center

Commentary

Anti-PD-1 vasculitis of the central nervous system or radionecrosis?

Roger Sun, Francois-Xavier Danlos, Samy Ammari, Guillaume Louvel, Frédéric Dhermain, Stéphane Champiat, Olivier Lambotte, and Eric Deutsch
Journal for ImmunoTherapy of Cancer 2017, 5:96 (19 December 2017)

From the Authors

"An interesting case of cerebral vasculitis after PD-1 blockade was reported in a previous issue by Läubli et al.  In regard to a such rare event, we wanted to provide further details on the etiological assessment of cerebral vasculitis and  to discuss the differential diagnosis of radionecrosis, in order to avoid misleading conclusions regarding the safety of immune checkpoint inhibitors and radiotherapy."

Roger Sun, MD, PhDc — Gustave Roussy

Research Article

A pilot study of an autologous tumor-derived autophagosome vaccine with docetaxel in patients with stage IV non-small cell lung cancer

Rachel E. Sanborn, Helen J. Ross, Sandra Aung, Anupama Acheson, Tarsem Moudgil, Sachin Puri, Traci Hilton, Brenda Fisher, Todd Coffey, Christopher Paustian, Michael Neuberger, Edwin Walker, Hong-Ming Hu, Walter J. Urba and Bernard A. Fox
Journal for ImmunoTherapy of Cancer 2017, 5:103 (19 December 2017)

From the Authors

"This is the first clinical trial to exploit proteosomal blockade and autophagy to create an autologous tumor vaccine containing short-lived proteins (SLiPs) and defective ribosomal products (DRiPs), considered to be the dominant epitopes presented by HLA of cancer cells. While vaccination-induced immune recognition to cancer proteins in all evaluable patients, vaccination alone failed to provide objective responses in these patients with advanced disease."

Rachel E. Sanborn, MD — Earle A. Chiles Research Institute

Retrospective review of safety and efficacy of programmed cell death-1 inhibitors in refractory high grade gliomas

Samantha N. Reiss, Prakirthi Yerram, Lisa Modelevsky and Christian Grommes
Journal for ImmunoTherapy of Cancer 2017, 5:99 (19 December 2017)

From the Authors

"In our retrospective review, the use of pembrolizumab alone or in combination with bevacizumab and/or temozolomide in 25 patients with refractory or recurrent high grade gliomas produced low response rates, with two partial responses. A few patients had prolonged progression-free survival and pembrolizumab was tolerated with few serious toxicities."

Samantha N. Reiss, PharmD, BCOP — Memorial Sloan Kettering Cancer Center

Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials

Roman Groisberg, David S. Hong, Amini Behrang, Kenneth Hess, Filip Janku, Sarina Piha-Paul, Aung Naing, Siqing Fu, Robert Benjamin, Shreyaskumar Patel, Neeta Somaiah, Anthony Conley, Funda Meric-Bernstam and Vivek Subbiah
Journal for ImmunoTherapy of Cancer 2017, 5:100 (19 December 2017)

From the Authors

"Patients with advanced sarcomas tolerate immunotherapy well. Alveolar soft part sarcomas respond well to PD-L1-based therapy. Minimal activity was seen in other sarcomas and requires further investigation."

Vivek Subbiah, MD — MD Anderson Cancer Center

Improved survival and tumor control with interleukin-2 associated with the development of immune-related adverse events: data from the PROCLAIM (SM) registry

Brendan Curti, Gregory A. Daniels, David F. McDermott, Joseph I. Clark, Howard L. Kaufman, Theodore F. Logan, Jatinder Singh, Meenu Kaur, Theresa L. Luna, Nancy Gregory, Michael A. Morse, Michael K. K. Wong and Janice P. Dutcher
Journal for ImmunoTherapy of Cancer 2017, 5:102 (19 December 2017)

From the Authors

"In a review of the PROCLAIM^SM Registry, 70% of interleukin-2 (IL-2)-related immune-related adverse events (irAEs) were low-grade, primarily vitiligo and thryoid dysfunction. irAEs following IL-2 are associated with improved tumor control and overall survival."

Janice P. Dutcher, MD — Cancer Research Foundation

Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment

Susanne M. Steggerda, Mark K. Bennett, Jason Chen, Ethan Emberley, Tony Huang, Julie R. Janes, Weiqun Li, Andrew L. MacKinnon, Amani Makkouk, Gisele Marguier, Peter J. Murray, Silinda Neou, Alison Pan, Francesco Parlati, Mirna L. M. Rodriguez, Lee-Ann Van de Velde, Tracy Wang, Melissa Works, Jing Zhang, Winter Zhang and Matthew I. Gross
Journal for ImmunoTherapy of Cancer 2017, 5:101 (19 December 2017)

From the Authors

"In the tumor microenvironment, metabolism of L-arginine by the enzyme arginase has been hypothesized to contribute to myeloid cell-mediated immune evasion by dampening the T cell response. In our report, we use CB-1158, a novel orally-bioavailable small molecule inhibitor of arginase activity, to demonstrate that arginase is a key mediator of tumor immune suppression and that inhibiting arginase shifts the tumor immune landscape toward a pro-inflammatory environment and reduces tumor growth."

Susanne M. Steggerda, PhD — Calithera Biosciences

Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial

Robert J. Canter, Steven K. Grossenbacher, Jennifer A. Foltz, Ian R. Sturgill, Jiwon S. Park, Jesus I. Luna, Michael S. Kent, William T. N. Culp, Mingyi Chen, Jaime F. Modiano, Arta M. Monjazeb, Dean A. Lee and William J. Murphy
Journal for ImmunoTherapy of Cancer 2017, 5:98 (19 December 2017)

From the Authors

"Using pre-clinical models and a first-in-dog clinical trial of dogs with spontaneous osteosarcomas, we show that radiation therapy increases the trafficking and cytotoxicity of natural killer cells to sarcomas, and we show evidence of both local and distant anti-tumor effects. Since dogs are outbred animals that develop spontaneous cancers in the setting of an intact immune system, these studies underscore the complex immune interactions which occur during radio-immunotherapy and provide preliminary data on efficacy and toxicity. Dog sarcomas appear to be a valuable model to speed the clinical translation of NK radio-immunotherapy."

Robert J. Canter, MD, MAS, FACS — University of California Davis Health System

November Highly Accessed Articles

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)

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)

In Case You Missed It: SITC 2017 Abstracts Available

32^nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017)

National Harbor, MD, USA, 8-12 November 2017

32^nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017): late breaking abstracts

National Harbor, MD, USA, 8-12 November 2017