JITC Digest September 2022

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Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

Welcome to the latest edition of the JITC digest. Our clinical readers are likely still buzzing with excitement over some of the exciting data that was recently presented at the European Society for Medical Oncology (ESMO) Annual Meeting earlier this month. Immunotherapy was certainly the star of the show, with jaw-dropping response rates to neoadjuvant nivolumab plus ipilimumab in colorectal cancer in NICHE-2 and the first randomized phase III trial showing benefit with cell therapy in a solid tumor in M14TIL. 

Our highlighted papers this month are a nice complement to the news from Paris, featuring real-world clinical data and a position paper with implications for contemporary practice, as well as important translational research to set the stage for future immunotherapies.

Ana Costa and colleagues use single-cell transcriptomics to characterize the tumor microenvironment of neuroblastoma in a clinically relevant murine model as well as samples from human patients, revealing new insights into the myeloid populations involved in suppressing T cell responses.

In a drug repurposing screen, Laura Schäkel et al identify the approved anaplastic lymphoma kinase (ALK) inhibitor ceritinib as a novel allosteric inhibitor of CD39, which catalyzes the hydrolysis of ATP to AMP in a key first step in establishing adenosine-mediated immunosuppression. An excellent review on CD39 by David Allard, Bertrand Allard, and John Stagg was published in 2020 in JITC’s Immune Checkpoints Beyond PD-1 series.

Zeynep Eroglu et al demonstrate that adjuvant anti-PD-1 in patients with sentinel lymph node positive melanoma who did not undergo immediate complete lymph node dissection (CLND) offers similar benefits in a retrospective analysis of real-world outcomes as was seen in the registrational trials of adjuvant therapy in which CLND was mandated.

Finally, a timely position article from Ahmad A Tarhini and colleagues on behalf of the National Cancer Institute Early Drug Development Neoadjuvant Immunotherapy Working Group summarizes the current state of neoadjuvant immunotherapy of solid tumors, offering suggestions for future progress across disease settings.



Best,

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


JITC Editor Picks

Single-cell transcriptomics reveals shared immunosuppressive landscapes of mouse and human neuroblastoma

Ana Costa, Cécile Thirant, Amira Kramdi, Cécile Pierre-Eugène, Caroline Louis-Brennetot, Orphée Blanchard, Didier Surdez, Nadege Gruel, Eve Lapouble, Gaëlle Pierron, Deborah Sitbon, Hervé Brisse, Arnaud Gauthier, Paul Fréneaux, Mylène Bohec, Virginie Raynal, Sylvain Baulande, Renaud Leclere, Gabriel Champenois, Andre Nicolas, Didier Meseure, Angela Bellini, Aurelien Marabelle, Birgit Geoerger, Fatima Mechta-Grigoriou, Gudrun Schleiermacher, Laurie Menger, Olivier Delattre, Isabelle Janoueix-Lerosey Journal for ImmunoTherapy of Cancer 2022;10:e004807 (5 August 2022)
RESEARCH
 
Summary:
The immune microenvironment of neuroblastoma is incompletely understood, with studies to date relying on limited numbers of markers to characterize the constituents. Using a combination of single-cell transcriptomics as well as multicolor flow cytometry and immunohistochemistry, Ana Costa and colleagues provide a complete characterization of the neuroblastoma tumor microenvironment in the commonly used TH-MYCN transgenic mouse model and biopsies from human patients. Common across the mouse models and the human specimens were abundant macrophages and myeloid cells, with macrophages expressing genes consistent with a suppressive M2 phenotype and the myeloid population displaying signatures consistent with neutrophils and myeloid-derived suppressor cells. Myeloid cells isolated from murine tumors strongly inhibited CD4+ and CD8+ T cell proliferation in vitro, confirming their suppressive phenotype. Heterogeneous populations of cancer-associated fibroblasts were also present in both mouse and human tumors. The rare T cells present in the tumors all expressed at least one exhaustion marker, including LAG3, TIGIT, CTLA-4, TIM3, and PD-L1. The data not only confirm the relevance of the TH-MYCN model to the immunosuppressed human neuroblastoma microenvironment, but also offer a rich resource for potential target identification for future immune therapies.

Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39 – a promising target for cancer immunotherapy

Laura Schäkel, Salahuddin Mirza, Riekje Winzer, Vittoria Lopez, Riham Idris, Haneen Al-Hroub, Julie Pelletier, Jean Sévigny, Eva Tolosa, Christa E Müller
Journal for ImmunoTherapy of Cancer 2022;10:e004325 (18 August 2022)
RESEARCH
 
Summary:
Hypoxia-induced upregulation of extracellular ectonucleases on cancer cells leads to an accumulation of adenosine in the tumor microenvironment, resulting in potent immunosuppression. Small molecule inhibitors of the key cell-surface ectonuclease CD39, which catalyzes the hydrolysis of ATP to AMP, are unfavorable drug candidates due to metabolic instability and lack of selectivity. Reasoning that approved ATP-competitive receptor tyrosine kinase inhibitors might also have activity against the ATP-binding site of CD39, Laura Schäkel et al identified ceritinib as a new chemotype of CD39 inhibitor in a repurposing screen. Out of the 50 compounds screened against in vitro preparations of CD39 expressed in umbilical cord membranes, the only hit with greater than 50% inhibition was the anaplastic lymphoma kinase (ALK) inhibitor ceritinib, which is approved in non-small cell lung cancer indications. Identical half maximal inhibitory concentrations in the micromolar range were observed across two different assays with substrate concentrations that varied by twofold. Surprisingly, characterization of the Michaelis constant and maximum reaction rate revealed that ceritinib inhibits CD39 in a non-competitive, allosteric manner. Consistent with the in vitro results, ceritinib inhibited extracellular ATP hydrolysis by primary human peripheral blood mononuclear cells, breast cancer and melanoma membrane preparations, as well as live cancer cells. These findings lay the groundwork for optimization of ceritinib as a modulator of adenosine-mediated immunosuppression.

 

Outcomes with adjuvant anti-PD-1 therapy in patients with sentinel lymph node-positive melanoma without completion lymph node dissection

Zeynep Eroglu, Kristy K Broman,John F Thompson, Amanda Nijhuis,Tina J Hieken, Lisa Kottschade, Jeffrey M Farma, Meghan Hotz, Jeremiah Deneve, Martin Fleming, Edmund K Bartlett, Avinash Sharma, Lesly Dossett, Tasha Hughes, David E Gyorki, Jennifer Downs, Giorgos Karakousis, Yun Song, Ann Lee, Russell S Berman, Alexander van Akkooi, Emma Stahlie, Dale Han, John Vetto, Georgia Beasley, Norma E Farrow, Jane Yuet Ching Hui, Marc Moncrieff, Jenny Nobes, Kirsten Baecher, Matthew Perez, Michael Lowe, David W Ollila, Frances A Collichio, Roger Olofsson Bagge, Jan Mattsson, Hidde M Kroon, Harvey Chai, Jyri Teras, James Sun, Michael J Carr, Ankita Tandon, Nalan Akgul Babacan, Younchul Kim, Mahrukh Naqvi, Jonathan Zager, Nikhil I Khushalani
Journal for ImmunoTherapy of Cancer 2022;10:e004417 (24 August 2022)
SHORT REPORT
 
Summary:
Since 2017, most patients with resectable, sentinel lymph node positive melanoma forgo complete lymph node dissection (CLND) based on no deficits in 3-year melanoma-specific survival and 5-year overall survival, respectively, in the MSLT-II and DeCOG-SLT trials. However, the registrational trials for adjuvant systemic immunotherapy for resectable melanoma, CheckMate 238 and EORTC1325/KEYNOTE-054, mandated CLND and outcomes for patients treated with adjuvant systemic therapy after a positive sentinel lymph node without a CLND are not known. In a multicenter retrospective analysis that included patients with sentinel lymph node positive melanoma treated at 21 centers in the USA, Europe, and Australia after the results from MSLT-II became available in 2017, Zeynep Eroglu and colleagues demonstrate that omitting CLND prior to adjuvant anti-PD-1 does not appear to negatively affect relapse-free survival. Interestingly, although the absolute rates of 2-year relapse-free survival were similar in this retrospective cohort to those seen in CheckMate 238 and EORTC1325/KEYNOTE-054, strikingly more frequent locoregional relapses were seen in the patients who did not undergo immediate CLND. This analysis provides important information on a major discrepancy between clinical trial conditions and real-world practice. Future trials and longer follow-up are needed to answer the open question of how to manage relapsed melanoma post-resection and adjuvant anti-PD-1. 

 

Neoadjuvant immunotherapy of locoregionally advanced solid tumors

Ahmad A Tarhini, Jennifer R Eads, Kathleen N Moore, Valerie Tatard-Leitman, John Wright, Patrick M Forde, Robert L Ferris
Journal for ImmunoTherapy of Cancer 2022;10:e004698 (16 August 2022)
POSITION ARTICLE AND GUIDELINES
 
Summary:
Administration of immunotherapy in the neoadjuvant setting has several theoretical benefits including the opportunity to prime a broad antitumor immunity while the tumor is still in situ and neoantigens are abundant as well as the ability to evaluate responses in the resection specimen. Motivated by recent progress and ongoing trials, Ahmad A Tarhini and colleagues on behalf of the National Cancer Institute Early Drug Development Neoadjuvant Immunotherapy Working Group summarize the current state of the field and offer expert recommendations for future neoadjuvant trial designs and associated clinical and translational research questions. Focusing on melanoma, gastrointestinal malignancies, gynecologic malignancies, head and neck malignancies, and non-small cell lung cancer, the working group explains the rationale for neoadjuvant approaches, reviews key milestones in clinical experience, and offers suggestions for future optimization such as combination approaches, preferred outcome measures, and risk-benefit tradeoffs. This position paper provides an important framework to support the ongoing incorporation of neoadjuvant immunotherapy into the standard of care in an increasing number of disease settings. 

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 Editor-in-Chief Pedro J. Romero, MD and Deputy Editor-in-Chief James L. Gulley, MD, PhD, FACP in person during the Meet the Editors Session 12:30–1 p.m. EST at the SITC booth

Friday, Nov. 11

  • Congratulate this year’s Pedro J. Romero Service to JITC Award recipient Cornelis J.M. “Kees” Melief, MD, PhD as well as the JITC Best Paper Award recipients at the awards ceremony starting at 8:05 a.m. EST in Hall B2
  • Learn more about JITC, journal metrics, and participate in a question and answer session with JITC Editorial Board leadership during Session 207: A Look at JITC's High-Impact Science, led by Co-Chairs Pedro J. Romero, MD and James L. Gulley, MD, PhD, FACP, 12:10–1:10 p.m. EST (location TBD)
  • Attend the poster reception and JITC 10th Anniversary Celebration Reception to join JITC editors, reviewers, authors, and readers in celebrating major accomplishments in the journal and in the field over the past ten years, 7–8:30 p.m. EST in Hall C

Throughout the Meeting

  • View and share SITC 2022 abstracts published in JITC as of Nov. 7
  • Follow @jitcancer on Twitter for additional coverage of SITC 2022
  • Visit the SITC exhibit booth to learn more about the journal

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 papers from special, thematic series in JITC over the years.
 
Explore additional thematic content in JITC's Collections and access the most popular content from the past few years for a deeper look at all the journal has to offer.

Talimogene Laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III-IV melanoma: a case series

Lillian Sun, Pauline Funchain, Jung Min Song, Patricia Rayman, Charles Tannenbaum, Jennifer Ko, Michael Mcnamara, C. Marcela Diaz-Montero, Brian Gastman Journal for ImmunoTherapy of Cancer 2018;6:36 (16 May 2018) MICROBIAL-BASED CANCER IMMUNOTHERAPY

Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade

Rikke B. Holmgaard, David A. Schaer, Yanxia Li, Stephen P. Castaneda, Mary Y. Murphy, Xiaohong Xu, Ivan Inigo, Julie Dobkin, Jason R. Manro, Philip W. Iversen, David Surguladze, Gerald E. Hall, Ruslan D. Novosiadly, Karim A. Benhadji, Gregory D. Plowman, Michael Kalos, Kyla E. Driscoll Journal for ImmunoTherapy of Cancer 2018;6:47 (4 June 2018) EMERGING IMMUNOTHERAPEUTIC AGENTS


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, Alessandra Cesano Journal for ImmunoTherapy of Cancer 2018;6:63 (22 June 2018) EMERGING IMMUNOTHERAPEUTIC AGENTS


White paper on microbial anti-cancer therapy and prevention

Robert D Leone and Leisha A Emens Journal for ImmunoTherapy of Cancer 2018;6:57 (18 June 2018)
CLINICAL TRIALS MONITOR

Monalizumab: inhibiting the novel immune checkpoint NKG2A

Thorbald van Hall, Pascale André, Amir Horowitz, Dan Fu Ruan, Linda Borst, Robert Zerbib, Emilie Narni-Mancinelli, Sjoerd H. van der Burg, Eric Vivier Journal for ImmunoTherapy of Cancer 2019;7:263 (1 December 2019) IMMUNE CHECKPOINTS BEYOND PD-1



Popular Archive Articles

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The selections below represent some of the most popular content published in JITC over the past two years. 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.

Tim-3 finds its place in the cancer immunotherapy landscape

Nandini Acharya, Catherine Sabatos-Peyton, Ana Carrizosa Anderson

Journal for ImmunoTherapy of Cancer 2020;8:e000911 (29 June 2020) IMMUNE CHECKPOINTS BEYOND PD-1

TIGIT in cancer immunotherapy

Joe- Marc Chauvin, Hassane M Zarour Journal for ImmunoTherapy of Cancer 2020;8:e000957 (7 September 2020) IMMUNE CHECKPOINTS BEYOND PD-1

LAG-3: from molecular functions to clinical applications

Takumi Maruhashi, Daisuke Sugiura, Il-mi Okazaki, Taku Okazaki Journal for ImmunoTherapy of Cancer 2020;8:e001014 (13 September 2020) IMMUNE CHECKPOINTS BEYOND PD-1

Severity of COVID-19 in patients with lung cancer: evidence and challenges

Antonio Passaro, Christine Bestvina, Maria Velez Velez, Marina Chiara Garassino, Edward Garon, Solange Peters Journal for ImmunoTherapy of Cancer 2021;9:e002266 (18 March 2021)
COVID-19 AND CANCER IMMUNOTHERAPY


COVID-19 in immunocompromised populations: implications for prognosis and repurposing of immunotherapies

Jason D Goldman, Philip C Robinson, Thomas S Uldrick, Per Ljungman Journal for ImmunoTherapy of Cancer 2021;9:e002630  (11 June 2021) COVID-19 AND CANCER IMMUNOTHERAPY


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.