JITC Digest December 2022

By JITC Publications posted 12-21-2022 00:00

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INSIDE THIS ISSUE:

LETTER FROM THE EDITOR JITC EDITOR PICKS FROM THE VAULT POPULAR ARCHIVE ARTICLES

Letter from the Editor

Dear JITC Readers,

Welcome to the last JITC Digest of 2022. It has been a busy and momentous year for the journal—we celebrated our 10^th anniversary, we launched our peer review mentorship program, we surpassed 40,000 total citations, and we accepted more than 500 high-quality articles for publication.

Among the excellent articles that we published this year, our review series, “Imaging and Immunotherapy,” featured eight fantastic papers from leading voices from a multitude of backgrounds, including oncologists, imaging scientists, and radiologists. Explore this month’s special feature to catch up on the reviews on topics including novel imaging strategies, new approaches to conventional imaging such as artificial intelligence and radiomics, as well as special considerations for radiotherapy, immunotherapy, and imaging.

This month’s original research highlights include two innovative approaches to cell therapy, a role for RNA editing in limiting antitumor immunity with DNA methyltransferase inhibition, and the first quantitative systems pharmacology model for hepatocellular carcinoma.

Alvaro Haroun-Izquierdo and colleagues lay the groundwork for off-the-shelf cell therapies by developing a GMP-compliant protocol to reproducibly and robustly expand adaptive NK cells. Mechanisms of resistance to anti-BCMA CAR T cells in multiple myeloma are characterized by Nicolas Camviel et al.

Stephanie Gomez and colleagues provide rationale for combination inhibition of adenosine deaminase 1 and DNA methyltransferases to enhance lymphocyte infiltration and interferon sensitivity in ovarian cancer.

Finally, Richard J Sové et al conduct a virtual clinical trial in advanced hepatocellular carcinoma and identify candidate biomarkers predicting response to combination PD-1 and CTLA-4 blockade.

Wishing you all a wonderful holiday season and looking forward to the year ahead.

Best,

Pedro J. Romero, MD

Editor-in-Chief, Journal for ImmunoTherapy of Cancer

JITC Editor Picks

ADAPTIVE SINGLE-KIR+NKG2C+ NK CELLS EXPANDED FROM SELECT SUPERDONORS SHOW POTENT MISSING-SELF REACTIVITY AND EFFICIENTLY CONTROL HLA-MISMATCHED ACUTE MYELOID LEUKEMIA

Alvaro Haroun-Izquierdo, Marianna Vincenti, Herman Netskar, Hanna van Ooijen, Bin Zhang, Laura Bendzick, Minoru Kanaya, Pouria Momayyezi, Shuo Li, Merete Thune Wiiger, Hanna Julie Hoel, Silje Zandstra Krokeide, Veronika Kremer, Geir Tjonnfjord, Stéphanie Berggren, Kristina Wikström, Pontus Blomberg, Evren Alici, Martin Felices, Björn Önfelt, Petter Höglund, Bahram Valamehr, Hans-Gustaf Ljunggren, Andreas Björklund, Quirin Hammer, Lise Kveberg, Frank Cichocki, Jeffrey S Miller, Karl-Johan Malmberg, Ebba Sohlberg
Journal for ImmunoTherapy of Cancer 2022;10:e005577 (01 November 2022)
RESEARCH

Summary:

Natural killer (NK) cells have emerged as a promising area for development of off-the-shelf adoptive cell therapies due to potent cytotoxicity triggered by “missing-self” recognition. Alloreactivity requires a mismatch between any of the three major killer immunoglobulin-like receptor (KIR) and cognate human leukocyte antigen (HLA) class I pairs, however, generation of homogenous NK cell products with single KIRs has been a bottleneck. Alvaro Haroun-Izquierdo and colleagues developed a GMP-compliant protocol to robustly expand NK cells expressing the activating receptor NKG2C and single self-HLA-specific KIRs. Healthy donors were identified with pre-existing repertoires of NKG2C⁺ NK cells with single self-KIR expression, and replicate expansions from the same donor yielded consistent purity. The expanded cells expressed phenotypic markers of adaptive NK cells, including CD16, CD2 and Siglec-7. Notably, while mass cytometry showed expression of the T cell exhaustion markers TIGIT, PD-1, and LAG-3 in the expanded cells, perforin, DNAM-1, and granzyme B proteins were also present at high levels. Furthermore, transcriptional signatures related to exhaustion or senescence were not observed. In vitro, the expanded NK cells killed HLA-C/KIR mismatched primary patient-derived acute myeloid leukemia (AML) blasts across a range of effector-to-target ratios, and cytotoxicity was enhanced in the presence of a CD16/IL-15/CD33 trispecific engager. In immunodeficient mice engrafted with AML, a single flat dose of the expanded NK cells with IL-15 support substantially reduced tumor burden. These results set the stage for future early phase human trials of off-the-shelf NK cells.

BOTH APRIL AND ANTIBODY-FRAGMENT-BASED CAR T CELLS FOR MYELOMA INDUCE BCMA DOWNMODULATION BY TROGOCYTOSIS AND INTERNALIZATION

Nicolas Camviel, Benita Wolf, Giancarlo Croce, David Gfeller, Vincent Zoete, Caroline Arber

Journal for ImmunoTherapy of Cancer 2022;10:e005091 (02 November 2022)

RESEARCH

Summary:

Despite rapid and deep initial responses to chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA), most patients with multiple myeloma experience disease recurrence after treatment with these therapies and the mechanisms of resistance are not well understood. Nicolas Camviel and colleagues describe novel CAR T cells with target-binding motifs derived from the natural ligand of BCMA, APRIL. They further identify BCMA internalization as well as trogocytosis as key mechanisms contributing to myeloma resistance to both these novel and commercially available CAR T cells. In vitro, the APRIL-based CAR T cells robustly killed multiple myeloma cell lines. Tonic signaling was minimal, with no spontaneous secretion of IL-2 or proliferation in the absence of target antigen. Polyfunctionality and strength of immune synapse formation was improved in CAR T cells with trimeric compared to monomeric extracellular APRIL domains. Trimeric APRIL CAR T cells also had the most potent tumor control and survival improvement in mouse xenograft models. Co-culture of multiple myeloma cell lines with APRIL CAR T cells or conventional antibody fragment-based CAR T cells resulted in significant downmodulation of tumor cell surface BCMA. Shedding did not play a role in the observed downregulation, but BCMA internalization and transfer to CAR T cells were both detected by confocal microscopy. Interestingly, even though APRIL- and antibody-based CAR T cells induced nuclear factor kappa B pathway activation in vitro, no evidence for tumor growth promotion was observed in the mouse models.

INHIBITING DNA METHYLATION AND RNA EDITING UPREGULATES IMMUNOGENIC RNA TO TRANSFORM THE TUMOR MICROENVIRONMENT AND PROLONG SURVIVAL IN OVARIAN CANCER

Stephanie Gomez, Olivia L Cox, Reddick R Walker III, Uzma Rentia, Melissa Hadley, Elisa Arthofer, Noor Diab, Erin E Grundy, Tomas Kanholm, James I McDonald, Julie Kobyra, Erica Palmer, Satish Noonepalle, Alejandro Villagra, David Leitenberg, Catherine M Bollard, Yogen Saunthararajah, Katherine B Chiappinelli
Journal for ImmunoTherapy of Cancer 2022;10:e004974 (07 November 2022)
RESEARCH

Summary:

DNA methyltranferase inhibitors (DNMTis) are known to induce type I interferon signaling in tumors through a mechanism involving transcriptional de-repression of mobile genetic elements resulting in activation of intracellular double-stranded RNA sensors such as the RIG-I-like receptors, MDA5, and toll-like receptor 3. However, interferon signaling induces adenosine deaminase 1 (ADAR1), an RNA editor that changes adenosine to inosine and thus destabilizes double-stranded RNA. Hypothesizing that this RNA editing limits antitumor immunity, Stephanie Gomez et al show that Adar1 loss enhances lymphocytic infiltration as well as tumor control and survival in combination with DNMTis in clinically relevant, immunocompetent murine models of ovarian cancer. In vitro, Adar1-knockdown significantly increased secretion of CXCL5 and CXCL10 from ovarian cancer cell lines as well as increased the sensitivity to interferon beta. In models of advanced ovarian cancer, knockdown of tumor Adar1 significantly increased the numbers of tumor-infiltrating lymphocytes, but not myeloid cells, after DNMTi treatment. Lymphocyte counts, but not myeloid cells, also correlated with mouse survival. Knockdown of Adar1 also led to perturbations in the infiltrating B cell compartment and ascites levels of IgM. Blockade of interferon alpha and beta subunit 1 with an antagonistic antibody rescued the growth of Adar1-knockdown tumors in DNMTi-treated mice. Across a panel of DNMTi-treated human ovarian cancer lines, RNA editing was evident from sequencing data, and ADAR1 knockdown had the most pronounced effect on TP53-mutant cells, which is the driver mutation found in nearly all high-grade serous ovarian cancers. Several ADAR1 inhibitors are currently in development, and these data provide rationale for investigation of these agents in combination with DNMTis in ovarian cancer.

VIRTUAL CLINICAL TRIALS OF ANTI-PD-1 AND ANTI-CTLA-4 IMMUNOTHERAPY IN ADVANCED HEPATOCELLULAR CARCINOMA USING A QUANTITATIVE SYSTEMS PHARMACOLOGY MODEL

Richard J Sové, Babita K Verma, Hanwen Wang, Won Jin Ho, Mark Yarchoan, Aleksander S Popel
Journal for ImmunoTherapy of Cancer 2022;10:e005414 (02 November 2022)
RESEARCH

Summary:

Immunotherapy is now standard of care for advanced hepatocellular carcinoma (HCC), with combination of anti-PD-1 with anti-CTLA-4 approved by the United States Food and Drug Administration for first-line treatment as well as for disease that progresses on tyrosine kinase inhibition. No quantitative systems pharmacology models have been developed for HCC. Using patient data from CheckMate 040, the open-label, multi-cohort study that was the basis for accelerated approval of ipilimumab in combination with nivolumab in the second-line setting in the United States, Richard J Sové et al created a four-compartment quantitative systems pharmacology model with a total of 140 parameters to simulate immune interactions in the tumor, tumor-draining lymph node, blood, and peripheral organ compartments and predict outcomes to therapy in a virtual clinical trial. In simulation experiments exposing a total of 1747 virtual patients to six different treatment conditions (including no intervention, ipilimumab monotherapy, and the doses of nivolumab alone or in combination with ipilimumab that were evaluated in CheckMate 040), the model’s data had good agreement with real-world outcomes for overall response rates and change in tumor volume over time. Machine learning identified six parameters as the most important predictors of response in the virtual patients: cytotoxic T cell density, regulatory T cell (Treg) density, T cell to Treg ratio, number of tumor-specific T cell clones, PD-L1 expression, and exhausted T cell density. These quantitative systems pharmacology modeling approaches are an exciting new frontier for initial evaluation of novel immunotherapy combinations and biomarkers through facilitating patient selection and clinical trial design.

**Other Recent JITC Articles**

VIEW OTHER ARTICLES FROM THIS ISSUE

Imaging and Immunotherapy Series


*Elisabeth G.E. de Vries, MD, PhD*	*Lawrence H.* *Schwartz, MD*

Hot off the press! JITC’s complete special series of review articles, Imaging and Immunotherapy, is now available. Edited by Elisabeth G.E. de Vries, MD, PhD, and Lawrence H. Schwartz, MD, and authored by leading voices from a multitude of backgrounds, this series explores novel imaging strategies, new approaches to conventional imaging – including the use of artificial intelligence, radiomics, and MRI – and special considerations for radiotherapy, immunotherapy, and imaging.

Readers will enjoy this insightful holiday reading and find it illustrative of the multidisciplinary approach vital to the use of imaging for immunotherapy while also addressing challenges to be overcome for new imaging methods to be implemented into daily use.

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 two newest sections, Immune Cell Therapies and Immune Cell Engineering, and Oncolytic and Local Immunotherapy.

CCL5-ARMED ONCOLYTIC VIRUS AUGMENTS CCR5-ENGINEERED NK CELL INFILTRATION AND ANTITUMOR EFFICIENCY

Feng Li, Yuqiao Sheng, Weizhou Hou, Padma Sampath, Daniel Byrd, Stephen Thorne, Yi Zhang
Journal for ImmunoTherapy of Cancer 2020;8:e000131 (24 February 2020) RESEARCH

INHIBITION OF TGF-Β-RECEPTOR SIGNALING AUGMENTS THE ANTITUMOR FUNCTION OF ROR1-SPECIFIC CAR T-CELLS AGAINST TRIPLE-NEGATIVE BREAST CANCER

Tanja Stüber, Razieh Monjezi, Lars Wallstabe, Johanna Kühnemundt, Sarah Louise Nietzer, Gudrun Dandekar, Achim Wöckel, Hermann Einsele, Jörg Wischhusen, Michael Hudecek
Journal for ImmunoTherapy of Cancer 2020;8:e000676 (16 April 2020) SHORT REPORT

THE FULLY HUMAN ANTI-CD47 ANTIBODY SRF231 EXERTS DUAL-MECHANISM ANTITUMOR ACTIVITY VIA ENGAGEMENT OF THE ACTIVATING RECEPTOR CD32A

Marisa O Peluso, Ammar Adam, Caroline M Armet, Li Zhang, Rachel W O’Connor, Benjamin H Lee, Andrew C Lake, Emmanuel Normant, Scott C Chappel, Jonathan A Hill, Vito J Palombella, Pamela M Holland and Alison M Paterson
Journal for ImmunoTherapy of Cancer 2020;8:e000413 (28 April 2020)RESEARCH

OVERCOMING HYPOXIA-INDUCED FUNCTIONAL SUPPRESSION OF NK CELLS

Kristen Solocinski, Michelle R Padget, Kellsye P Fabian, Benjamin Wolfson, Fabiola Cecchi, Todd Hembrough, Stephen C Benz, Shahrooz Rabizadeh, Patrick Soon-Shiong, Jeffrey Schlom, James W Hodge
Journal for ImmunoTherapy of Cancer 2020;8:e000246 (28 April 2020) RESEARCH

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

Marion Allouchery, Thomas Lombard, Mickael Martin, Franck Rouby, Marion Sassier, Celia Bertin, Marina Atzenhoffer, Ghada Miremont-Salame, Marie-Christine Perault-Pochat, Mathieu Puyade
Journal for ImmunoTherapy of Cancer 2020;8:e001622 (21 December 2020)RESEARCH

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