JITC Digest December 2021

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Inside this Issue:

Letter from the Editor

Hello JITC Readers,pedro-romero_1__1_.jpg

Welcome to the final JITC digest of 2021. This past year has not been without its challenges, but the immunotherapy field has also seen tremendous advancement. Checkpoint inhibitors are moving into the standard of care for an ever increasing number of tumor types as well as in earlier stages of disease and the number of approved CAR T cell products has more than doubled in the past year alone.
 

The journal has also progressed by leaps and bounds this year, and the more than three-point bump in JITC’s impact factor in 2021 reflects the high quality of research found in every issue. As the journal continues to grow and excel, I am excited to announce that James L. Gulley MD, PhD, FACP, has been appointed to the role of Deputy Editor-in-Chief. Be sure to read this month’s special feature for a biography of JITC’s new second-in-command and the extensive experience he brings to the role.

For the final digest of the year, we are highlighting four exemplary original research articles that offer innovative approaches for modulation of the tumor microenvironment.

Intratumoral immunotherapy is the focus of Yu-Chao Zhu and colleagues and Maite Alvarez et al. The first group demonstrate feasibility of intratumoral administration of an attenuated strain of the protozoan parasite Toxoplasma gondii leading to tumor rejection and immune memory. The second manuscript shows synergistic activity of a poly I:C derivative and a STING agonist even when injected into separate lesions.

New mechanistic insight into mechanisms of immune evasion are also offered. Inhibition of dipeptidyl peptidase is identified as a strategy to enhance efficacy of anti-PD-1 against the immunologically cold tumor pancreatic ductal adenocarcinoma by Allison A. Fitzgerald et al. A new soluble immune checkpoint, chitinase 3-like-1, is revealed as an inhibitor of natural killer (NK) cell antibody-dependent cellular cytotoxicity by Abbass Darwich and colleagues.

With well-wishes for the holidays and optimism for what 2022 will bring.

Best,

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


JITC Editor Picks

Synergy between Toxoplasma gondii type I deltaGRA17 immunotherapy and PD-L1 checkpoint inhibition triggers the regression of targeted and distal tumors

Yu-Chao Zhu, Hany M Elsheikha, Jian-Hua Wang, Shuai Fang, Jun-Jun He, Xing-Quan Zhu, Jia Chen

Journal for ImmunoTherapy of Cancer 2021;9:e002970 (1 November 2021)
Research

Summary:

Attenuated strains of the obligate intracellular protozoan parasite Toxoplasma gondii have been demonstrated to increase antigen processing and presentation, as well as priming and activation of tumor antigen-specific CD8+ T cells in the tumor microenvironment. Yu-Chao Zhu and colleagues show that intratumoral administration of the T. gondii strain deltaGRA17 not only mediates regression of injected and distal lesions, but also enhances therapeutic benefits of immune checkpoint blockade. In immunocompetent murine models of melanoma, intratumoral injection of deltaGRA17 led to regressions and 70% of the mice rejected tumors upon rechallenge. No attenuation of tumor growth was seen when the parasites were administered intravenously or intraperitoneally nor if the protozoans were heat-killed before injection. Robust infiltration of CD3+ T cells, CD4+ T cells, CD8+ T cells, natural killer (NK) cells, NKT cells, macrophages, and dendritic cells was seen in both injected and distal tumors after administration of the parasite. An intact immune system was required for benefit. Unlike what has been seen with oncolytic viruses, latent infection with a different T. gondii strain did not compromise anti-tumor effects. When deltaGRA17 was administered along with anti-PD-L1 antibody, complete tumor rejection was observed in injected and distal tumors and regressions were observed at an earlier time point compared to monotherapy with the protozoan alone. Both NK and CD8+ cells were necessary for efficacy of the combination treatment. Although deltaGRA17 is not suitable for use in humans due to its virulence at moderate infection doses, the findings highlight the potential for parasite therapy to render tumors responsive to immunotherapy.

Intratumoral co-injection of the poly I:C-derivative BO-112 and a STING agonist synergize to achieve local and distant anti-tumor efficacy

Maite Alvarez, Carmen Molina, Carlos E De Andrea, Myriam Fernandez-Sendin, Maria Villalba, Jose Gonzalez-Gomariz, Maria Carmen Ochoa, Alvaro Teijeira, Javier Glez-Vaz, Fernando Aranda, Miguel F Sanmamed, Maria E Rodriguez-Ruiz, Xinyi Fan, Wen H Shen, Pedro Berraondo, Marisol Quintero, Ignacio Melero

Journal for ImmunoTherapy of Cancer 2021;9:e002953  (25 November 2021)

Research

Summary:

The TLR3, MDA5, and PKR agonist poly I:C-derivative BO-112 and the STING agonist DMXAA both mediate rejection of directly injected tumors but have only modest efficacy against distant untreated lesions in preclinical models. Based on the partially shared but non-overlapping mechanisms of action, Maite Alvarez and colleagues evaluated potential synergy with co-administration of BO-112 and DMXAA. In the MC38 murine model of colorectal cancer, co-injection of BO-112 and DMXAA led to complete control of injected lesions and shrinkage of distal tumors. Control of distal tumors was sub-optimal even with the dual injection in mice bearing B16.OVA-derived melanomas, yet the addition of anti-PD-1 was associated with enhanced disease control. In the MC38 model, injection of both agents led to higher ratios of infiltrating CD8+ to regulatory T cells compared to either monotherapy. Strikingly, changes in the lymphocytic infiltrate after co-administration of BO-112 and DMXAA were also seen in uninjected tumors as soon as 72 hours after the last injection. No evidence for synergy between the agents was seen in lymphocyte populations in the tumor-draining lymph node nor in serum cytokine concentrations after co-injection. Conventional type 1 dendritic cells were required for distal tumor regression after co-injection, as was intact type 1 interferon signaling. Injection of BO-112 and DMXAA into separate lesions led to complete regression of a third untreated mass in 8 out of 12 MC38-bearing mice. The findings lay the foundation for investigation of co-administration of multiple intratumoral immunotherapy agents to enhance the efficacy of these approaches.

DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma

Allison A Fitzgerald, Shangzi Wang, Veena Agarwal, Emily F Marcisak, Annie Zuo, Sandra A Jablonski, Melanie Loth, Elana J Fertig, John MacDougall, Eugene Zhukovsky, Shubhendu Trivedi, Dimple Bhatia, Vince O'Neill, Louis M Weiner
Journal for ImmunoTherapy of Cancer
 
2021;9:e002837 (4 November 2021)
Research

Summary:

Dipeptidyl peptidase (DPP) inhibitors of various classes can enhance recruitment of natural killer (NK) and T cells into tumors as well as induce pyroptosis leading to release of proinflammatory cytokines. Allison A Fitzgerald et al provide evidence that DPP inhibition enhances anti-PD-1 efficacy in mouse models of the immunologically cold tumor pancreatic ductal adenocarcinoma (PDAC). Administration of the oral DPP inhibitor BXCL701 led to durable disease control even after cessation of therapy in murine p53- and KRAS-mutant PDAC. BXCL701 treatment was associated with elevated serum levels of IL-1beta and IL-18, consistent with induction of pyroptosis, as well as Th1 cytokines such as interferon gamma, IL-2, and IL-12. Transcriptomic analyses of BXCL701-treated tumors revealed enrichment for interferon gamma signatures and genes involved in Th1 lineage commitment. Treatment with BXCL701 led to increased intratumoral counts of CXCR3+ cells, specifically CD4+ T cells, CD8+ T cells, and NK cells. Combination therapy with BXCL701 and anti-PD-1 led to complete tumor rejection with resistance to rechallenge in 10 of 13 treated mice. Efficacy of the combination was significantly impaired when either CD8+ T cells or NK cells were depleted. Data from The Cancer Genome Atlas revealed a correlation between high tumor expression of the NK cell markers NCAM1 (CD56) and LAMP1 (CD107a) with longer overall survival in patients with PDAC. These findings support further clinical development of DPP inhibitors in combination with anti-PD-1 for the treatment of immunologically cold tumors.

Paralysis of the cytotoxic granule machinery is a new cancer immune evasion mechanism mediated by chitinase 3-like-1

Abbass Darwich, Alessandra Silvestri, Mohamed-Reda Benmebarek, Juliette Mouriès, Bruno Cadilha, Alessia Melacarne, Lapo Morelli, Domenico Supino, Alexandre Taleb, Hannah Obeck, Claudio Sustmann, Agnese Losurdo, Giovanna Masci, Giuseppe Curigliano, Sebastian Kobold, Giuseppe Penna, Maria Rescigno

Journal for ImmunoTherapy of Cancer 2021;9:e003224 (25 November 2021)

Research

Summary:

Natural killer (NK) cells have recently gained recognition as essential players in the control of solid tumors and the mechanisms by which cancer cells escape lysis are poorly understood. By screening sera from patients with trastuzumab-resistant HER2+ breast cancer, Abbass Darwich and colleagues identify the inflammatory protein chitinase 3-like-1 (CHI3L1) as an inhibitor of NK cell antibody-dependent cellular cytotoxicity (ADCC) that functions mechanistically by inhibiting polarization of the microtubule-organizing center at the immune synapse. CHI3L1 did not affect in vitro NK cell degranulation as measured by CD107a staining nor the expression of cytotoxicity receptors CD16 and NKG2D. Confocal microscopy and live-cell imaging showed that CHI3L1 impaired perforin polarization to the immune synapse despite correct progression through early stages of lytic conjugation. Efficient target cell engagement was observed in CHI3L1-treated NK cells, however, detachment occurred without productive release of lytic granules. Incubation with CHI3L1 led to downmodulation of the receptor of advanced glycation end products (RAGE), which was associated with impaired induction of JNK. Treatment with the JNK inhibitor SP600125 phenocopied CHI3L1. In vivo, tumor engraftment and growth of NK cell-susceptible RMA-S lymphoma cells was markedly enhanced by injections of recombinant CHI3L1. Furthermore, in NSG mice subcutaneously implanted with HCC1569 HER2+ breast cancer cells and adoptively transferred with ex vivo expanded human NK cells, complete tumor regressions were observed after combination therapy with trastuzumab and anti-CHI3L1 antibody. ADCC was necessary for benefit with the combination, as an Fc-silent isotype of trastuzumab failed to control tumor growth when given with anti-CHI3L1. The findings demonstrate a new role of CHI3L1 as a soluble immune checkpoint molecule that impairs the NK cell cytotoxic machinery.

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JITC's New Deputy Editor-in-Chief

Meet JITC's New Deputy Editor-in-Chief: James L. Gulley, MD, PhD, FACP

Given the continuing growth of JITC, the position of Deputy Editor-in-Chief has been added to JITC’s leadership to support the JITC Editor-in-Chief in leading the strategic and editorial direction of the journal, serving as second-in-command of the Editorial Board. JITC is proud to announce the appointment of Dr. James L. Gulley as JITC’s inaugural Deputy Editor-in-Chief.

Dr. Gulley has served as a Section Editor for JITC’s Clinical/Translational Cancer Immunotherapy section since 2017. Dr. Gulley has been instrumental in preparing for, responding to, and managing the growth of what is JITC’s largest section over the past four years. With his leadership and strategic insights, the section welcomed the addition of a second Section Editor, was the first to introduce Deputy Editor roles at a section level, and expanded its Associate Editor representation. He also received the 2021 Pedro J. Romero Service to JITC Award in November 2021.

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