JITC Digest April 2017


Inside this Issue:

Letter from the Editor

pedro-romero_1__1_.jpgDear JITC Readers:

This month’s issue of the Journal for ImmunoTherapy of Cancer (JITC) features a variety of topics, including three that I wish to highlight in this April Digest: defining the value of cancer immunotherapy, the new Foundation for the Accreditation of Cellular Therapy (FACT) Standard for Immune Effector Cell (IEC) Administration, and the combination of imatinib and ipilimumab in a phase I clinical trial in patients with advanced malignancies.

As health care costs continue to rise, there has been intense interest in better defining the value of current strategies for the treatment of cancer. Cancer immunotherapy has emerged as a clinically beneficial alternative to conventional therapies for many types of cancer. However, to date most value assessments in oncology have not focused on the unique aspects of tumor immunotherapy, resulting in uncertainty about their real value. “The Value of Cancer Immunotherapy Summit at the 2016 Society for Immunotherapy of Cancer 31st Anniversary Annual Meeting” article by Kaufman et al. reports on SITC’s Value of Cancer Immunotherapy Summit, a collaboration with the American Society of Clinical Oncology (ASCO) that brought together a diverse group of stakeholders to discuss the var ious parameters that may define the value of cancer immunotherapy. This report presents a multidisciplinary approach to defining the value of cancer immunotherapy for patients with cancer.

SITC has been a key collaborator in the development of FACT’s new Standards for Immune Effector Cell Administration, with Marcela Maus, MD, PhD serving as SITC’s official liaison to the FACT CAR-T Cell Task Force. “The why, what, and how of the new FACT standards for immune effector cells” by Maus and Nikiforow is a timely piece that discusses why these standards – which include gene-modified T and NK cells – were developed, the clinical and quality infrastructure needed to facilitate safe administration of immune effector cells and formalize monitoring and reporting of patient outcomes, and how a clinical team could implement the standards. With program accreditation beginning in 2017, this commentary provides a great introduction to the standards as they apply to institutions and clinical service lines seeking access to these treatments.

Also in this issue, Reilley et al. share data from a phase I trial of the combination of imatinib and ipilimumab in multiple advanced tumor types in an article entitled “Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies”. The primary objective of the trial – to establish the maximum tolerated dose (MTD) of this combination – was achieved. Accordingly, the authors recommend ipilimumab 3mg/kg every 3 weeks and imatinib 400mg twice daily for phase II testing. Secondary objectives, including evaluation of antitumor activity based on KIT mutation status and the capacity of tumor-associated immune biomarkers to predict response, were also examined. Combining these findings with the results of an ongoing expansion cohort will provide additional evidence as to whether to pursue this combination in KIT-mutated melanoma.

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

Case Report

Response after treatment with pembrolizumab in a patient with myelophthisis due to melanoma: the role of checkpoint inhibition in the bone

Samuel Rosner, Filiz Sen and Michael Postow
Journal for ImmunoTherapy of Cancer 2017, 5:34 (18 April 2017)

From the Authors

"This is the first report demonstrating the ability of a PD-1 immune checkpoint inhibitor to dramatically help a patient with extensive bone marrow involvement from metastatic melanoma."

Michael Postow, MD — Memorial Sloan Kettering Cancer Center

Long-term complete remission with ipilimumab in metastatic castrate-resistant prostate cancer: case report of two patients

Luc Cabel, Elika Loir, Gwenaelle Gravis, Pernelle Lavaud, Christophe Massard, Laurence Albiges, Giulia Baciarello, Yohann Loriot and Karim Fizazi
Journal for ImmunoTherapy of Cancer 2017, 5:31 (18 April 2017)

From the Authors

"In metastatic castrate-resistant prostate cancer, ipilimumab, an anti-CTLA-4 antibody, improved progression-free survival, but did not statistically improve overall survival in two large trials. However, we report on two patients who received ipilimumab in these trials and are still in long-term complete remission with a follow-up of 64 and 52 months, respectively, after the initiation of ipilimumab, which warrants further investigation on biomarkers."

Luc Cabel, MD — Institut Gustave Roussy


The why, what, and how of the new FACT standards for immune effector cells

Marcela V. Maus and Sarah Nikiforow
Journal for ImmunoTherapy of Cancer 2017, 5:36 (18 April 2017)

From the Authors

"Cellular therapies including T cells modified with chimeric antigen receptors (CAR-T) are poised to become approved treatments for certain leukemias and lymphomas. The Foundation for the Accreditation of Cellular Therapies, or FACT, has published standards related to the administration of these new therapies. We discuss the rationale and process for the new standards."

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

Meeting Report

The Value of Cancer Immunotherapy Summit at the 2016 Society for Immunotherapy of Cancer 31st Anniversary Annual Meeting

Howard L. Kaufman, Michael B. Atkins, Adam P. Dicker, Heather S. Jim, Louis P. Garrison, Roy S. Herbst, William T. McGivney, Steven Silverstein, Jon M. Wigginton and Peter P. Yu
Journal for ImmunoTherapy of Cancer 2017, 5:38 (18 April 2017)

From the Authors

"The advances in cancer immunotherapy have provided patients with an important new treatment option. Progress, however, can be hampered if patients are unable to access new drugs or healthcare providers cannot afford to provide these agents. SITC has taken a bold step forward to define the real value of immunotherapy by bringing together academic, patient, industry and economic experts to discuss perspectives on immunotherapy value from the key stakeholders. The insights from the SITC Summit provide new insights into the complexities of value determinations and provide a path forward for ensuring that immunotherapy value is clearly defined and calculated at this critical juncture in American medicine."

Howard L. Kaufman, MD, FACS — Rutgers Cancer Institute of New Jersey

Research Article

Differential phenotypes of memory CD4 and CD8 T cells in the spleen and peripheral tissues following immunostimulatory therapy

Gail D. Sckisel, Annie Mirsoian, Christine M. Minnar, Marka Crittenden, Brendan Curti, Jane Q. Chen, Bruce R. Blazar, Alexander D. Borowsky, Arta M. Monjazeb and William J. Murphy
Journal for ImmunoTherapy of Cancer 2017, 5:33 (18 April 2017)

From the Authors

"In preclinical mouse models, the spleen is commonly used as a cell source to provide representative immune phenotypic profiles mirroring human peripheral blood lymphocyte assessments. We show that following immunotherapy, there are significant differences between CD4+ and CD8+ T cells with regard to expansion and PD-1 expression in spleen and lymphoid organs compared to peripheral tissues in mice, or peripheral blood in humans, indicating that the location of the cell populations studied may markedly impact interpretation of immune effects occurring."

William J. Murphy, PhD — University of California, Davis

Nano-Pulse Stimulation is a physical modality that can trigger immunogenic tumor cell death

Richard Nuccitelli, Amanda McDaniel, Snjezana Anand, John Cha, Zachary Mallon, Jon Casey Berridge and Darrin Uecker
Journal for ImmunoTherapy of Cancer 2017, 5:32 (18 April 2017)

From the Authors

"There is a new type of tumor therapy using electric pulses called Nano-Pulse Stimulation (NPS). NPS is a non-thermal and drug-free modality that initiates immunogenic cell death (ICD) in treated tumors. ICD presents tumor antigens to the immune system to generate a systemic adaptive immune response to the treated tumor. The adaptive immune response prevents secondary tumor growth and may inhibit metastasis."

Richard Nuccitelli, MS, PhD — Pulse Biosciences Inc.

Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies

Matthew J. Reilley, Ann Bailey, Vivek Subbiah, Filip Janku, Aung Naing, Gerald Falchook, Daniel Karp, Sarina Piha-Paul, Apostolia Tsimberidou, Siqing Fu, JoAnn Lim, Stacie Bean, Allison Bass, Sandra Montez, Luis Vence, Padmanee Sharma, James Allison, Funda Meric-Bernstam and David S. Hong
Journal for ImmunoTherapy of Cancer 2017, 5:35 (18 April 2017)

From the Authors

"This trial is one of the first clinical trials in oncology to combine an immunotherapy agent with a targeted drug. While a clear signal for synergy was not observed, we believe our findings may inform future trials that seek to combine TKIs and checkpoint blockade."

Matthew Reilley, MD — Division of Cancer Medicine, MD Anderson Cancer Center

Vaccination with inhibin-α provides effective immunotherapy against testicular stromal cell tumors

Robert Aguilar, Justin M. Johnson, Patrick Barrett and Vincent K. Tuohy
Journal for ImmunoTherapy of Cancer 2017, 5:37 (18 April 2017)

From the Authors

"Although germ-line testicular tumors respond quite favorably to chemotherapy and radiation therapy, testicular stromal cell (TSC) tumors derived from Sertoli cells or Leydig cells are often unresponsive to such conventional treatments, resulting in a relatively poor prognosis for patients with these tumors. We found that inhibin-α protein is expressed in the majority of human TSC tumors and that inhibin-α vaccination provides significantly enhanced overall survival of mice with growing TSC tumors. Thus, our study provides a rational basis for immune-mediated treatment and control of these aggressive and lethal variants of testicular cancer."

Vincent K. Tuohy, PhD — Cleveland Clinic

Differential intratumoral distributions of CD8 and CD163 immune cells as prognostic biomarkers in breast cancer

Sotirios P. Fortis, Michael Sofopoulos, Nectaria N. Sotiriadou, Christoforos Haritos, Christoforos K. Vaxevanis, Eleftheria A. Anastasopoulou, Nicole Janssen, Niki Arnogiannaki, Alexandros Ardavanis, Graham Pawelec, Sonia A. Perez and Constantin N. Baxevanis
Journal for ImmunoTherapy of Cancer 2017, 5:39 (18 April 2017)

From the Authors

"It has become established that tumor immune cell infiltrates are essential in controlling cancer progression and may complement the TNM classification. CD8+ and CD163+ cells have prognostic impact in breast cancer but their spatial heterogeneity has not been extensively explored in this type of cancer. The present study is the first to reveal that differential densities of the same immune cell subpopulation(s), namely CD8+ and CD163+, infiltrating the primary tumor at the tumor center and the invasive margin may have opposing prognostic impacts in breast cancer. The combined evaluation of CD8+ and CD163+ cell densities jointly in TC and IM further improves prediction of clinical outcomes based on disease-free and overall survival."

Sonia A. Perez, PhD — Cancer Immunology and Immunotherapy Center, St. Savas Cancer Hospital

A systems biology approach to investigating the influence of exercise and fitness on the composition of leukocytes in peripheral blood

Michael P. Gustafson, Ara Celi DiCostanzo, Courtney M. Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A. Gastineau, Bruce D. Johnson and Allan B. Dietz
Journal for ImmunoTherapy of Cancer 2017, 5:30 (18 April 2017)

From the Author(s)

"This work reflects our intent to design a well-controlled study to investigate the effects of acute exercise and physical fitness on immune cell populations. Since exercise-induced leukocytosis is a well-established phenomenon, we wanted to assess changes in populations in relation to each other and examine how the peripheral blood immune system changes as a whole, while additionally measuring phenotypes that negatively impact anti-tumor immune responses. Being able to accurately measure immune cell mobilization may put a quantitative tool in the hand of researchers allowing them to tailor exercise regimens to improve responses in cancer patients receiving immunotherapy."

Michael P. Gustafson, PhD — Mayo Clinic

March Highly Accessed Articles


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)


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)