JITC Digest October 2022

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Inside this Issue:

Letter from the Editor

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Welcome to the latest edition of the JITC digest. October is an exciting and busy time here at the journal as preparations are underway for the Society for Immunotherapy of Cancer (SITC) Annual Meeting & Pre-Conference Programs, held this year at the Boston Convention & Exhibition Center, November 8–12.

If you’ll be in Boston, be sure to stop by the society booth at 12:30 p.m. EST on Thursday, November 10, to say hello during our meet the editors session. On Friday, November 11 at 12:10 p.m., you can catch rapid oral presentations from this year’s JITC Best Paper Award Winners along with an update from our editorial leadership during session 207, "A Look at JITC's High-Impact Science." Finally, we hope you will join us for a special JITC 10th Anniversary Reception on Friday night at 7 p.m., held during the poster reception.

If you can’t make it to Boston, you can always follow along from afar on JITC’s social media channels. In addition to our Twitter feed, JITC now has a LinkedIn profile, and we encourage you to connect with us!

This month’s JITC digest features three excellent original research articles and an intriguing short report. In a timely article given the ongoing viral vector backlog that is causing months-long delays in treatment for some patients with hematological malignancies, Katherine P Mueller et al describe CRISPR-Cas9-based manufacturing of chimeric antigen receptor T cells enriched for memory phenotypes. Two papers provide novel insights into mechanisms of immune exclusion. Anqi Li and colleagues demonstrate that therapeutic targeting of the cell surface docking receptor that activates all major isoforms of latent transforming growth factor beta improves responses to anti-PD-1 in multiple relevant preclinical models. Carsten Krieg et al identify a role for the complement anaphylatoxin C3a receptor in resistance to anti-PD-1 and the establishment of the immunologically cold colorectal cancer tumor microenvironment. Finally, Kok Haw Jonathan Lim et al put forward a short report with evidence that the extracellular plasma protein secreted gelsolin is a negative regulator of immunogenic cell death in response to chemotherapy, radiation, and targeted therapy. Thank you for reading, and I hope to see some of you in Boston.

Best,

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


JITC Editor Picks

Production and characterization of virus-free, CRISPR-CAR T cells capable of inducing solid tumor regression

Katherine P Mueller, Nicole J Piscopo, Matthew H Forsberg, Louise A Saraspe, Amritava Das, Brittany Russell, Madeline Smerchansky, Dan Cappabianca, Lei Shi, Keerthana Shankar, Lauren Sarko, Namita Khajanchi, Nina La Vonne Denne, Apoorva Ramamurthy, Adeela Ali, Cicera R Lazzarotto, Shengdar Q Tsai, Christian M Capitini, Krishanu Saha
Journal for ImmunoTherapy of Cancer 2022;10:e004446 (7 September 2022)
RESEARCH
 
Summary:
All currently commercially available chimeric antigen receptor (CAR) T cell products rely on viral vectors for transduction of their respective CARs, which leads to a lack of control over the integration locus, heterogeneous CAR expression due to variable adjacent regulatory elements, the potential for insertional mutagenesis, and delayed access to treatment arising from vector backlogs. Using CRISPR-Cas9 editing, Katherine P Mueller et al inserted an anti-GD2 CAR into the T cell receptor alpha constant gene (TRAC) to generate CAR T cells capable of inducing regression of solid tumors in mouse models. The CRISPR-Cas9 gene-edited CAR T cells secreted comparable or higher levels of proinflammatory cytokines upon antigen stimulation as conventionally generated CAR T cells, with lower levels of baseline cytokine secretion in the absence of stimulation. Retrovirally transduced CAR T cells were enriched for a more differentiated, effector-like transcriptional signature after completion of manufacturing, whereas a memory-like phenotype was seen in the majority of CRISPR-Cas9-edited CAR T cells. In an established human GD2+ neuroblastoma xenograft model, CRISPR-Cas9-edited CAR T cells persisted in spleens and tumors and expressed memory markers at high levels. A majority of mice treated with the gene-edited CAR T cells had complete tumor regression and survived past 96 days. These findings support further development of virus-free CAR T cell manufacturing approaches in order to generate products with favorable characteristics for the treatment of solid tumors.

Selective targeting of GARP-LTGFβ axis in the tumor microenvironment augments PD-1 blockade via enhancing CD8+ T cell antitumor immunity

Anqi Li, Yuzhou Chang, No-Joon Song, Xingjun Wu, Dongjun Chung, Brian P Riesenberg, Maria Velegraki, Giuseppe D Giuliani, Komal Das, Tamio Okimoto, Hyunwoo Kwon, Karthik B Chakravarthy, Chelsea Bolyard, Yi Wang, Kai He, Margaret Gatti-Mays, Jayajit Das, Yiping Yang, Daniel T Gewirth, Qin Ma, David Carbone, Zihai Li
Journal for ImmunoTherapy of Cancer 2022;10:e005433 (12 September 2022)
RESEARCH
 
Summary:
Accumulation of transforming growth factor beta (TGF-B) in the tumor microenvironment is a major mechanism of resistance to PD-(L)1 blockade, yet therapeutic targeting of TGF-B signaling has been limited by the cytokine’s pleiotropic roles in maintaining tissue homeostasis, with adverse events including on-target cardiovascular toxicity. Anqi Li and colleagues describe a novel tumor microenvironment-specific antibody targeting the cell surface docking receptor that activates all major isoforms of latent TGF-B, GARP, and demonstrate its safety and anti-tumor efficacy in combination with anti-PD-1 in multiple relevant preclinical models. The antibody, PII0-1, was specific for the ligand-free membrane-bound form of GARP—in contrast to another related antibody in clinical development that binds to the GARP-TGF-B complex (Liénart S et al, Science, 2018)—that is found on cancer cells and regulatory T cells, but not platelets, and it did not cause significant thrombocytopenia or overt toxicity in mice with germline expression of the human extracellular GARP domains. Treatment with PIIO-1 plus anti-PD-1 slowed tumor growth in multiple models, including immunologically cold tumors and tumors that do not express GARP. PIIO-1 treatment was associated with reduced levels of markers of TGF-B activation and cancer associated fibroblasts in treated mice. A reduction in terminally exhausted effector CD8+ T cells and an increase in transcripts for proinflammatory cytokines and chemokines were also observed with PIIO-1 treatment. Blockade of T cell egress from the draining lymph node or CXCL3 eliminated antitumor efficacy of PIIO-1. In datasets from human patients, increased expression of the locus encoding GARP was associated with immune exclusion and non-response to anti-PD-(L)1, further supporting additional development of selective TGF-B targeting with PIIO-1 to overcome immunotherapy resistance.

Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy

Carsten Krieg, Lukas M Weber, Bruno Fosso, Marinella Marzano, Gary Hardiman, Monica M Olcina, Enric Domingo, Sahar El Aidy, Khalil Mallah, Mark D Robinson, Silvia Guglietta
Journal for ImmunoTherapy of Cancer 2022;10:e004717 (22 September 2022)
RESEARCH
 
Summary:

Microsatellite stable colorectal cancer (CRC) is immunologically cold and poorly responsive to checkpoint blockade, despite a well-established role for inflammation in driving tumorigenesis. Carsten Krieg et al identify the complement anaphylatoxin C3a receptor (C3aR) as a novel checkpoint that not only suppresses tumorigenesis, but also is involved in the establishment of the immunologically cold CRC tumor microenvironment and resistance to checkpoint inhibition. In murine models of carcinogen-induced CRC, loss of C3aR was associated with higher tumor burden in addition to elevated numbers of tumor-infiltrating CD11c+ macrophages, activated CD4+ T cells, and T helper type 1 cells. Similarly, in spontaneous tumor models, germline deletion of C3aR resulted in elevated tumor burden with significantly higher numbers of Th17, Th1, Th1/Th17, and CD8+ T cells in the colon lamina propria. Loss of C3aR was associated with differential expression of more than 400 genes in colon polyps including loci involved in interferon gamma signaling, leukocyte migration, natural killer cell activation, and Wnt signaling. Strikingly, fecal microbiota transfer from C3aR deficient mice to the parental strain phenocopied the effects on tumor formation and inflammatory immune cells in the lamina propria. Anti-PD-1 reduced tumor number and tumor load in C3aR deficient mice and treatment was associated with increased frequencies of intratumoral polyfunctional natural killer cells. In human datasets across four independent cohorts, the locus encoding C3aR was highly methylated and downregulation was seen in 33% of patients with microsatellite instability high CRC and 34% of patients with microsatellite stable CRC. Recapitulating the mouse models, C3aR downregulation correlated with increased intratumoral innate and adaptive immune cells in the human datasets.

Loss of secreted gelsolin enhances response to anticancer therapies

Kok Haw Jonathan Lim, Evangelos Giampazolias, Oliver Schulz, Neil C Rogers, Anna Wilkins, Erik Sahai, Jessica Strid, Caetano Reis e Sousa
Journal for ImmunoTherapy of Cancer 2022;10:e005245 (26 September 2022)
SHORT REPORT
 
Summary:
In addition to direct cytotoxicity, chemotherapy, radiotherapy, and targeted therapy are also known to induce immune-mediated elimination of cancer cells due to the induction of immunogenic cell death. Conventional type 1 dendritic cells (cDC1s) play a key role in priming tumor antigen-specific cytotoxic T cells under conditions of immunogenic cell death, via signaling through the F-acting-binding receptor DNGR-1. Kok Haw Jonathan Lim et al demonstrate that secreted gelsolin (sGSN), an extracellular plasma protein that competes for F-actin binding on DNGR-1, limits the antitumor efficacy of intratumoral doxorubicin, radiotherapy, and BRAF inhibition in relevant orthotopic murine models. As expected, mature lymphocytes and dendritic cells were required for optimal tumor control. Surprisingly, in this short report, mice lacking sGSN had significantly improved tumor control across modalities. The improvement required DNGR-1—mice lacking both DNGR-1 and sGSN did not have significantly different outcomes compared to wild type controls. These findings extend previous evidence that sGSN-deficiency improves responses to checkpoint blockade and lay the groundwork for future studies’ interventions to enhance immune-mediated antitumor activity of “conventional” cancer modalities.

View other articles from this issue


    

JITC at SITC 2022

JITC is celebrating its 10th anniversary and will be featured prominently throughout SITC’s 37th Annual Meeting and Pre-Conference Programs, November 8–12. Discover the numerous opportunities to learn more about the journal and interact with members of JITC’s Editorial Board.

    

Thursday, Nov. 10

Meet the Editors Session 12:30–1:00 p.m. EST – SITC Booth (#700 in the Exhibit Hall)

Visit the SITC booth to meet Editor-in-Chief Pedro J. Romero, MD and Deputy Editor-in-Chief James L. Gulley, MD, PhD, FACP. Say hello, discuss your research, and share your thoughts on JITC and the field.


Friday, Nov. 11

Pedro J. Romero Service to JITC Award and JITC Best Paper Awards 8:05–8:20 a.m. EST – Hall B2

Join us in congratulating those honored by SITC for their achievements with JITC. See below for additional information on this year’s recipients of the Pedro J. Romero Service to JITC Award and the JITC Best Paper Awards.


Session 207: A Look at JITC's High-Impact Science
12:10–1:10 p.m. EST – 205ABC

Learn more about JITC during, “A Look at JITC's High-Impact Science.” The session will be led by Co-Chairs Pedro J. Romero, MD and James L. Gulley, MD, PhD, FACP, and features:

  • Discussion on journal and article metrics
  • Five-minute rapid oral presentations on each of the five 2022 JITC Best Paper Award winners
  • The future for JITC: the next 10 years
  • A question and answer session

JITC
10th Anniversary Celebration Reception

7:00–8:30 p.m. EST – Hall C

Celebrate major accomplishments in the journal and in the field over the past ten years and mingle with JITC editors, reviewers, authors, and readers, to all of whom the journal owes its tremendous growth and success, during the Friday poster reception and JITC 10th Anniversary Celebration Reception.


Throughout the Meeting

Additional JITC content will be available throughout the Annual Meeting and Pre-Conference Programs.
  • View and share SITC 2022 abstracts published in JITC as of Nov. 7
  • Follow @jitcancer on Twitter and JITC on LinkedIn for additional coverage of SITC 2022
  • Visit the SITC exhibit booth to learn more about the journal
View all JITC activities at SITC 2022 here.



Popular Archive Articles

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The selections below spotlight the JITC Best Paper Award winners from 2020 and 2021, and represent some of the most popular content recently published in JITC. Explore additional thematic content in JITC's Collections or access the rest of JITC's archives for a look at all the journal has to offer.

Mechanisms regulating PD-L1 expression on tumor and immune cells

Shuming Chen, George A. Crabill, Theresa S. Pritchard, Tracee L. McMiller, Ping Wei, Drew M. Pardoll, Fan Pan and Suzanne L. Topalian Journal for ImmunoTherapy of Cancer 2019;7:305 (15 November 2019) 2020 JITC Best Basic Science Paper

CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma

Bryan D. Choi, Xiaoling Yu, Ana P. Castano, Henia Darr, Daniel B. Henderson, Amanda A. Bouffard, Rebecca C. Larson, Irene Scarfò, Stefanie R. Bailey, Genevieve M. Gerhard, Matthew J. Frigault, Mark B. Leick, Andrea Schmidts, Jason G. Sagert, William T. Curry, Bob S. Carter and Marcela V. Maus Journal for ImmunoTherapy of Cancer 2019;7:304 (14 November 2019) 2020 JITC Best Clinical/Translational Paper

Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity

Iuliia Efimova, Elena Catanzaro, Louis Van der Meeren, Victoria D Turubanova, Hamida Hammad, Tatiana A Mishchenko, Maria V Vedunova, Carmela Fimognari, Claus Bachert, Frauke Coppieters, Steve Lefever, Andre G Skirtach, Olga Krysko and Dmitri V Krysko
Journal for ImmunoTherapy of Cancer 2020;8:e001369 (13 November 2020) 2021 JITC Best Basic Tumor Immunology Paper

Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice

Alessio Cortellini, Marco Tucci, Vincenzo Adamo, Luigia Stefania Stucci, Alessandro Russo, Enrica Teresa Tanda, Francesco Spagnolo, Francesca Rastelli, Renato Bisonni, Daniele Santini, Marco Russano, Cecilia Anesi, Raffaele Giusti, Marco Filetti, Paolo Marchetti, Andrea Botticelli, Alain Gelibter, Mario Alberto Occhipinti, Riccardo Marconcini, Maria Giuseppa Vitale, Linda Nicolardi, Rita Chiari, Claudia Bareggi, Olga Nigro, Alessandro Tuzi, Michele De Tursi, Nicola Petragnani, Laura Pala, Sergio Bracarda, Serena Macrini, Alessandro Inno, Federica Zoratto, Enzo Veltri, Barbara Di Cocco, Domenico Mallardo, Maria Grazia Vitale, David James Pinato, Giampiero Porzio, Corrado Ficorella and Paolo Antonio Ascierto Journal for ImmunoTherapy of Cancer 2020;8:e001361 (5 November 2020) 2021 JITC Best Clinical/Translational Cancer Immunotherapy Paper

Development of a CD8 co-receptor independent T-cell receptor specific for tumor-associated antigen MAGE-A4 for next generation T-cell-based immunotherapy

Kathrin Davari, Tristan Holland, Laura Prassmayer, Giulia Longinotti, Kenneth P Ganley, Lisa J Pechilis, Iulia Diaconu, Prashant R Nambiar, Michael S Magee, Dolores J Schendel, Daniel Sommermeyer and Christian Ellinger Journal for ImmunoTherapy of Cancer 2021;9:e002035 (25 March 2021) 2021 JITC Best Immune Cell Therapies and Immune Cell Engineering Paper


Differential expansion of circulating human MDSC subsets in patients with cancer, infection and inflammation

Luca Cassetta, Kirsten Bruderek, Joanna Skrzeczynska-Moncznik, Oktawia Osiecka, Xiaoying Hu, Ida Marie Rundgren, Ang Lin, Kim Santegoets, Utku Horzum, Ana Godinho-Santos, Gennadiy Zelinskyy, Thalia Garcia-Tellez, Sunčica Bjelica, Bartłomiej Taciak, Astrid Olsnes Kittang, Benedikt Höing, Stephan Lang, Michael Dixon, Verena Müller, Jochen Sven Utikal, Derya Karakoç, Kerim Bora Yilmaz, Emilia Górka, Lubomir Bodnar, Olympia Evdoxia Anastasiou, Christine Bourgeois, Robert Badura, Monika Kapinska-Mrowiecka, Mirjana Gotic, Mark ter Laan, Esther Kers-Rebel, Magdalena Król, Juan Francisco Santibañez, Michaela Müller-Trutwin, Ulf Dittmer, Ana Espada de Sousa, Güneş Esendağlı, Adema, Karin Loré, Elisabeth Ersvær, Viktor Umansky, Jeffrey W Pollard, Joanna Cichy and Sven Brandau Journal for ImmunoTherapy of Cancer 2020;8:e001223 (8 September 2020) 2021 JITC Best Immunotherapy Biomarkers Paper

A systemically deliverable Vaccinia virus with increased capacity for intertumoral and intratumoral spread effectively treats pancreatic cancer

Giulia Marelli, Louisa S Chard Dunmall, Ming Yuan, Carmela Di Gioia, Jinxin Miao, Zhenguo Cheng, Zhongxian Zhang, Peng Liu, Jahangir Ahmed, Rathi Gangeswaran, Nicholas Lemoine and Yaohe Wang Journal for ImmunoTherapy of Cancer 2021;9:e001624 (26 January 21) 2021 JITC Best Oncolytic and Local Immunotherapy Paper

From the Vault

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Throughout the journal’s celebratory 10th 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 articles that were JITC Best Paper Award winners in years past.

Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8+ T cells directly within the tumor microenvironment

Stefani Spranger, Holly K. Koblish, Brendan Horton, Peggy A. Scherle, Robert Newton and Thomas F. Gajewski Journal for ImmunoTherapy of Cancer 2014 2:3 (18 February 2014) 2014 JITC Best Basic Science Paper

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 and Bernard A. Fox Journal for ImmunoTherapy of Cancer 2015 3:4 (20 October 2015) 2016 JITC Best Clinical/Translational Paper

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer

Kristen M. Hege, Emily K. Bergsland, George A. Fisher, John J. Nemunaitis, Robert S. Warren, James G. McArthur, Andy A. Lin, Jeffrey Schlom, Carl H. June and Stephen A. Sherwin Journal for ImmunoTherapy of Cancer 2017, 5:22 (21 March 2017) 2017 JITC Best Clinical/Translational Paper

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) 2018 JITC Best Basic Science Paper

Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study

Asim Amin, Elizabeth R. Plimack, Marc S. Ernstoff, Lionel D. Lewis, Todd M. Bauer, David F. McDermott, Michael Carducci, Christian Kollmannsberger, Brian I. Rini, Daniel Y.C. Heng, Jennifer Knox, Martin H. Voss, Jennifer Spratlin, Elmer Berghorn, Lingfeng Yang, Hans J. Hammers Journal for ImmunoTherapy of Cancer 2018, 6:109 (22 October 2018) 2019 JITC Best Clinical/Translational Paper

SITC Members Receive a 50 Percent Discount on Article Processing Charges in 2022
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 50 percent discount on article processing fees for all JITC articles accepted in 2022.
 
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.