JITC Digest May 2019

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Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

In the May edition of the JITC Digest, I would like to call your attention to the following five articles of special interest. First, “Determinant roles of dendritic cell-expressed Notch Delta-like and Jagged ligands on anti-tumor T cell immunity” by Elena E. Tchekneva et al. investigates the specific roles of Notch ligands in modulating T cell responses through genetic and pharmacological approaches in mouse models of lung and pancreatic tumors and cardiac allograft rejection. This study emphasizes the importance of specific expression of Notch ligands on dendritic cells by revealing their distinct roles in the regulation of T cell immunity, and suggests opportunities for modulating immune outcomes using engineered Notch ligand constructs.

Next, “Effective cancer immunotherapy by natural mouse conventional type-1 dendritic cells bearing dead tumor antigen,” by Stefanie K. Wculek et al. discusses the potential of using natural conventional type 1 DCs (cDC1s) as a syngeneic vaccine in cancer therapy and in a proof-of-principle study, demonstrates the feasibility and efficacy of a personalized anti-cancer treatment based on cross-presenting cDC1-based vaccination that does not require identification of tumor neoantigens. Such results provide valuable pre-clinical data regarding the efficacy of therapeutic cDC1-based anti-cancer vaccination for the development of next-generation DC vaccines.

Furthermore, the article, “CEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids,” by Reyes Gonzalez-Exposito et al. describes the benefits of using 3D in vitro patient derived organoid (PDO) models in place of patient cells lines to better represent the biological characteristics of patient tumors. The authors assess carcinoembryonic antigen (CEA) expression heterogeneity as a common finding in colorectal cancer PDOs from therapy resistant metastatic CRCs and the possible mechanisms by which resistance to cibisatamab immunotherapy may occur.

“Exploring the emerging role of the microbiome in cancer immunotherapy,” by Jessica Fessler et al. examines recent research on the bacterial component of the microbiota, the connection between certain bacteria and the process of carcinogenesis, as well as implications for how the microbiota may be modulating the efficacy and toxicity of cancer immunotherapy. Importantly, this review suggests future clinical implications involving exploitation of the host-microbiome interdependency for delivery of more potent therapy.

Finally, Marjolaine Debant et al.’s article, “STIM1 at the plasma membrane as a new target in progressive chronic lymphocytic leukemia,” extensively analyzes calcium entry in CLL cells, revealing that in patients with progressive disease, calcium signaling deregulation may be due to a constitutive and B cell receptor (BCR)-independent calcium entry pathway involving membrane-associated STIM1. This study warrants further evaluation of a mAb targeting STIM1PM in cancer therapy alone or in combination.

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


JITC Editor Picks

Determinant roles of dendritic cell-expressed Notch Delta-like and Jagged ligands on anti-tumor T cell immunity

Elena E. Tchekneva, Mounika U.L. Goruganthu, Roman V. Uzhachenko, Portia L. Thomas, Anneliese Antonucci, Irina Chekneva, Michael Koenig, Longzhu Piao, Anwari Akhter, Maria Teresa P. de Aquino, Parvathi Ranganathan, Nicholas Long, Thomas Magliery, Anna Valujskikh, Jason V. Evans, Rajeswara R. Arasada, Pierre P. Massion, David P. Carbone, Anil Shanker and Mikhail M. Dikov
Journal for ImmunoTherapy of Cancer, 7:95 (2 April 2019)
Research Article

Summary:

Both Notch1 and Notch2 have been identified as key players in anti-tumor T cell immunity including induction of tumor-specific cytotoxic T lymphocytes (CTL) and memory T cells; however, it remains unclear what specific roles different Notch ligands play in modulating T cell responses. Tchekneva et al. used genetic and pharmacological approaches to investigate the roles of various Delta-like and Jagged ligands in the regulation of T cell-mediated immunity. Results demonstrate that dendritic cell (DC)-expressed DLL1, but not Jag2, is essential for the induction of antigen-specific responses and generation of effector and memory T cells. Thus, this study emphasizes the importance of specific expression of Notch ligands on DCs, suggesting a possible role for engineered Notch ligands as a novel class of immunomodulatory agents.

Effective cancer immunotherapy by natural mouse conventional type-1 dendritic cells bearing dead tumor antigen

Stefanie K. Wculek, Joaquín Amores-Iniesta, Ruth Conde-Garrosa, Sofía C. Khouili, Ignacio Melero and David Sancho
Journal for ImmunoTherapy of Cancer, 7:100 (8 April 2019)
Research Article

Summary:

Although several studies show that the presence of cross-presenting BDCA3+ conventional type-1 dendritic cells (cDC1s) or their gene signatures in the tumor correlates with enhanced T cell infiltration, improved prognosis and survival of cancer patients, natural cDC1s have not yet been tested as a syngeneic vaccine in cancer therapy. Wculek et al. demonstrated the viability and efficacy of an anti-cancer treatment based on adoptive transfer of the natural cross-presenting mouse cDC1 subset loaded ex vivo with an autologous whole tumor cell lysate (TCL) obtained after induction of immunogenic cell death (ICD) by UV irradiation. This proof-of-principle study provides novel pre-clinical data regarding the efficacy of a cDC1-based anti-cancer vaccination that does not require identification of tumor neoantigens and suggests the potential for future development of next-generation DC vaccines.

CEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids

Reyes Gonzalez-Exposito, Maria Semiannikova, Beatrice Griffiths, Khurum Khan, Louise J. Barber, Andrew Woolston, Georgia Spain, Katharina von Loga, Ben Challoner, Radhika Patel, Michael Ranes, Amanda Swain, Janet Thomas, Annette Bryant, Claire Saffery, Nicos Fotiadis, Sebastian Guettler, David Mansfield, Alan Melcher, Thomas Powles, Sheela Rao, David Watkins, Ian Chau, Nik Matthews, Fredrik Wallberg, Naureen Starling, David Cunningham and Marco Gerlinger
Journal for ImmunoTherapy of Cancer, 7:101 (15 April 2019)
Research Article

Summary:

Patient derived organoids (PDOs) are 3D in vitro models which can recapitulate basic features of primary tumors and may better represent the biological characteristics of patient tumors than cancer cell lines. Working in a model of colorectal cancer (CRC), Gonzalez-Exposito et al. investigated mechanisms of resistance to cibisatamab, a bispecific monoclonal antibody which binds to and triggers T cell killing of cancer cells expressing moderate to high levels of carcino-embryonic antigen (CEA) at the cell surface. This study resulted in 7 PDOs from chemotherapy resistant metastatic CRCs, one PDO from a treatment naïve primary CRC, and an in vitro co-culture assay with CD8 T cells to assess cibisatamab efficacy. The findings warrant further investigation in clinical trial samples as to whether CEA expression heterogeneity is associated with cibisatamab resistance.

Exploring the emerging role of the microbiome in cancer immunotherapy

Jessica Fessler, Vyara Matson and Thomas F. Gajewski
Journal for ImmunoTherapy of Cancer, 7:108 (17 April 2019)
Review

Summary:

Recent research has focused on the bacterial component of the microbiota, suggesting that alterations in the normal microbiota may contribute to the development of many diseases, specifically indicating a connection between certain bacteria and the process of carcinogenesis. The microbiota has also been implicated in modulating the efficacy and toxicity of cancer therapy, including chemotherapy and immunotherapy, reinforcing preclinical data which show that modulation of the microbiota could become a novel strategy for improving the efficacy of immune-based therapies for cancer, in particular checkpoint blockade approaches targeting the CTLA-4 and PD-1 pathways. This review by Fessler et al. discusses evidence linking the gut microbiome to cancer immunotherapy, analyzes the biological mechanism of microbiome mediated immune modulation and suggests future clinical implications involving exploitation of the host-microbiome interdependency for delivery of more potent therapy.

STIM1 at the plasma membrane as a new target in progressive chronic lymphocytic leukemia

Marjolaine Debant, Miguel Burgos, Patrice Hemon, Paul Buscaglia, Tinhinane Fali, Sarra Melayah, Nelig Le Goux, Christophe Vandier, Marie Potier-Cartereau, Jacques-Olivier Pers, Adrian Tempescul, Christian Berthou, Cristina Bagacean, Olivier Mignen and Yves Renaudineau
Journal for ImmunoTherapy of Cancer, 7:111 (23 April 2019)
Research Article

Summary:

It has long been understood that CLL B cells (B-CLL) present an altered calcium signaling pathway, which evolves with disease progression; however, the mechanisms governing deregulation of calcium in B-CLL cells and their correlation with disease are not fully understood. Debant et al. investigated calcium entry deregulation in B-CLL cells and tested whether BCR-dependent or BCR-independent calcium entry was involved in CLL outcome. This study characterized a novel calcium signaling pathway, referred to as constitutive calcium entry (CE), which is triggered by STIM1 located at the plasma-membrane (STIM1PM), and demonstrated that blocking CE with an anti-STIM1 monoclonal antibody represents a new first-in-class therapeutic pathway for combating CLL.

Could the menagerie of the gut microbiome really cure cancer? Hope or hype

Muhammad Bilal Abid
Journal for ImmunoTherapy of Cancer, 7:92 (2 April 2019)
Commentary

Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor–induced colitis

Hamzah Abu-Sbeih, Faisal S. Ali, Xuemei Wang, Niharika Mallepally, Ellie Chen, Mehmet Altan, Robert S. Bresalier, Aline Charabaty, Ramona Dadu, Amir Jazaeri, Bret Lashner and Yinghong Wang
Journal for ImmunoTherapy of Cancer, 7:93 (2 April 2019)
Research Article

Comparative analysis of the phase III clinical trials of anti-PD1 monotherapy in head and neck squamous cell carcinoma patients (CheckMate 141 and KEYNOTE 040)

Sara I. Pai, Sandrine Faivre, Lisa Licitra, Jean-Pascal Machiels, Jan B. Vermorken, Paolo Bruzzi, Viktor Gruenwald, Raul E. Giglio, C. René Leemans, Tanguy Y. Seiwert and Denis Soulieres
Journal for ImmunoTherapy of Cancer, 7:96 (3 April 2019)
Commentary

Severe cytokine release syndrome resulting in purpura fulminans despite successful response to nivolumab therapy in a patient with pleomorphic carcinoma of the lung: a case report

Osamu Honjo, Terufumi Kubo, Fumiko Sugaya, Takahiro Nishizaka, Koji Kato, Yoshihiko Hirohashi, Hiroki Takahashi and Toshihiko Torigoe
Journal for ImmunoTherapy of Cancer, 7:97 (3 April 2019)
Case Report

The correlations of tumor mutational burden among single-region tissue, multi-region tissues and blood in non-small cell lung cancer

Yaxiong Zhang, Lianpeng Chang, Yunpeng Yang, Wenfeng Fang, Yanfang Guan, Aiwei Wu, Shaodong Hong, Huaqiang Zhou, Gang Chen, Xi Chen, Shen Zhao, Qiufan Zheng, Hui Pan, Lanjun Zhang, Hao Long, Haoxian Yang, Xin Wang, Zhesheng Wen, Junye Wang, Hong Yang, Xuefeng Xia, Yuanyuan Zhao, Xue Hou, Yuxiang Ma, Ting Zhou, Zhonghan Zhang, Jianhua Zhan, Yan Huang, Hongyun Zhao, Ningning Zhou, Xin Yi and Li Zhang
Journal for ImmunoTherapy of Cancer, 7:98 (3 April 2019)
Short Report

Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program

Elena Verzoni, Giacomo Cartenì, Enrico Cortesi, Diana Giannarelli, Andrea De Giglio, Roberto Sabbatini, Sebastiano Buti, Sabrina Rossetti, Francesco Cognetti, Francesca Rastelli, Alberto Sobrero, Daniele Turci, Cora N. Sternberg, Camillo Porta, Federico Cappuzzo, Giampaolo Tortora, Davide Tassinari, Stefano Panni, Antonio Pazzola, Gianmarco Surico, Alessandra Raimondi, Ugo De Giorgi, Giuseppe Procopio and on behalf of the Italian Nivolumab Renal Cell Cancer Early Access Program group
Journal for ImmunoTherapy of Cancer, 7:99 (3 April 2019)
Research Article

Immune profiling of pre- and post-treatment breast cancer tissues from the SWOG S0800 neoadjuvant trial

Xiaotong Li, Sarah Warren, Vasiliki Pelekanou, Vikram Wali, Alessandra Cesano, Mingdong Liu, Patrick Danaher, Nathane Elliott, Zeina A. Nahleh, Daniel F. Hayes, Gabriel N. Hortobagyi, William E. Barlow, Christos Hatzis and Lajos Pusztai
Journal for ImmunoTherapy of Cancer, 7:88 (10 April 2019)
Research Article

Stereotactic radiosurgery combined with nivolumab or Ipilimumab for patients with melanoma brain metastases: evaluation of brain control and toxicity

Giuseppe Minniti, Dimitri Anzellini, Chiara Reverberi, Gian Carlo Antonini Cappellini, Luca Marchetti, Federico Bianciardi, Alessandro Bozzao, Mattia Osti, Pier Carlo Gentile and Vincenzo Esposito
Journal for ImmunoTherapy of Cancer, 7:102 (11 April 2019)
Research Article

The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation

Anne Månsson Kvarnhammar, Niina Veitonmäki, Karin Hägerbrand, Anna Dahlman, Karin Enell Smith, Sara Fritzell, Laura von Schantz, Mia Thagesson, Doreen Werchau, Kristine Smedenfors, Maria Johansson, Anna Rosén, Ida Åberg, Magnus Winnerstam, Eva Nyblom, Karin Barchan, Christina Furebring, Per Norlén and Peter Ellmark
Journal for ImmunoTherapy of Cancer, 7:103 (11 April 2019)
Research Article

Immunogenicity of immunomodulatory, antibody-based, oncology therapeutics

Jasmine Davda, Paul Declerck, Siwen Hu-Lieskovan, Timothy P. Hickling, Ira A. Jacobs, Jeffrey Chou, Shahram Salek-Ardakani and Eugenia Kraynov
Journal for ImmunoTherapy of Cancer, 7:105 (15 April 2019)
Review

Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature

Noha Abdel-Wahab, Houssein Safa, Ala Abudayyeh, Daniel H. Johnson, Van Anh Trinh, Chrystia M. Zobniw, Heather Lin, Michael K. Wong, Maen Abdelrahim, A. Osama Gaber, Maria E. Suarez-Almazor and Adi Diab
Journal for ImmunoTherapy of Cancer, 7:106 (16 April 2019)
Research Article

The clinical application of cancer immunotherapy based on naturally circulating dendritic cells

Kalijn F. Bol, Gerty Schreibelt, Katrin Rabold, Stefanie K. Wculek, Julia Katharina Schwarze, Andrzej Dzionek, Alvaro Teijeira, Lana E. Kandalaft, Pedro Romero, George Coukos, Bart Neyns, David Sancho, Ignacio Melero and I. Jolanda M. de Vries
Journal for ImmunoTherapy of Cancer, 7:109 (18 April 2019)
Review

Treatment of malignant pleural effusions: the case for localized immunotherapy

Albert D. Donnenberg, James D. Luketich, Rajeev Dhupar and Vera S. Donnenberg
Journal for ImmunoTherapy of Cancer, 7:104 (23 April 2019)
Commentary

Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients

Adam E. Snook, Trevor R. Baybutt, Bo Xiang, Tara S. Abraham, John C. Flickinger Jr, Terry Hyslop, Tingting Zhan, Walter K. Kraft, Takami Sato and Scott A. Waldman
Journal for ImmunoTherapy of Cancer, 7:104 (23 April 2019)
Research Article

Pneumonitis resulting from radiation and immune checkpoint blockade illustrates characteristic clinical, radiologic and circulating biomarker features

Jonathan D. Schoenfeld, Mizuki Nishino, Mariano Severgnini, Michael Manos, Raymond H. Mak and F. Stephen Hodi
Journal for ImmunoTherapy of Cancer, 7:112 (24 April 2019)
Case Report

Multiple antigen-engineered DC vaccines with or without IFNα to promote antitumor immunity in melanoma

Lisa H. Butterfield, Lazar Vujanovic, Patricia M. Santos, Deena M. Maurer, Andrea Gambotto, Joel Lohr, Chunlei Li, Jacob Waldman, Uma Chandran, Yan Lin, Huang Lin, Hussein A. Tawbi, Ahmad A. Tarhini and John M. Kirkwood
Journal for ImmunoTherapy of Cancer, 7:113 (24 April 2019)
Research Article

Vaccination with nanoparticles combined with micro-adjuvants protects against cancer

Mona O. Mohsen, Matthew D. Heath, Gustavo Cabral-Miranda, Cyrill Lipp, Andris Zeltins, Marcos Sande, Jens V. Stein, Carsten Riether, Elisa Roesti, Lisha Zha, Paul Engroff, Aadil El-Turabi, Thomas M. Kundig, Monique Vogel, Murray A. Skinner, Daniel E. Speiser, Alexander Knuth, Matthias F. Kramer and Martin F. Bachmann
Journal for ImmunoTherapy of Cancer, 7:114 (26 April 2019)
Research Article

SITC Members Receive 60 Percent Submission Discount in 2019

*As a way to thank the SITC members who work tirelessly to advance the science and improve the lives of cancer patients, SITC will provide SITC members with a 60 percent discount on processing fees for all JITC articles accepted in 2019. To take advantage of this SITC member benefit, authors must contact JITC Managing Editor Andrea Kunz at JITCEditor@sitcancer.org or 1-414-271-2456 prior to submission to obtain a discount code and instructions.