JITC Digest February 2018

Inside this Issue:

Letter from the Editor

Dear JITC Readers:

Over the last month, the Journal for ImmunoTherapy of Cancer (JITC) is pleased to have published eight new, peer-reviewed manuscripts. In 2017 alone, nearly 200 reviewers volunteered their time to provide insightful comments, which was essential to the successful publication of a range of excellent manuscripts in JITC. Please join me in thanking our committed reviewers for their rigor and dedication. JITC would not be thriving as it is today without them.

Featured in this month’s Basic Tumor Immunology section, Grace Mahlbacher et al. report on a novel bio-mathematical modeling framework in the article, “Mathematical modeling of tumor-associated macrophage interactions with the cancer microenvironment.” In this study, Mahlbacher’s group develops a computational model of a metastatic lesion in a highly vascularized organ to investigate the role of three tumor-associated macrophage subtypes that are implicated in promoting or inhibiting tumor growth. Their modeling exercise suggests that Tie2-expressing macrophages (TEM) become the majority cell type but the presence of M2 cells still enhanced tumor growth. Such new mathematical models, like the one put forward in this article, should help to develop innovative frameworks of thinking for deepening our understanding of the tumor microenvironments and assist drug development and predictive biomarkers for therapy in the future.

Despite FDA approval of anti-PD1 nivolumab for treatment of patients with metastatic renal cell carcinoma, very little is known about its clinical efficacy in treating non-clear cell disease subtypes. In this month’s clinical/translational cancer immunotherapy section, Vadim Koshkin et al. in “Clinical activity of nivolumab in patients with non-clear cell renal cell carcinoma” conducted a retrospective analysis of 35 evaluable patients with metastatic, non-clear cell renal cell carcinoma who had been treated with nivolumab. Researchers noted promising results with nivolumab monotherapy in this population showing median progression-free survival of 3.5 months (95% CI: 1.9 - 5.0 months), a ten-month overall survival of 68%, and that median overall survival was not reached. The measured objective response rate was 20%, with all seven patients having a partial response. Ten additional patients (29%) achieved stable disease. Treatment-related adverse events were observed in 37% of patients. Together, these data suggest that anti-PD-1 blockade may be both effective and well-tolerated in patients with metastatic, non-clear cell renal cell carcinoma.

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

Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond

Jason Zhu, Andrew J. Armstrong, Terence W. Friedlander, Won Kim, Sumanta K. Pal, Daniel J. George and Tian Zhang
Journal for ImmunoTherapy of Cancer 2017, 6:4 (25 January 2018)

Review
From the Authors

"Immunotherapy has changed the treatment landscape in urothelial and renal cell carcinomas, but predictive biomarkers remain elusive for detecting treatment sensitivity and resistance. We review the data for PD-L1, tumor mutational burden, and other biomarker platforms for PD-1-targeting therapies in urothelial and renal cell carcinoma."

Tian Zhang, MD — Duke Cancer Institute

Change in neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma

Aly-Khan A. Lalani, Wanling Xie, Dylan J. Martini, John A. Steinharter, Craig K. Norton, Katherine M. Krajewski, Audrey Duquette, Dominick Bossé, Joaquim Bellmunt, Eliezer M. Van Allen, Bradley A. McGregor, Chad J. Creighton, Lauren C. Harshman and Toni K. Choueiri
Journal for ImmunoTherapy of Cancer 2017, 6:5 (22 January 2018)

Research Article
From the Authors

"An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several cancers, but its role with contemporary immune checkpoint blockade is unknown. We found that early decline in NLR was a strong predictor of response rate, PFS and OS. The prognostic value of the readily-available NLR warrants larger, prospective validation."

Toni K. Choueiri, MD — Dana-Farber Cancer Institute

Incorporating Radiation Oncology into Immunotherapy: proceedings from the ASTRO-SITC-NCI immunotherapy workshop

Ariel E. Marciscano, Joshua M. Walker, Heather M. McGee, Michelle M. Kim, Charles A. Kunos, Arta M. Monjazeb, Stephen L. Shiao, Phuoc T. Tran and Mansoor M. Ahmed
Journal for ImmunoTherapy of Cancer 2017, 6:6 (29 January 2018)

Meeting Report
From the Authors

"Combining radiotherapy and immunotherapy is an increasingly attractive approach for cancer patients. Despite growing clinical investigation in this arena, the underlying mechanisms of synergy and the optimal way to promote immunogenicity remain largely undefined. To help bridge these gaps, ASTRO, SITC and the NCI co-sponsored a workshop entitled 'Incorporating Radiation Oncology into Immunotherapy' to provide a platform for experts and stakeholders to foster collaboration and disseminate knowledge in order to advance the field of radio-immuno-oncology."

Ariel E. Marciscano, MD — National Cancer Institute

Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial

Howard L. Kaufman, Jeffery S. Russell, Omid Hamid, Shailender Bhatia, Patrick Terheyden, Sandra P. D’Angelo, Kent C. Shih, Céleste Lebbé, Michele Milella, Isaac Brownell, Karl D. Lewis, Jochen H. Lorch, Anja von Heydebreck, Meliessa Hennessy and Paul Nghiem
Journal for ImmunoTherapy of Cancer 2017, 6:7 (19 January 2018)

Short Report
From the Authors

"Avelumab is the first drug approved for the treatment of metastatic Merkel cell carcinoma based on a single arm clinical trial which reported a response rate of 31.8% in patients who had failed prior chemotherapy. We now report further follow-up of these patients at 16 months and found a slightly higher response rate of 33% with two patients achieving a compete response with longer follow-up, and over 72% of responding patients remain in response. These data help support the durable clinical benefit of avelumab in patients with metastatic Merkel cell carcinoma and provide additional validation for the FDA breakthrough designation program designed to bring earlier access to life-saving drugs for patients with rare and aggressive cancers, such as Merkel cell carcinoma."

Howard L. Kaufman, MD, FACS — Replimune Group, Inc.

Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

Jun Gong, Alexander Chehrazi-Raffle, Srikanth Reddi and Ravi Salgia
Journal for ImmunoTherapy of Cancer 2017, 6:8 (23 January 2018)

Review
From the Authors

"This is a state-of-the-art review summarizing the clinical development of PD-1 and PD-L1 inhibitors in cancer therapy, and especially the registration trials that have led to FDA-approval. As we look to the future, we also discuss predictive biomarkers, mechanisms of resistance, hyperprogressors, treatment benefits and toxicities, and other concepts related to immunotherapy."

Ravi Salgia, MD — City of Hope

Clinical activity of nivolumab in patients with non-clear cell renal cell carcinoma

Vadim S. Koshkin, Pedro C. Barata, Tian Zhang, Daniel J. George, Michael B. Atkins, William J. Kelly, Nicholas J. Vogelzang, Sumanta K. Pal, JoAnn Hsu, Leonard J. Appleman, Moshe C. Ornstein, Timothy Gilligan, Petros Grivas, Jorge A. Garcia and Brian I. Rini
Journal for ImmunoTherapy of Cancer 2017, 6:9 (29 January 2018)

Research Article
From the Authors

"These data support that nivolumab has activity in non-clear cell RCC. These histologic subtypes are not well-characterized biologically and desperately in need of new therapy. While prospective trials are ongoing, these data provide support for the use of nivolumab in this population."

Brian I. Rini, MD — Cleveland Clinic Taussig Cancer Center

Mathematical modeling of tumor-associated macrophage interactions with the cancer microenvironment

Grace Mahlbacher, Louis T. Curtis, John Lowengrub and Hermann B. Frieboes
Journal for ImmunoTherapy of Cancer 2017, 6:10 (30 January 2018)

Research Article
From the Authors

"This study develops a modeling framework to evaluate macrophage interactions with the tumor microenvironment, enabling assessment of how these interactions may affect tumor progression. The results suggest that influencing monocyte differentiation into various macrophage types by taking into account the tumor state may help to leverage the various macrophage interactions to impede rather than promote the tumor progression."

Hermann B. Frieboes, PhD — University of Louisville

Inflammatory demyelinating polyneuropathy versus leptomeningeal disease following Ipilimumab

Lorraine Cafuir, David Lawson, Nilesh Desai, Vita Kesner and Alfredo Voloschin
Journal for ImmunoTherapy of Cancer 2017, 6:11 (30 January 2018)

Case Report
From the Authors

"Leptomeningeal carcinomatosis and inflammatory demyelinating polyneuropathy may have similar clinical presentation, thus making diagnosis difficult. In this case report, we present a patient who developed inflammatory demyelinating polyneuropathy while taking ipilimumab, initially thought to be leptomeningeal carcinomatosis, and highlight important diagnostic features to consider when differentiating these two clinical entities."

Lorraine Cafuir, MD — Emory University

January Highly Accessed Articles

Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

Jun Gong, Alexander Chehrazi-Raffle, Srikanth Reddi and Ravi Salgia
Journal for ImmunoTherapy of Cancer, 6:8 (23 January 2018)

Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond

Jason Zhu, Andrew J. Armstrong, Terence W. Friedlander, Won Kim, Sumanta K. Pal, Daniel J. George and Tian Zhang
Journal for ImmunoTherapy of Cancer, 6:4 (25 January 2018)