JITC Digest March 2023

By JITC Publications posted 03-22-2023 00:00

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INSIDE THIS ISSUE:

LETTER FROM THE EDITOR JITC EDITOR PICKS OTHER RECENT JITC ARTICLES

Letter from the Editor

Dear JITC Readers,

For more than 10 years, I have had the honor and the pleasure of being at the helm of the Journal for ImmunoTherapy of Cancer (JITC). It has been an absolutely extraordinary experience. Many of you know that I have transitioned already to Professor Emeritus at University of Lausanne. As I contemplate the next phase of my career, the time has come for me to pass the baton on to another to lead JITC so that they may experience all the inspiration and community that the journal has to offer.

Being the Founding Editor-in-Chief of JITC has been one of the most exciting and rewarding tasks in my academic career. The effort to build JITC, shared with several successive leaders at the Society for Immunotherapy of Cancer (SITC) as well as publishers BMC (2013–2019) and BMJ (2020–present), has made it all the more special.

I would like to express my appreciation to the team of nearly 100 editors, especially to Section Editors—Kees Melief, Sjoerd van der Burg, Douglas McNeel, Claudia Palena, Jeff Weber, Ignacio Melero, Alexandra Snyder, Howard Kaufman, Sebastian Kobold, Marcela Maus, Robert Ferris, Sandra Demaria, Laurence Fong, and Christian Capitini—former Section Editors, and Specialty Editors. I also thank the multiple teams at SITC that support the journal in various, critical ways. Most especially, I express my deepest gratitude to our Managing Editor, Andrea Kunz, and Assistant Managing Editor, Matthew Erickson, who are the tireless brains and hands keeping JITC thriving and vibrant. There simply is not enough space here to name all of the society’s and scientific community’s members who have generously accompanied us in this successful publishing adventure.

As I transition into a new role with the journal as a Consulting Editor for Special Series and Reviews, I am pleased to share that our current JITC Deputy Editor-in-Chief, Dr. James Gulley, is stepping into the role of Interim Editor-in-Chief starting in April while SITC conducts an open search for the next Editor-in-Chief later this year. Having worked with him on the journal over the past several years, I am grateful to see his leadership recognized and know he will carry the role of Interim Editor-in-Chief with pride. I also congratulate our dedicated Section Editor, Sjoerd van der Burg, who will be promoted to Interim Deputy Editor-in-Chief during this transition period. I wish James, Sjoerd, the editorial team, and all the JITC family continued success. With them in the pilot’s cockpit, the journal enters into its second decade of its life as the vehicle to accelerate the discovery and implementation of new treatments for cancers based on the immune system.

Regards,

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

**Other Recent JITC Articles**

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JITC Editor Picks

INHIBITION OF MYELOPEROXIDASE ENHANCES IMMUNE CHECKPOINT THERAPY FOR MELANOMA

Tracy W Liu, Seth T Gammon, Ping Yang, Wencai Ma, Jing Wang, David Piwnica-Worms
Journal for ImmunoTherapy of Cancer 2023;11:e005837 (17 February 2023)
Research

Summary:

Production of reactive oxygen species (ROS) is a major mechanism by which myeloid cells in the tumor microenvironment suppress anti-tumor immunity. The myeloid lineage-restricted enzyme myeloperoxidase has previously been shown to promote early progression of melanoma in mouse models, and Tracy W Liu et al demonstrate that inhibition of MPO enhances response to checkpoint blockade in two preclinical models of established tumors: B16F10 and YUMM3.3. Homozygous deletion of the locus encoding MPO increased the numbers of melanoma-bearing mice that survived long-term after treatment with combination anti-PD-1 and anti-CTLA-4. Mice lacking MPO had significantly reduced myeloid cells and increased numbers of T cells within tumors. In the blood, spleen, and bone marrow, animals lacking MPO had fewer cells expressing markers consistent with neutrophils and myeloid-derived suppressor cells and elevated numbers of B cells and dendritic cells. Myeloid cells isolated from the spleen and peritoneal cavity of melanoma-bearing mice produced increased amounts of ROS compared to matched cells from healthy controls. Strikingly, however, no obvious differences in MPO protein levels between cells from tumor-bearing and healthy animals was detectable by western blot. Pharmacologic inhibition of MPO phenocopied the genetic ablation of MPO, leading to enhanced survival when administered in combination with checkpoint blockade, with the magnitude of benefit varying across models and compounds.

PHASE I/II STUDY OF PEXAVEC IN COMBINATION WITH IMMUNE CHECKPOINT INHIBITION IN REFRACTORY METASTATIC COLORECTAL CANCER

Cecilia Monge, Changqing Xie, Yuta Myojin, Kelley Coffman, Donna Mabry Hrones, Sophie Wang, Jonathan M Hernandez, Bradford J Wood, Elliot B Levy, Israa Juburi, Stephen M Hewitt, David E Kleiner, Seth M Steinberg, William D Figg, Bernadette Redd, Philip Homan, Maggie Cam, Benjamin Ruf, Austin G Duffy, Tim F Greten

Journal for ImmunoTherapy of Cancer 2023;11:e005871 (8 February 2023)

Research

Summary:

Mismatch repair proficient (pMMR) colorectal cancer (CRC) is an immunologically cold tumor type largely insensitive to immune checkpoint blockade. Reporting results from a phase I/II trial, Cecilia Monge and colleagues demonstrate feasibility, safety, and initial clinical activity for the combination of pexastimogene devacirepvec (PexaVec) and durvalumab with or without tremelimumab in patients with standard chemotherapy-refractory pMMR CRC. PexaVec is a genetically engineered oncolytic vaccinia virus that expresses human granulocyte macrophage colony-stimulating factor (hGM-CSF). Due to disruption of the viral thymidine kinase gene as well as VEGF-stimulated vaccinia virus replication, PexaVec has highly specific tumor tropism even when delivered intravenously. A total of 34 patients were enrolled: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Patients received four doses of PexaVec at two different dose levels and durvalumab (with or without a single priming dose of tremilimumab) was initiated 12 days after the first PexaVec infusion. No new safety signals or unexpected toxicities were observed with the combination. Median progression free survival, a secondary endpoint, was 2.3 months (95% CI 2.2–3.2 months) and 2.1 months (95% CI 1.7–2.8 months) for the cohorts that did and did not receive tremilimumab, respectively.

TUNED ACTIVATION OF MSLN-CAR T CELLS INDUCES SUPERIOR ANTITUMOR RESPONSES IN OVARIAN CANCER MODELS

Esther Schoutrop, Thomas Poiret, Ibrahim El-Serafi, Ying Zhao, Rui He, Alina Moter, Johan Henriksson, Moustapha Hassan, Isabelle Magalhaes, Jonas Mattsson

Journal for ImmunoTherapy of Cancer 2023;11:e005691 (6 February 2023)

Research

Summary:

Chimeric antigen receptor (CAR) T cells become exhausted and fail to persist within solid tumors. Strong T cell activation contributes to exhaustion, and fine-tuning activation by mutating the immunoreceptor tyrosine-based activation motifs (ITAMs) in CD19-directed CAR T cells has extended functional persistence in preclinical models. Esther Schoutrop and colleagues generated a mesothelin-directed CAR T cell construct with a CD28 costimulatory domain and a CD3zeta chain containing a single immunoreceptor tyrosine-based activation motif (ITAM), instead of the three in the wild type, which had enhanced antitumor potency and persistence in murine ovarian cancer models as well as improved ex vivo effector functions. Compared to conventional second-generation mesothelin-CAR T cells (ie, either a CD28 or 4-1BB costimulatory domain fused to CD3zeta with three ITAMs), the single-ITAM CAR T cells significantly reduced tumor burden and prolonged survival in localized and disseminated cancer models. CAR T cells were detectable in blood samples by flow cytometry at sacrifice in 70% of animals treated with the single-ITAM CAR T cells, compared to 36% and 45% for the CD28- and 4-1BB-based conventional CAR T cells, respectively. Ex vivo, single-ITAM CAR T cells isolated from spleens after sacrifice were polyfunctional and produced higher amounts of interferon gamma, granzyme B, and tumor necrosis factor alpha compared to conventional CAR T cells. While the infusion products were transcriptionally similar regardless of the intracellular domain, single-ITAM CAR T cells isolated from spleens after sacrifice upregulated fewer genes involved in long-term activation and dysfunction and more genes associated with non-effector naïve or memory T cells.

SINGLE-CELL SPATIAL LANDSCAPE OF IMMUNOTHERAPY RESPONSE REVEALS MECHANISMS OF CXCL13 ENHANCED ANTITUMOR IMMUNITY

Mark Sorin, Elham Karimi, Morteza Rezanejad, Miranda W Yu, Lysanne Desharnais, Sheri A C McDowell, Samuel Doré, Azadeh Arabzadeh, Valerie Breton, Benoit Fiset, Yuhong Wei, Roni Rayes, Michele Orain, Francois Coulombe, Venkata S K Manem, Andreanne Gagne, Daniela F Quail, Philippe Joubert, Jonathan D Spicer, Logan A Walsh

Journal for ImmunoTherapy of Cancer 2023;11:e005545 (1 February 2023)

Research

Summary:

Tumor rejection requires coordinated activity of several distinct cellular lineages, and newer multiplex technologies now allow for high-resolution information on the spatial organization and interactions between cancer and immune cells in the microenvironment. Using a panel of 35 antibodies targeting 14 cell lineage markers, 11 co-stimulatory/inhibitory markers, 6 immune signaling markers and 4 tissue structural markers, Mark Sorin and colleagues resolved 114,524 single cells from samples from 27 checkpoint blockade-treated patients with non-small cell lung cancer (NSCLC). Among the 11 patients with tumors resected from the lung, 6 had disease that responded to checkpoint inhibition. One of the most upregulated markers on CD8⁺T cells in samples from responding tumors was CXCL13. Strikingly, 63% of the total cells expressing CXCL13 were endothelial cells, macrophages, monocytes, B cells, and cancer cells. In samples from metastases, by contrast, there was no association between CXCL13 expression on T cells and response to checkpoint inhibition. In murine models, recombinant CXCL13 enhanced responses to anti-PD-1 therapy in tumors with pre-existing immune infiltration, even those that were resistant to checkpoint blockade monotherapy alone. For tumors with no immune infiltration, mimicking an “immune desert” phenotype, recombinant CXCL13 did not improve responses to anti-PD-1. These findings highlight the hypothesis-generating potential for spatial single-cell interrogation of the tumor immune microenvironment.

From the Vault

Throughout the journal’s celebratory 10^th Anniversary year, this From the Vault special feature will highlight influential papers covering the wide variety of content the journal has published to advance the field. This month’s From the Vault takes a look at some of the top papers from JITC’s ten-year history.

TARGETING TUMOR-NECROSIS FACTOR RECEPTOR PATHWAYS FOR TUMOR IMMUNOTHERAPY

David A Schaer, Daniel Hirschhorn-Cymerman, Jedd D Wolchok
Journal for ImmunoTherapy of Cancer 2014;2:7 (15 April 2014)REVIEW

MULTISPECTRAL IMAGING OF FORMALIN-FIXED TISSUE PREDICTS ABILITY TO GENERATE TUMOR-INFILTRATING LYMPHOCYTES FROM MELANOMA

Zipei Feng, Sachin Puri, Tarsem Moudgil, William Wood, Clifford C. Hoyt, Chichung Wang, Walter J. Urba, Brendan D. Curti, Carlo B. Bifulco, Bernard A. Fox
Journal for ImmunoTherapy of Cancer 2015;3:47 (20 October 2015)RESEARCH

ADJUVANTS FOR PEPTIDE-BASED CANCER VACCINES

Hiep Khong, Willem W. Overwijk
Journal for ImmunoTherapy of Cancer 2016;4:56 (20 September 2016)REVIEW

SMOLDERING MYOCARDITIS FOLLOWING IMMUNE CHECKPOINT BLOCKADE

Timothy G. Norwood, Brian C. Westbrook, Douglas B. Johnson, Silvio H. Litovsky, Nina L. Terry, Svetlana B. McKee, Alan S. Gertler, Javid J. Moslehi, Robert M. Conry
Journal for ImmunoTherapy of Cancer 2017;5:91 (21 November 2017)CASE REPORT

SAFETY OF IMMUNE CHECKPOINT INHIBITOR RECHALLENGE AFTER DISCONTINUATION FOR GRADE ≥2 IMMUNE-RELATED ADVERSE EVENTS IN PATIENTS WITH CANCER

Rawad Elias, Anita Giobbie-Hurder, Nadine Jackson McCleary, Patrick Ott, F. Stephen Hodi, Osama Rahma
Journal for ImmunoTherapy of Cancer 2018;6:26 (4 April 2018)RESEARCH

SITC Members Receive Substantial Discounts on Article Processing Charges

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 members with a substantial discount on processing fees for all accepted JITC articles.

Become a SITC Member Today!

JITC also offers waivers for the APC (100% discount of the APC) where all authors are based in low-income countries (see policy). Requests for waivers must be made prior to submission. For additional information regarding these discounts, as well as institutional arrangements, view the journal's APC policy. Additional questions may be directed to JITCEditor@sitcancer.org.

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