JITC Digest March 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. If any of our readers will be in New Orleans next month for the 2022 American Association for Cancer Research (AACR) Annual Meeting, we hope you will stop by the SITC booth in the exhibition hall for an opportunity to interact in person with JITC Deputy Editor-in-Chief Dr. James L. Gulley during one of our two Meet the Editor Sessions scheduled for 11:50 a.m.–12:20 p.m. on Monday, April 11 and Tuesday, April 12.

If you won’t be traveling to AACR, you can always take a virtual trip back in time with our popular archive articles, spotlighting important publications from the journal’s recent past.

Of course, the main attraction for the JITC digest is the exciting new papers in the current issue. This month we have two original research articles and a short report from the Clinical/Translational Cancer Immunotherapy section as well as original research from the Immunotherapy Biomarkers section.

Martina Svenja Lutz and colleagues describe a new mechanism of tumor immune escape from bispecific antibody treatment mediated by platelet activation.

A pan-cancer predictor for immune-related toxicity after anti-PD-1 monotherapy based on germline variants in microRNAs and their targets is identified by Joanne Weidhaas et al.

Treatment with anti-CCR4 leads to regulatory T cell depletion and meaningful tumor control in a canine clinical trial enrolling dogs with spontaneous prostate cancer reported by Shingo Maeda and colleagues.

Dipti Thakkar and colleagues demonstrate tumor control and microenvironment remodeling in multiple models with a first-in-class rationally targeted and non-depleting IgG4 isotype anti-VISTA antibody. After reading this comprehensive and meticulous work, be sure to continue your reading on VISTA and other promising targets in JITC’s Immune Checkpoints Beyond PD-1 Series.

Best regards,

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

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JITC Editor Picks

Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies

Martina Svenja Lutz, Boris Klimovich, Stefanie Maurer, Jonas S Heitmann, Melanie Märklin, Latifa Zekri, Gundram Jung, Helmut R Salih, Clemens Hinterleitner
Journal for ImmunoTherapy of Cancer 2022;10:e003655 (2 February 2022)
Research

Summary:

During a phase I study evaluating a PSMAxCD3 bispecific antibody for the treatment of metastatic castration-resistant prostate cancer, Martina Svenja Lutz et al noticed a marked decrease in platelet counts accompanied by an upregulation of the activation marker P-selectin (CD62P) on platelets. Activated T cells were necessary for the bispecific antibody to induce CD62P upregulation in vitro and blockade of the CD40–CD40L axis reduced platelet activation. Notably, platelets inhibited T cell activation during coculture with target cells not only for the PSMAxCD3 bispecific but also with an investigational NKG2D×CD3 bispecific fusion protein and the approved CD19xCD3 bispecific T cell engager, blinatumomab. Platelets reduced the numbers of perforin-positive effector cells as well as target cell lysis induced by the PMSAxCD3 bispecific and treatment with the anticoagulant dabigatran rescued T cell activation whereas the non-steroidal anti-inflammatory agent indomethacin had no effect. Platelet releasate (supernatant from activated platelets) was sufficient to impair bispecific antibody-mediated tumor cell lysis, and TGF-beta was found to be the most elevated cytokine within releasate preparations. Blockade of TGF-beta restored T cell reactivity with the bispecific when platelets were present. The findings describe a new mechanism of tumor immune escape through a feedback loop wherein T cells recruited by bispecific antibodies induce platelet activation leading to TGF-beta-mediated suppression of effector functions—this mechanism may have implications for other T cell redirecting immunotherapies including CAR T cells.

Germline biomarkers predict toxicity to anti-PD1/PDL1 checkpoint therapy

Joanne Weidhaas, Nicholas Marco, Aaron W Scheffler, Anusha Kalbasi, Kirk Wilenius, Emily Rietdorf, Jaya Gill, Mara Heilig, Caroline Desler, Robert K Chin, Tania Kaprealian, Susan McCloskey, Ann Raldow, Naga P Raja, Santosh Kesari, Jose Carrillo, Alexandra Drakaki, Mark Scholz, Donatello Telesca
Journal for ImmunoTherapy of Cancer 2022;10:e003625  (3 February 2022)

Research

Summary:

There are no validated biomarkers to predict which patients will develop immune-related adverse events following anti-PD-(L)1 checkpoint blockade. Hypothesizing that toxicity with checkpoint blockade represents a patient-specific (rather than tumor-specific) immune response, Joanne Weidhaas and colleagues developed a predictive signature based on germline variants in a panel of microRNAs and target sites known to regulate DNA repair and immune response. In a training cohort that included 62 patients with melanoma treated with single-agent anti-PD-1 (21 of whom developed grade 2 or higher irAEs), the signature predicted toxicity with roughly 75%–80% accuracy across four statistical models. The classifiers had similar accuracy in a validation cohort that included 99 patients with several different types of cancer, including prostate, non-prostate GU cancer, NSCLC, head and neck cancer, sarcoma, and others. For patients with the signature variants, the risk of toxicity increased with time on treatment. The most significant component of the signature was a mutation in the 3’ untranslated region of RAC1, which encodes a protein that has been implicated in autoimmune-mediated epidermal dysfunction as well as Th17-driven autoimmune encephalomyelitis. No association was seen between the overall toxicity signature and response to checkpoint blockade nor the single RAC1 variant and clinical benefit. These findings are an important first step toward personalized immunotherapy and underscore the importance of noncoding regions for genomic biomarker analysis.

Fine-tuned long-acting interleukin-2 superkine potentiates durable immune responses in mice and non-human primate

Shingo Maeda, Tomoki Motegi, Aki Iio, Kenjiro Kaji, Yuko Goto-Koshino, Shotaro Eto, Namiko Ikeda, Takayuki Nakagawa, Ryohei Nishimura, Tomohiro Yonezawa, Yasuyuki Momoi
Journal for ImmunoTherapy of Cancer 2022;10:e003731 (7 February 2022)
Research

Summary:

To evaluate the therapeutic potential of depletion of regulatory T cells (Tregs) in prostate tumors, Shingo Maeda and colleagues conducted a non-randomized clinical trial evaluating the CCR4-targeting antibody mogamulizumab in canine companion animals with spontaneous prostate cancer. Motivation for the study was provided by dramatic upregulation of the mRNA encoding the CCR4 ligand CCL17 observed in canine prostate tumors compared to normal prostate tissue. The increased chemokine expression was accompanied by a high abundance of CCR4-expressing Foxp3+ Tregs, and the degree of Treg infiltration was inversely correlated with overall survival in the dogs. For the canine clinical trial, a total of 23 dogs were treated with mogamulizumab in combination with the COX inhibitor piroxicam and compared to 23 age-, sex-, and tumor-stage-matched dogs in the control arm who received piroxicam alone. Treatment with mogamulizumab was associated with reduced numbers of circulating CD4+Foxp3+ Tregs and CCR4+ Tregs but not CD8+ cytotoxic T cells and CD4+ helper T cells. Dogs treated with mogamulizumab had a roughly 10-fold greater reduction in size of the primary tumor with approximately 3-fold longer median overall and 4-fold longer progression-free survival compared to the control arm. No severe adverse events occurred. Higher pretreatment levels of urinary CCL17 were associated with longer overall survival and tumor response in the mogamulizumab treatment arm as was the presence of BRAFV595E mutation (analogous to human BRAFV600 mutations). Data from human patients from The Cancer Genome Atlas identified enrichment for Foxp3+ Tregs and CCR4+ cells were more frequent in patients with prostate cancer and CCL17 expression predicted poor progression-free survival. The findings identify the CCR4-CCL17 axis as a viable target to alleviate Treg-mediated immunosuppression in the prostate tumor microenvironment.

Rationally targeted anti-VISTA antibody that blockades the C-C’ loop region can reverse VISTA immune suppression and remodel the immune microenvironment to potently inhibit tumor growth in an Fc independent manner

Dipti Thakkar, Shalini Paliwal, Bhushan Dharmadhikari, Siyu Guan, Lillian Liu, Shreya Kar, Nikhil K Tulsian, Joshua J Gruber, Leah DiMascio, Konrad H Paszkiewicz, Piers J Ingram, Jerome D Boyd-Kirkup
Journal for ImmunoTherapy of Cancer 2022;10:e003382 (7 February 2022)

Research

Summary:

Using an artificial intelligence-directed rational antibody discovery approach, Dipti Thakkar and colleagues developed the first anti-VISTA antibody that inhibits tumor growth in vivo without requiring Fc-mediated effector functions for anti-tumor activity. Candidate epitopes were identified by mapping the VISTA structure onto the PD-1/PD-L1 interface and the resulting antibody bound rodent, primate, and human VISTA orthologs with picomolar affinity across a range of physiological pHs. The anti-VISTA antibody reversed T cell suppression by myeloid derived suppressor cells, suppressed neutrophil migration, and polarized mixed lymphocytes toward a proinflammatory Th1/Th17 cytokine response. Single-agent anti-tumor efficacy was seen in multiple models, including syngeneic and orthotopic murine tumors as well as with human cell lines in humanized mice engrafted with CD34+ cord blood hematopoietic stem cells. Treatment was associated with significant increases in antigen presenting cells, macrophages and dendritic cells in the tumor microenvironment, reduced numbers of suppressive cells, and enhanced cytotoxic activity by tumor infiltrating lymphocytes in antigen recall assays. The pharmacokinetics were reasonable across mice, rats, and non-human primates, with reduced clearance compared to other anti-VISTA antibodies and no evidence or treatment-related morbidity or clinical signs nor significant cytokine release were seen. The findings provide preclinical evidence supporting further development of this anti-VISTA antibody to overcome myeloid-mediated immunosuppression and enhance T cell-mediated tumor rejection either as a monotherapy or in combination with anti-PD-1.

Immune Checkpoints Beyond PD-1 Series

JITC continues the impetus of recognizing a widening range of checkpoint targets that are advancing the field forward in “Immune Checkpoints Beyond PD-1,” a special series comprised of several authoritative reviews that supports the ongoing momentum for investigation and clinical development of immune checkpoints therapies beyond the PD-1 axis. Edited by Guest Editors Ana Carrizosa Anderson, PhD, and Dario A.A. Vignali, PhD, “Immune Checkpoints Beyond PD-1” promotes the tremendous research that is opening new pathways for treating patients with cancer.

PD1

Popular Archive Articles

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

Intratumoral TIGIT+ CD8+ T-cell infiltration determines poor prognosis and immune evasion in patients with muscle-invasive bladder cancer

Zhaopei Liu, Quan Zhou, Zewei Wang, Hongyu Zhang, Han Zeng, Qiuren Huang, Yifan Chen, Wenbin Jiang, Zhiyuan Lin, Yang Qu, Ying Xiong, Qi Bai, Yu Xia, Yiwei Wang, Li Liu, Yu Zhu, Le Xu, Bo Dai, Jianming Guo, Jiajun Wang, Yuan Chang, Weijuan Zhang
Journal for ImmunoTherapy of Cancer 2020;8:e000978 (16 August 2020)
Research

Eftilagimod alpha, a soluble lymphocyte activation gene-3 (LAG-3) protein plus pembrolizumab in patients with metastatic melanoma

Victoria Atkinson, Adnan Khattak, Andrew Haydon, Melissa Eastgate, Amitesh Roy, Prashanth Prithviraj, Christian Mueller, Chrystelle Brignone, Frederic Triebel
Journal for ImmunoTherapy of Cancer 2020;8:e001681 (20 November 2020)
Research

Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade

Rui Yang, Samah Elsaadi, Kristine Misund, Pegah Abdollahi, Esten Nymoen Vandsemb, Siv Helen Moen, Anna Kusnierczyk, Geir Slupphaug, Therese Standal, Anders Waage, Tobias S Slørdahl, Torstein Baade Rø, Even Rustad, Anders Sundan, Carl Hay, Zachary Cooper, Alwin G Schuller, Richard Woessner, Alexandra Borodovsky, Eline Menu, Magne Børset, Anne Marit Sponaas
Journal for ImmunoTherapy of Cancer 2020;8:e000610 (14 May 2020)
Research

Stromal LAG-3+ cells infiltration defines poor prognosis subtype muscle-invasive bladder cancer with immunoevasive contexture

Han Zeng, Quan Zhou, Zewei Wang, Hongyu Zhang, Zhaopei Liu, Qiuren Huang, Jiajun Wang, Yuan Chang, Qi Bai, Yu Xia, Yiwei Wang, Le Xu, Bo Dai, Jianming Guo, Li Liu, Yu Zhu, Jiejie Xu
Journal for ImmunoTherapy of Cancer 2020;8:e000651 (14 June 2020)
Research



SITC Members Receive 50 Percent Submission Discount in 2021

*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 processing fees for all JITC articles accepted in 2021.