Letter from the Editor | JITC Editor Picks | In Memoriam: Jeffrey S. Weber | Popular Archive Articles
Letter from the Editor
Hello JITC Readers,
These welcome messages typically feature upcoming notable events, advances in the I-O space, and other newsworthy happenings in the field. However, I must begin this month on a more somber note to commemorate the passing of a friend and colleague, our dear Jeff Weber.
I had the pleasure of knowing Jeff since he joined us as a fellow in the Surgery Branch of the National Cancer Institute (NCI) in the late ‘80s. His sense of humor and razor-sharp intelligence always shined. He was a dedicated clinician-scientist, quickly brought onto the Senior Staff of the NCI, knowledgeable broadly in the field, and quickly recruited to the West Coast to launch his academic career. He served as an advisor to our Interleukin 18 Program at GSK, where I was working on advancing inflammation/tissue repair and oncology in 2000. He then advised me on his experience with tumor infiltrating lymphocytes while he was at Moffitt, which championed this approach to adoptive cell therapy. This helped me immensely at Lion/Iovance in 2015 when we overlapped briefly in Tampa. For those of you less familiar with his major contributions, I point you to two of his recent publications leading the way for modern mRNA vaccines to melanoma neoepitopes in a randomized study, Keynote-942. The second, recommended treatment for patients with melanoma first administered adjuvant immune checkpoint blockade in the setting of Checkmate 238. As you can see in these two recent publications from Jeff, he was busy working on patients’ behalf until the end!
I encourage you to read the recently published editorial in JITC to learn more not only about Jeff’s professional life, but the personal side of this gracious, witty, and generous man, one who will be deeply missed but whose impact on the field and the lives of so many of us that had the pleasure of knowing him, will never be forgotten.
Two keys to success Jeff innately understood were the importance of a good mentor and the need to train the next generation. With that, I would like to give one last call to early career researchers to apply to be a mentee in the 2025 JITC Peer Review Mentorship Program. Applications are being collected for one more day, through September 19th. Learn more about the program and apply now! Our application window closes just ahead of Peer Review Week, an annual event during which the value of peer review is celebrated across the scholarly publishing world.
As for the latest research, highlights this month include findings from Congwen Wang et al that support sialoglycan-sialic acid-binding immunoglobulin-like lectin (Siglec)-10 as a novel dendritic cell (DC) checkpoint blockade target in patients with cervical cancer. By disrupting Siglec-10 signaling, the authors showed that the DC-induced tumoricidal response was restored along with enhanced efficacy of anti-PD-1/PD-L1 therapy. This timely publication comes ahead of the 17th International Symposium on Dendritic Cells in Barcelona next month.
In a study in which 201 patients with refractory metastatic/unresectable tumors who were tissue tumor mutational burden-high (tTMB-H) and/or blood mutational burden-high (bTMB-H) were enrolled and randomized 2:1 to receive either nivolumab+ipilimumab or nivolumab monotherapy, Michael Schenker and colleagues found a better objective response rate for those receiving nivolumab+ipilimumab. This suggests the combination therapy as a potential treatment option for patients with high TMB.
Read more about these and other recent publications below, as well as more on the life of Jeff Weber and his remarkable contributions to our journal.
Regards,
Michael T. Lotze, MD
Editor-in-Chief
Journal for ImmunoTherapy of Cancer
JITC Editor Picks
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Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden
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Michael Schenker, Mauricio Burotto, Martin Richardet, Tudor-Eliade Ciuleanu, Anthony Gonçalves, Neeltje Steeghs, Patrick Schoffski, Paolo A Ascierto, Michele Maio, Iwona Lugowska, Lorena Lupinacci, Alexandra Leary, Jean-Pierre Delord, Julieta Grasselli, David S P Tan, Jennifer Friedmann, Jacqueline Vuky, Marina Tschaika, Somasekhar Konduru, Sai Vikram Vemula, Ruta Slepetis, Georgia Kollia, Misena Pacius, Quyen Duong, Ning Huang, Parul Doshi, Jonathan Baden, Massimo Di Nicola
Journal for ImmunoTherapy of Cancer 2024;12:e008872 (6 August 2024)
RESEARCH
Summary:
High tumor mutational burden (TMB-H) (≥10 mutations/Mb) in solid tumors is often a predictive biomarker for response to immune checkpoint inhibitor (ICI) therapy. Analysis of TMB can be accomplished through either tumor tissue samples (tTMB) or blood samples (bTMB). Although tissue samples allow for staging and histology, blood samples are much easier to collect and process. This phase II study (NCT03668119) enrolled 201 patients with refractory metastatic/unresectable tumors who were tTMB-H and/or bTMB-H, and randomized them 2:1 to receive either nivolumab+ipilimumab combination therapy or nivolumab monotherapy. Among tTMB-H patients, the objective response rate (ORR) was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, the ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. This study suggests that nivolumab+ipilimumab may be a promising potential treatment option for patients with high TMB, which can be measured through obtaining tumor tissue or a blood sample when a biopsy is not feasible.
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An IL-7 fusion protein targeting EDA fibronectin upregulates TCF1 on CD8+ T-cells, preferentially accumulates to neoplastic lesions, and boosts PD-1 blockade
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Cesare Di Nitto, Domenico Ravazza, Ettore Gilardoni, Thomas Look, Miaomiao Sun, Eleonora Prodi, Vlad Moisoiu, Christian Pellegrino, Markus G. Manz, Emanuele Puca, Michael Weller, Tobias Weiss, Dario Neri, Roberto De Luca
Journal for ImmunoTherapy of Cancer 2024;12:e008504 (13 August 2024)
RESEARCH
Summary:
Immune checkpoint blockade (ICB) therapy provides long-lasting and durable responses for subsets of patients but remains ineffective for many others, often due to resistance originating from a dynamic immunosuppressive tumor microenvironment (TME). Understanding and manipulating the TME through antibody-cytokine fusion proteins represents a novel method at predicting and improving ICB response. Using in vitro cell-based assays and in vivo mouse-models, this study developed an interleukin-7-based TME-targeting fusion protein termed F8(scDb)-IL7. It demonstrated immunostimulatory activity by targeting extradomain A (EDA-FN) on tumor cells. Incubation with F8(scDb)-IL7 resulted in significant upregulation of TCF-1 on CD8+ T-cells, a known transcription factor essential for maintaining memory and driving effective immune responses. Treatment with F8(scDb)-IL7 in a mouse-model demonstrated significant anti-tumor activity as a monotherapy (14% achieving complete remission) and with increased activity in combination with anti-PD-1 treatment (86% achieving complete remission). The novel cytokine-fusion protein F8(scDb)-IL7 shows promising evidence as an immunotherapy treatment as a single-agent and even greater in combination with ICB.
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Neutralizing IL-38 activates γδ T cell-dependent antitumor immunity and sensitizes for chemotherapy
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Priscila da Silva, Javier Mora, Xin You, Svenja Wiechmann, Mateusz Putyrski, Javier Garcia-Pardo, Aimo Kannt, Andreas Ernst, Bernhard Bruene, Andreas Weigert
Journal for ImmunoTherapy of Cancer 2024;12:e008641 (28 August 2024)
RESEARCH
Summary:
The interleukin (IL)-1-family receptor antagonist, IL-38, is known to negatively regulate auto-inflammation, however, its interaction with specific cell types is not well understood. This study investigated the role of IL-38 within the tumor immune response by introducing IL-38 neutralizing antibodies in the mammary tumor mouse model (PyMT) that expresses IL-38 in wildtype (WT) levels. Interestingly, they also measured tumor/immune cell characteristics in IL-38 knockout (PyMT- IL-38 KO) and WT mice. This included in vitro cell-based assays, RNA-sequencing, and immunohistochemistry. They showed that both genetic ablation and neutralization of IL-38 resulted in increased tumor infiltration of both γδT-cells and CD8+ T-cells, driven by γδT-cells producing the XCL1 chemokine and recruiting conventional dendritic cells (cDCs). Additionally, inhibition or knockout of IL-38 led to reduced tumor growth and improved response to chemotherapy. In tumor samples taken from patients with breast cancer, IL-38 transcripts were negatively correlated with the presence of cDCs, XCL1-producing γδT-cells, and tumor infiltrating lymphocytes. These findings highlight the mechanistic role of IL-38 in suppressing or modulating the immune response. As such, they provide exciting support for IL-38 interference as a novel strategy for improving anti-tumor immunity.
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Identification of Siglec-10 as a new dendritic cell checkpoint for cervical cancer immunotherapy
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Congwen Wang, Lewei He, Jing Peng, Chong Lu, Meng Zhang, Xingling Qi, Mingxing Zhang, Yumeng Wang
Journal for ImmunoTherapy of Cancer 2024;12:e009404 (28 August 2024)
RESEARCH
Summary:
Despite high dendritic cell (DC) infiltration within the tumor of many patients with cervical cancer (CC), immune response is often limited due to an immunosuppressive tumor microenvironment (TME). The sialoglycan-sialic acid-binding immunoglobulin-like lectin (Siglec) axis within the TME has shown potential as an immune checkpoint. Still, the role of the Siglec axis in influencing DC functionality is not well understood. This study used single-cell RNA sequencing data and tumor samples from patients with CC to uncover the function of the Siglec-10 axis on DCs. Siglec-10+ DCs exhibited significant downregulation of co-stimulatory factors (CD40, CD80, CD83, CD86), while inhibitory receptors (PD-1, Tim-3) were highly upregulated. Additionally, Siglec-10+ DC infiltration was strongly associated with T-cell dysfunction. Interference with the Siglec-10 signaling axis reinvigorated anti-tumor activity by promoting increased secretion of costimulatory agents and effector cytokines in Siglec-10+ DCs, which further enhanced the efficacy of anti-PD-1/PD-L1 therapy. These findings provide substantial support for Siglec-10 as a novel DC checkpoint blockade target that may enhance anti-PD-1/PD-L1 therapy in patients with CC.
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Other Recent JITC Articles
In Memoriam: Jeffrey S. Weber
Jeffrey S. Weber, MD, PhD, passed away on August 18, 2024, at the age of 72. Dr. Weber’s tremendous influence on immuno-oncology helped shape the current state of the field. While his impact will be felt for years and generations to come―not only through his immeasurable contributions to I-O as well as the countless lives he touched among friends, colleagues, and, most significantly, patients―Dr. Weber also played a considerable role in helping JITC achieve the stature it has today.
From 2013 to 2022, Dr. Weber actively served as an editor for the Clinical/Translational Cancer Immunotherapy section. He worked his way through the editorial ranks, beginning as Associate Editor before becoming Deputy Editor in 2020, and finally co-Section Editor in 2022. Throughout those years, Dr. Weber was also among the most active reviewers for JITC. As the journal began to receive an increasing amount of submissions, Dr. Weber in turn tirelessly provided a growing number of reviews, annually ranking among the most prolific reviewers. He also volunteered to be a mentor in the inaugural class of the JITC Peer Review Mentorship Program. In 2023, he was deservedly honored by SITC as the Pedro J. Romero Service to JITC Award recipient.
Dr. Weber’s presence is and will continue to be sorely missed. But through his unique voice on our Editorial Board, the generosity of his time, and his enduring dedication to publishing quality science at JITC, his imprint on the journal will live on. Read the tribute honoring Dr. Weber (1952-2024).
Popular Archive Articles
In honor of Dr. Jeffrey S. Weber and his unending dedication to advancing the science of tumor immunology and cancer immunotherapy, the selections below represent recent JITC articles on which Dr. Weber served as author.
Explore other popular articles, 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.
Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events
Faisal Fa'ak, Maryam Buni, Adewunmi Falohun, Huifang Lu, Juhee Song, Daniel H Johnson, Chrystia M Zobniw, Van A Trinh, Muhammad Osama Awiwi, Nourel Hoda Tahon, Khaled M Elsayes, Kaysia Ludford, Emma J Montazari, Julia Chernis, Maya Dimitrova, Sabina Sandigursky, Jeffrey A Sparks, Osama Abu-Shawer, Osama Rahma, Uma Thanarajasingam, Ashley M Zeman, Rafee Talukder, Namrata Singh, Sarah H Chung, Petros Grivas, May Daher, Ala Abudayyeh, Iman Osman, Jeffrey Weber, Jean H Tayar, Maria E Suarez-Almazor, Noha Abdel-Wahab, Adi Diab
Journal for ImmunoTherapy of Cancer 2023;11:e006814 (16 June 2023)
RESEARCH
Society for Immunotherapy of Cancer (SITC) consensus definitions for immune checkpoint inhibitor-associated immune-related adverse events (irAEs) terminology
Jarushka Naidoo, Catherine Murphy, Michael B Atkins, Julie R Brahmer, Stephane Champiat, David Feltquate, Lee M Krug, Javid Moslehi, M Catherine Pietanza, Joanne Riemer, Caroline Robert, Elad Sharon, Maria E Suarez-Almazor, Karthik Suresh, Michelle Turner, Jeffrey Weber, Laura C Cappelli
Journal for ImmunoTherapy of Cancer 2023;11:e006398 (31 March 2023)
POSITION ARTICLE AND GUIDELINES
First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1)
Sophie Postel-Vinay, Vincent K Lam, Willeke Ros, Todd M Bauer, Aaron R Hansen, Daniel C Cho, F Stephen Hodi, Jan H M Schellens, Jennifer K Litton, Sandrine Aspeslagh, Karen A Autio, Frans L Opdam, Meredith McKean, Neeta Somaiah, Stephane Champiat, Mehmet Altan, Anna Spreafico, Osama Rahma, Elaine M Paul, Christoph M Ahlers, Helen Zhou, Herbert Struemper, Shelby A Gorman, Maura Watmuff, Kaitlin M Yablonski, Niranjan Yanamandra, Michael J Chisamore, Emmett V Schmidt, Axel Hoos, Aurelien Marabelle, Jeffrey S Weber, John V Heymach
Journal for ImmunoTherapy of Cancer 2023;11:e005301 (16 March 2023)
RESEARCH
Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study
Jason Chesney, Karl D Lewis, Harriet Kluger, Omid Hamid, Eric Whitman, Sajeve Thomas, Martin Wermke, Mike Cusnir, Evidio Domingo-Musibay, Giao Q Phan, John M Kirkwood, Jessica C Hassel, Marlana Orloff, James Larkin, Jeffrey Weber, Andrew J S Furness, Nikhil I Khushalani, Theresa Medina, Michael E Egger, Friedrich Graf Finckenstein, Madan Jagasia, Parameswaran Hari, Giri Sulur, Wen Shi, Xiao Wu, Amod Sarnaik
Journal for ImmunoTherapy of Cancer 2022;10:e005755 (13 December 2022)
RESEARCH
Phase II clinical and immune correlate study of adjuvant nivolumab plus ipilimumab for high-risk resected melanoma
Nikhil I Khushalani, Melinda Vassallo, Judith D Goldberg, Zeynep Eroglu, Younchul Kim, Biwei Cao, Robert Ferguson, Kelsey R Monson, Tomas Kirchhoff, Carol M Amato, Paulo Burke, Ann Strange, Emily Monk, Geoffrey Thomas Gibney, Ragini Kudchadkar, Joseph Markowitz, Andrew S Brohl, Anna Pavlick, Alison Richards, David M Woods, Jeffrey Weber
Journal for ImmunoTherapy of Cancer 2022;10:e005684 (30 November 2022)
RESEARCH
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APC Discounts
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 35% discount on Article Processing Charges (APCs) for all accepted JITC articles submitted in 2024. This discount is applied post-acceptance, at which point a discount code is shared with the corresponding author.
Become a SITC Member Today!
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JITC also offers full waivers for the full 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 and editor/reviewer discounts, view the journal's APC policy. Additional questions may be directed to JITCEditor@sitcancer.org.
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