JITC Digest August 2018

Letter from the Editor

Dear JITC Readers,

In the August edition of the JITC Digest, there are four articles of note in the Clinical/Translational Cancer Immunotherapy section of which I wish to draw special attention. First, “The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC),” by Julie R. Brahmer et al. provides evidence-based recommendations to help clinicians integrate immunotherapy into the treatment plan for patients with NSCLC. With three immune checkpoint inhibitors now approved for use in first- and second-line NSCLC, immuno-oncology (IO) is dramatically altering the treatment landscape for patients whose tumors lack targetable mutations. Thus, clinical guidance provided in this piece is needed regarding the use of IO agents, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing.

In the article, “Isolation of T cell receptors targeting recurrent neoantigens in hematological malignancies,” Vanessa M. Tubb et al. explore the genetic engineering of patient T cells with tumor-specific T cell receptors (TCRs), known as TCR gene therapy. Specifically, Dr. Tubb’s team investigated whether mutations found recurrently in hematological malignancies encode immunogenic neoantigens presented by common European Caucasoid HLA class I alleles. Their results illustrate the complexities and potential pitfalls in this, now popular, undertaking.

Next, the article, “Tumor matrix remodeling and novel immunotherapies: the promise of matrix-derived immune biomarkers,” by Muhammad Umair Mushtaq et al. addresses the urgent need to discover novel IO biomarkers beyond PD-L1, tumor mutational burden and tumor-infiltrating lymphocytes in order to develop superior combination strategies and better predict treatment efficacy. This article provides a detailed and potentially useful review of extracellular matrix-derived components with potential for IO biomarker development by virtue of their participation in the immunomodulatory events taking place in the tumor microenvironment.

Andrew Hantel et al.’s article, “Severe hemophagocytic lymphohistiocytosis in a melanoma patient treated with ipilimumab + nivolumab,” presents a case study reporting on the rare, but very serious immune-related adverse event (irAE), Hemophagocytic Lymphohistiocytosis (HLH). Interestingly, Masood Sadaat and Sekwon Jang also reported on this under-recognized irAE and presented similar findings in their article, “Hemophagocytic lymphohistiocytosis with immunotherapy: brief review and case report” in a previous issue of JITC. Hantel’s study underlines the importance of vigilant monitoring for immune-activating side effects due to checkpoint inhibitor therapy.

Finally, please take a moment to remember and honor Henry “Hank” Porterfield, a man who changed the lives of many patients and families facing the prognosis and treatment of prostate cancer. Beyond representing patients as an advocate author in the JITC publication, “The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma”, Mr. Porterfield was the founding member and Chair of Us Too International and the Alliance for Prostate Cancer Prevention (APCaP).

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

Recent Articles

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, 6:64 (2 July 2018)
Research Article

From the Authors

"Metformin has demonstrated potential antitumor properties in various pre-clinical and retrospective clinical studies. Metformin is also known to potentiate the PD-1 blockade by anti-PD-1 monoclonal antibodies, as metformin might increases the PD-1 expression. In this retrospective study with melanoma patients, we observed potential benefits of metformin in combination with immune checkpoint inhibitors. However, large prospective studies are needed.’"

Keisuke Shirai, MD — Dartmouth-Hitchcock Medical Center

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, 6:65 (3 July 2018)
Review

From the Authors

"Tumor cells and immune cells do not interact in vacuo but are encased within a highly ‘intelligent’ tumor matrix structure. The tumor matrix undergoes continuous laying down and proteolytic remodeling in a highly regulated fashion. These processes generate bioactive fragments (“matrikines”) that control the numbers and polarization of tumor-infiltrating immune cells. For example, matrix remodeling products appear to influence the abundance of immunogenic dendritic cells within the tumor bed, thus determining the likelihood of productive anti-tumor immune responses. We propose that the tumor matrix constitutes a treasure trove for novel immune biomarkers to help gauge the immunogenicity of a tumor microenvironment and predict the likelihood of response to immunotherapy."

Fotis Asimakopoulos, MB, BChir, PhD – University of Wisconsin School of Medicine and Public Health

Complete response to ipilimumab and nivolumab therapy in a patient with extensive extrapulmonary high-grade small cell carcinoma of the pancreas and HIV infection

Muhammad Husnain, Wungki Park, Juan Carlos Ramos, Thomas E. Johnson, Joseph Chan, Arvind Dasari, Raja Mudad and Peter J. Hosein
Journal for ImmunoTherapy of Cancer, 6:66 (9 July 2018)
Case Report

From the Authors

"This case highlights a patient with HIV infection with an advanced cancer who was rapidly deteriorating and had run out of standard options for therapy. Based on the encouraging results using dual checkpoint inhibitor blockade in small cell lung cancer, we felt that this would be a good option for him. Not only did he achieve a complete response to therapy, but his HIV infection was not adversely affected with this therapy. He continues to be in complete remission one year after initiation of this therapy."

Peter J. Hosein, MD – University of Miami Miller School of Medicine

A team effort: natural killer cells on the first leg of the tumor immunity relay race

Timothy B. Fessenden, Ellen Duong and Stefani Spranger
Journal for ImmunoTherapy of Cancer, 6:67 (9 July 2018)
Commentary

From the Authors

"Elucidating the interplay between tumor-resident immune cells will be instrumental to understand the hallmarks of anti-tumor immune responses. The manuscript by Boettcher et al. discussed here is an excellent example for a study addressing immune cell crosstalk within the tumor microenvironment."

Stefani Spranger, PhD – Koch Institute for Integrative Cancer Research at MIT

Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma

Priyanka C. Iyer, Ramona Dadu, Maria Gule-Monroe, Naifa L. Busaidy, Renata Ferrarotto, Mouhammed Amir Habra, Mark Zafereo, Michelle D. Williams, G. Brandon Gunn, Horiana Grosu, Heath D. Skinner, Erich M. Sturgis, Neil Gross and Maria E. Cabanillas
Journal for ImmunoTherapy of Cancer, 6:68 (11 July 2018)
Research Article

From the Authors

"Immunotherapy has shown remarkably favorable responses in improving survival in several cancers. Anaplastic thyroid cancer (ATC) is one of the deadliest forms of thyroid cancer which can be rapidly fatal if left untreated. While newer targeted therapies have shown promise in BRAF mutated ATC leading to approval by the FDA, resistance to kinase inhibitors eventually develop. Single agent immunotherapy with anti-PD1 have shown disappointing results similar to traditional systemic chemotherapy in this aggressive cancer. We present our experience of adding pembrolizumab, an anti-PD1 immunotherapy, at the first sign of progression in ATC patients who are being treated with kinase inhibitors. Combining targeted therapies with immunotherapy in the front-line setting bears promise in the treatment of ATC and is being prospectively explored in clinical trials."

Maria E. Cabanillas, MD – University of Texas MD Anderson Cancer Center

Perspectives in immunotherapy: meeting report from the Immunotherapy Bridge (29-30 November, 2017, Naples, Italy)

Paolo A. Ascierto, James Brugarolas, Luigi Buonaguro, Lisa H. Butterfield, David Carbone, Bruno Daniele, Robert Ferris, Bernard A. Fox, Jérôme Galon, Cesare Gridelli, Howard L. Kaufman, Christopher A. Klebanoff, Ignacio Melero, Paul Nathan, Chrystal M. Paulos, Marco Ruella, Ryan Sullivan, Hassane Zarour and Igor Puzanov
Journal for ImmunoTherapy of Cancer, 6:69 (11 July 2018)
Review

From the Authors

"This is a report from the third “Immunotherapy Bridge” meeting held in Naples on 29-30th November 2017. In this report are described the most important advances in the field of immunotherapies both in traslational and clinical research, with a focus on lung cancer, renal cell cancer, hepatocellular carcinoma, head and neck cancer, and haematological malignancies."

Paolo Antonio Ascierto, MD – Istituto Nazionale Tumori-Fondazione 'G. Pascale'

Isolation of T cell receptors targeting recurrent neoantigens in hematological malignancies

Vanessa M. Tubb, Deborah S. Schrikkema, Nathan P. Croft, Anthony W. Purcell, Carsten Linnemann, Manon R. Freriks, Frederick Chen, Heather M. Long, Steven P. Lee and Gavin M. Bendle
Journal for ImmunoTherapy of Cancer, 6:70 (13 July 2018)
Research Article

From the Authors

"Recognition of neoantigens by the endogenous T cell repertoire has been shown to contribute to the therapeutic efficacy of cancer immunotherapy, therefore neoantigens represent an important class of tumour-specific antigens which can be targeted by T cell receptors (TCRs). Although the majority of neoantigens are patient-specific, we investigate whether mutations found recurrently in hematological malignancies, including mutations in CALR and FBXW7, encode immunogenic neoantigens presented by common European Caucasoid HLA class I alleles, and represent potential targets for neoantigen-specific TCR gene therapy that is more widely applicable."

Vanessa M. Tubb, PhD – University of Birmingham

CART cells are prone to Fas- and DR5-mediated cell death

Benjamin O. Tschumi, Nina Dumauthioz, Bastien Marti, Lianjun Zhang, Pascal Schneider, Jean-Pierre Mach, Pedro Romero and Alena Donda
Journal for ImmunoTherapy of Cancer, 6:71 (13 July 2018)
Short Report

From the Authors

"Our study demonstrates that CART cells are prone to Programed Cell Death, which correlates with the progressive up-regulation of Fas/FasL and TRAIL-R2/TRAIL. CART cell death is potentiated upon CAR or TCR activation, but also occurs in homeostatic conditions. The susceptibility of CART cells to apoptosis does not challenge their immediate antitumor efficacy, but limits the long-term tumor control. The possible mechanisms as well as the alternatives to prevent CART cell apoptosis are discussed."

Alenda Donda, PhD – University of Lausanne

Severe hemophagocytic lymphohistiocytosis in a melanoma patient treated with ipilimumab + nivolumab

Andrew Hantel, Brooke Gabster, Jason X. Cheng, Harvey Golomb and Thomas F. Gajewski
Journal for ImmunoTherapy of Cancer, 6:73 (16 July 2018)
Short Report

From the Authors

"Hematologic immune-related adverse events are less common with checkpoint blockade immunotherapy, but important to recognize as they can be life-threatening. We report on a case of severe HLH, which was identified during evaluation of severe anemia after ipilimumab/nivolumab therapy that paradoxically showed vigorous hemolysis but also a low reticulocyte count. Bone marrow biopsy confirmed HLH, and the patient was successfully treated with high-dose steroids. Early diagnosis and treatment was key for this patient, and since she had a complete response of her melanoma, the case should highlight the need for vigilance by treatment oncologists to ensure optimal patient outcomes with checkpoint blockade."

Thomas F. Gajewski, MD, PhD – University of Chicago

Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab

Mariaelena Capone, Diana Giannarelli, Domenico Mallardo, Gabriele Madonna, Lucia Festino, Antonio Maria Grimaldi, Vito Vanella, Ester Simeone, Miriam Paone, Giuseppe Palmieri, Ernesta Cavalcanti, Corrado Caracò and Paolo Antonio Ascierto
Journal for ImmunoTherapy of Cancer, 6:74 (16 July 2018)
Research Article

From the Authors

"Elevated neutrophil-to-lymphocyte ratio (NLR) is prognostic for worse outcomes in patients treated with immune checkpoint. In this single Institution retrospective analysis of 97 consecutive patients with stage IV melanoma treated with nivolumab, increasing baseline absolute neutrophil count (ANC), NLR, derived (d) NLR and lactate dehydrogenase (LDH) were all significantly associated with OS at univariate analysis. However, only NLR and LDH maintained a significant association with OS in multivariate analysis. NLR and dNLR are simple and inexpensive biomarkers that could be used to predict response to checkpoint inhibitors. Such biomarkers should be evaluated and validated in perspective studies."

Paolo Antonio Ascierto, MD – Istituto Nazionale Tumori-Fondazione 'G. Pascale'

Sick sinus syndrome associated with anti-programmed cell death-1

Chien-Yi Hsu, Yu-Wen Su and San-Chi Chen
Journal for ImmunoTherapy of Cancer, 6:72 (16 July 2018)
Case Report

From the Authors

"Immune-related cardiotoxicity has recently become a focus of attention, including myocarditis, cardiomyopathy, cardiac fibrosis, heart block and cardiac arrest. The article “Sick sinus syndrome associated with anti-programmed cell death-1” by Hsu et al. reported a case of sick sinus syndrome, a rare cardiotoxicity induced by anti-PD-1. A 42-year-old male with metastatic hepatocellular carcinoma who presented with progressive sick sinus syndrome with a lowest heart rate of 38 bpm after six cycles of pembrolizumab. Simultaneously, he also presented with adrenal insufficiency with low cortisol and ACTH levels. Low-dose cortisone was prescribed, and the patient’s symptoms were rapidly improved. From this case, we learned that sick sinus syndrome may be a presentation of immune- or adrenal insufficiency-mediated sinus node dysfunction, both could be reversed with a glucocorticoid supplement."

San-Chi Chen – National Yang-Ming University

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, 6:75 (17 July 2018)
Position Article and Guidelines

From the Authors

"Recent developments in new therapies for lung cancer—targeted therapies, immunotherapies—are historic advances. As exciting as these are, it’s important to note that they’re not benefitting all patients with lung cancer, and resistance is often a setback for many patients. We have to continually raise the bar with new therapies. Change is so rapid—as it must be—that guidelines for treatment must be continually updated. SITC has developed guidance that will greatly benefit physicians in the communities where most cancer patients are cared for. I urge all oncologists to review the new guidelines for use in their practices."

Roy S. Herbst, MD, PhD – Yale Cancer Center

A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma

Joseph I. Clark, Jatinder Singh, Marc S. Ernstoff, Christopher D. Lao, Lawrence E. Flaherty, Theodore F. Logan, Brendan Curti, Sanjiv S. Agarwala, Bret Taback, Lee Cranmer, Jose Lutzky, Theresa L. Luna, Sandra Aung and David H. Lawson
Journal for ImmunoTherapy of Cancer, 6:76 (27 July 2018)
Research Article

From the Authors

"Combination high dose interleukin-2, (HD IL-2), with vemurafenib in BRAF-mutated metastatic melanoma patients was feasible, without excess toxicity, but efficacy outcomes were similar to what would be expected with HD IL-2 alone. This study supports the concept regarding the safety of combining immunotherapeutic agents with targeted therapy in the treatment of advanced melanoma, which is an attractive approach based on preclinical and early clinical data."

Joseph I. Clark, MD – Loyola University Medical Center

Delayed onset of neurosarcoidosis after concurrent ipilimumab/nivolumab therapy

Irena Tan, Michael Malinzak and April K. S. Salama
Journal for ImmunoTherapy of Cancer, 6:77 (31 July 2018)
Case Report

From the Authors

"We describe the first reported case of presumed neurosarcoidosis as an immune-related adverse effect that developed nearly a year after discontinuation of treatment with combination ipilimumab and nivolumab for recurrent metastatic melanoma. This case should raise awareness that serious IRAE may still develop long after the administration of immunotherapy. With expanding indications for immunotherapy in many cancer types, it is more important than ever for patients, oncologists and other care providers to recognize this potential."

Irena Tan, MD – Duke University

Highly Accessed Articles

Pan-cancer adaptive immune resistance as defined by the Tumor Inflammation Signature (TIS): results from The Cancer Genome Atlas (TCGA)

Patrick Danaher, Sarah Warren Rongze Lu, Josue Samayoa, Amy Sullivan, Irena Pekker, Brett Wallden, Francesco M. Marincola and Alessandra Cesano
Journal for ImmunoTherapy of Cancer 2018, 6:63 (22 June 2018)

Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy

Amber J. Giles Marsha-Kay N. D. Hutchinson, Heather M. Sonnemann, Jinkyu Jung, Peter E. Fecci, Nivedita M. Ratnam, Wei Zhang, Hua Song, Rolanda Bailey, Dionne Davis, Caitlin M. Reid, Deric M. Park and Mark R. Gilbert
Journal for ImmunoTherapy of Cancer 2018, 6:51 (11 June 2018)

Immune oncology, immune responsiveness and the theory of everything

Tolga Turan, Deepti Kannan, Maulik Patel, J. Matthew Barnes, Sonia G. Tanlimco, Rongze Lu, Kyle Halliwill, Sarah Kongpachith, Douglas E. Kline, Wouter Hendrickx, Alessandra Cesano, Lisa H. Butterfield, Howard L. Kaufman, Thomas J. Hudson, Davide Bedognetti, Francesco Marincola and Josue Samayoa
Journal for ImmunoTherapy of Cancer 2018, 6:50 (5 June 2018)