JITC Digest September 2018

Letter from the Editor

Dear JITC Readers,

In the September edition of the JITC Digest, there are three key articles in the Clinical/Translational Cancer Immunotherapy section of which I wish to draw special attention. First, “Resident memory T cells, critical components in tumor immunology,” by Fathia Mami-Chouaib et al. explores the anti-tumor potential of tissue-resident memory T (TRM) cells, a highly activated sub-population of memory CD8+T cells residing within non-lymphoid tissues. In this review, Dr. Mami-Chouaib’s team suggests an important role for TRM cells as not only predictive markers of patient survival but also in potentiating the success of immunotherapeutic approaches targeting solid tumors through tumor-specific T cell responses.

Next, the article, “Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity,” by Orneala Bakos et al. addresses the issue of postoperative immunosuppression following first-line surgical resection of solid cancers. This article discusses the prometastatic effect of oncologic surgical stress due to the disruption of immunological pathways and how the perioperative period may provide a window of opportunity to harness the immune system for attenuation of cancer recurrence. Bakos’s review proposes a rationale for the combination of surgery and immunotherapy in the immediate postoperative setting.

Nolan A. Wages et al.’s article, “Design considerations for early-phase clinical trials of immune-oncology agents,” summarizes fundamental statistical challenges in designing early phase immunotherapy-based clinical trials. Specifically, this article provides a detailed review and breakdown of the hurdles experienced in adapting to alternative trial designs including immune-related toxicity management, integration of novel endpoints, and understanding mechanisms of response. Wages’ study recognizes the need to move away from traditional clinical trial strategies centered on testing cytotoxic agents in exchange for innovative models apt at discerning complex patient responses to immunotherapy.

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

Recent Articles

White paper on microbial anti-cancer therapy and prevention

Neil S. Forbes, Robert S. Coffin, Liang Deng, Laura Evgin, Steve Fiering, Matthew Giacalone, Claudia Gravekamp, James L. Gulley, Hal Gunn, Robert M. Hoffman, Balveen Kaur, Ke Liu, Herbert Kim Lyerly, Ariel E. Marciscano, Eddie Moradian, Sheryl Ruppel, Daniel A. Saltzman, Peter J. Tattersall, Steve Thorne, Richard G. Vile, Halle Huihong Zhang, Shibin Zhou and Grant McFadden
Journal for ImmunoTherapy of Cancer, 6:78 (6 August 2018)
Research Article

Excerpt:

"This White Paper is designed to increase the interactions between these growing fields [oncolytic virotherapy and bacterial therapy of microbial oncolytics], and introduce their advances to the wider community of scientists and clinicians working on immunotherapies for cancer. We also describe the state of the field of microbial cancer therapy and point the direction where development and greater synergies with other fields are needed to increase the number of patients and indications that could benefit from this powerful modality."

A possible new pathway in natural killer cell activation also reveals the difficulty in determining human NK cell function in cancer

Robert J. Canter and William J. Murphy
Journal for ImmunoTherapy of Cancer, 6:79 (7 August 2018)
Commentary

About:

"With only a 25% response rate in patients treated with immunotherapy, researchers are looking to further explore the role of natural killer (NK) cells in cancer immunotherapy. Robert J. Canter and William J. Murphy comment on studies highlighting the potential efficacy and hurdles of utilizing NK cells to overcome immune resistance through novel mechanisms in which NK cells are able to seek out and respond to tumors. The authors discuss the strong biological role of NK cells in tumor immunology as well as critical issues which arise during in vivo validation of human NK cell effects observed in vitro due to the differences between mouse and human NK cells."

The age of enlightenment in melanoma immunotherapy

Mark R. Albertini
Journal for ImmunoTherapy of Cancer, 6:80 (22 August 2018)
Commentary

From the Authors

"The February 1, 2018 Journal of Clinical Oncology article "Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study" by Callahan et al reports a 3-year overall survival rate of 63% for 94 patients with previously treated or untreated advanced melanoma who received ipilimumab and nivolumab as concurrent therapy. That accomplishment is a major one in our field and demonstrates the progress made via evidence-based understanding of cause and effect related to the immunotherapy of human melanoma. This commentary provides an historical perspective for the greatly improved overall survival with immunotherapy for metastatic melanoma patients, discusses the transition from the dark ages to the age of enlightenment in melanoma immunotherapy, and provides a roadmap for a better tomorrow for patients with metastatic melanoma."

Mark R. Albertini, MD — University of Wisconsin Carbone Cancer Center

Design considerations for early-phase clinical trials of immune-oncology agents

Nolan A. Wages, Cody Chiuzan and Katherine S. Panageas
Journal for ImmunoTherapy of Cancer, 6:81 (22 August 2018)
Clinical Trials Monitor

From the Authors

"In early-phase clinical trials, the classic assumptions imposed by cytotoxic agents may no longer be applicable to immune-oncology agents, requiring new strategies for dose selection and trial design. The main goal of this article is to summarize and highlight main challenges of early-phase study design of immunotherapies from a statistical perspective. Further advances in the effectiveness of cancer immunotherapies will require new approaches that include redefining the optimal dose to be carried forward in later phases, incorporating additional endpoints in the dose selection process, developing personalized biomarker profiles, or testing drug combination therapies to improve efficacy and reduce toxicity."

Nolan A. Wages, PhD — University of Virginia

Association between pretreatment lymphocyte count and response to PD1 inhibitors in head and neck squamous cell carcinomas

Won Jin Ho, Mark Yarchoan, Alex Hopkins, Ranee Mehra, Stuart Grossman and Hyunseok Kang
Journal for ImmunoTherapy of Cancer, 6:84 (31 August 2018)
Research Article

From the Authors

"In our single-institution retrospective study, baseline lymphopenia was significantly associated with poorer response to PD1 inhibitor therapy in patients with metastatic head and neck cancer. This is particularly important since a substantial proportion of patients with head and neck cancers develop persistent treatment-related lymphopenia while undergoing first-line concurrent chemoradiotherapy. Further work is warranted to confirm the utility of baseline lymphocyte count as a predictive biomarker of checkpoint immunotherapy in a prospective setting."

Hyunseok Kang, MD, MPH — University of California, San Francisco

Neurologic immune-related adverse events associated with adjuvant ipilimumab: report of two cases

Christine A. Garcia, Alex El-Ali, Tanya J. Rath, Lydia C. Contis, Vikram Gorantla, Jan Drappatz and Diwakar Davar
Journal for ImmunoTherapy of Cancer, 6:83 (31 August 2018)
Case Report

About:

"Although PD-1 and CTLA-4 inhibitors are widely known to induce immune-related adverse events (irAEs) in patients, neurologic-specific irAEs are not well characterized. Christine A. Garcia et al. presents a case report detailing two melanoma patients treated with ipilimumab in the adjuvant setting who subsequently developed ipilimumab-related neurologic irAEs. This report highlights the importance of early symptom recognition followed by proper diagnostic evaluation in order to identify unusual neurologic irAEs and promptly initiate immunosuppressive therapy for reversal of neurological effects."

Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report

Jacob Appelbaum, David Wells, Joseph B. Hiatt, Gideon Steinbach, F. Marc Stewart, Hannah Thomas, Paul Nghiem, Raj P. Kapur, John A. Thompson and Shailender Bhatia 
Journal for ImmunoTherapy of Cancer, 6:82 (31 August 2018)
Case Report

Excerpt:

"Immunotherapy with ICIs improves cancer outcomes, but can be associated with varied side effects. In the case above, a single dose of nivolumab plus ipilimumab led to complete eradication of a patient’s widely metastatic MCC [merkel cell carcinoma], but unfortunately was complicated by rapid and irreversible destruction of the patient’s myenteric ganglions that ultimately proved fatal. The case described above illustrates both the promises and pitfalls of the power of immune checkpoint blockade."

Treatment of mycophenolate-resistant immune-related organizing pneumonia with infliximab

Guacimara Ortega Sanchez, Kathleen Jahn, Spasenija Savic, Alfred Zippelius and Heinz Läubli
Journal for ImmunoTherapy of Cancer, 6:85 (3 September 2018)
Case Report

From the Authors

"Immune checkpoint inhibitors lead to pulmonary immune-related adverse events in a minority of treated patients. However, acute and chronic late-onset pneumonitis are severe side effects and algorithms for the initial treatment with corticosteroids have been well established, but the treatment of patients with corticosteroid-refractory or -dependent pneumonitis is less clear. Here, we describe the successful treatment with infliximab of a patient with a chronic late-onset pneumonitis due to PD-1 blockade that was corticosteroid-dependent and mycophenolate-resistant. This case report demonstrates how difficult-to-treat pulmonary patients could be managed and infliximab might be preferable in such situations."

Heinz Läubli, MD, PhD — University Hospital Basel

Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity

Orneala Bakos, Christine Lawson, Samuel Rouleau and Lee-Hwa Tai
Journal for ImmunoTherapy of Cancer, 6:86 (3 September 2018)
Review

From the Authors

"Nearly all patients with solid tumors receive standard-of-care surgical resection of their primary tumor because it represents their best chance for cure. Despite complete resection, many patients recur or develop metastases and ultimately die of disease. Existing and emerging immunotherapies are ideally suited to target minimal residual disease such as in the postoperative period where tumor burden is at its lowest. In this review, we highlight the importance of rationally combining surgery and immunotherapy to reduce postoperative recurrence and metastases."

Lee-Hwa Tai, PhD — Universite de Sherbrooke

Resident memory T cells, critical components in tumor immunology

Fathia Mami-Chouaib, Charlotte Blanc, Stéphanie Corgnac, Sophie Hans, Ines Malenica, Clémence Granier, Isabelle Tihy and Eric Tartour
Journal for ImmunoTherapy of Cancer, 6:87 (4 September 2018)
Review

From the Authors

"This review focuses on the emerging role of resident memory T (TRM) cells in anti-tumor immune responses and their ability to remain permanently in the tumor microenvironment and to specifically recognize and kill malignant cells. TRM cells are enriched with tumor-specific T cells explaining their good prognostic value in cancer patients. The ability to target and expand this T-cell population may be associated with clinical response to immunotherapy."

Fathia Mami-Chouaib, PhD — Inserm

Highly Accessed Articles

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC)

Julie R. Brahmer, Ramaswamy Govindan, Robert A. Anders, Scott J. Antonia, Sarah Sagorsky, Marianne J. Davies, Steven M. Dubinett, Andrea Ferris, Leena Gandhi, Edward B. Garon, Matthew D. Hellmann, Fred R. Hirsch, Shakuntala Malik, Joel W. Neal, Vassiliki A. Papadimitrakopoulou, David L. Rimm, Lawrence H. Schwartz, Boris Sepesi, Beow Yong Yeap, Naiyer A. Rizvi and Roy S. Herbst
Journal for ImmunoTherapy of Cancer 2018, 6:75 (17 July 2018)

Tumor matrix remodeling and novel immunotherapies: the promise of matrix-derived immune biomarkers

Muhammad Umair Mushtaq, Athanasios Papadas, Adam Pagenkopf, Evan Flietner, Zachary Morrow, Sibgha Gull Chaudhary and Fotis Asimakopoulos
Journal for ImmunoTherapy of Cancer 2018, 6:65 (3 July 2018)

Efficacy of metformin in combination with immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) in metastatic malignant melanoma

Muhammad Zubair Afzal, Rima R. Mercado and Keisuke Shirai
Journal for ImmunoTherapy of Cancer 2018, 6:64 (2 July 2018)