Dendritic cell vaccination and CD40-agonist combination therapy licenses T cell-dependent antitumor immunity in a pancreatic carcinoma murine model

Lau, Sai Ping; Montfoort, Nadine van; Kinderman, Priscilla; Lukkes, Melanie; Klaase, Larissa; Nimwegen, Menno van; Gulijk, Mandy van; Dumas, Jasper; Mustafa, Dana A. M.; Lievense, Sanne; Groeneveldt, Christianne; Stadhouders, Ralph; Li, Yunlei; Stubbs, Andrew; Marijt, Koen A.; Vroman, Heleen; Burg, Sjoerd H. van der; Aerts, Joachim; Hall, Thorbald van; Dammeijer, Floris; Eijck, Casper H.J. van

doi:10.1136/jitc-2020-000772

Cited by 43 publications

(44 citation statements)

References 50 publications

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“…Since PDAC has a high macrophage content this triggered high interest in the clinical application of agonistic CD40 antibodies in PDAC. CD40 agonists, in combination with mesothelioma-lysate loaded DCs [100] or IL-15 [101], have demonstrated promising pre-clinical results in PDAC models. Beatty et al [83,84] combined a CD40 agonist with gemcitabine in 22 chemotherapy-naïve advanced PDAC patients (Table 3).…”

Section: Cd40 Agonistmentioning

confidence: 99%

Pancreatic Cancer and Immunotherapy: A Clinical Overview

Timmer

Geboers

Nieuwenhuizen

et al. 2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC’s immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.

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Section: Cd40 Agonistmentioning

confidence: 99%

Pancreatic Cancer and Immunotherapy: A Clinical Overview

Timmer

Geboers

Nieuwenhuizen

et al. 2021

Cancers

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“…Delivering vaccines to DC via CD40 antibodies with peptide vaccines chemically linked to the antibody, resulted in superior CD8 + T cell priming when compared to targeting of other receptors such as various c-type lectins, mannose receptors and integrins [119] [120]. Further, the importance of CD40 activation in a cancer vaccination setting has been confirmed in various other preclinical models [121][122][123][124].…”

Section: Vaccinesmentioning

confidence: 95%

Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy

Smith

Deronic

Hägerbrand

et al. 2021

Expert Opinion on Biological Therapy

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CD40 signaling activates dendritic cells leading to improved T cell priming against tumor antigens. CD40 agonism expands the tumor-specific T cell repertoire and has the potential to increase the fraction of patients that respond to established immunotherapies. Areas covered:This article reviews current as well as emerging CD40 agonist therapies with a focus on antibody-based therapies, including next generation bispecific CD40 agonists. The scientific rationale for different design criteria, binding epitopes and formats are discussed.

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“…In macrophages, CD40 stimulation leads to TNF receptorassociated factor (TRAF)-mediated intracellular signaling and cell activation [161]. In mononuclear phagocytes, it upregulates the expression of several costimulatory molecules, leading to enhanced antigen presentation and subsequent activation of cytotoxic T lymphocytes [162,163]. Myeloid cells, including CD11b lo F4/80 + macrophages, have been reported to enhance CD80, CD86 and MHC class II expression following treatment with anti-CD40 agonistic mAbs in mice bearing Pan02 tumors, improving overall survival [164].…”

Section: Tam Repolarization 81 Cd40mentioning

confidence: 99%

Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies

Hussain

Cragg

Beers

2021

Cancers

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Among the diverse tumor resident immune cell types, tumor-associated macrophages (TAMs) are often the most abundant, possess an anti-inflammatory phenotype, orchestrate tumor immune evasion and are frequently associated with poor prognosis. However, TAMs can also be harnessed to destroy antibody-opsonized tumor cells through the process of antibody-dependent cellular phagocytosis (ADCP). Clinically important tumor-targeting monoclonal antibodies (mAb) such as Rituximab, Herceptin and Cetuximab, function, at least in part, by inducing macrophages to eliminate tumor cells via ADCP. For IgG mAb, this is mediated by antibody-binding activating Fc gamma receptors (FcγR), with resultant phagocytic activity impacted by the level of co-engagement with the single inhibitory FcγRIIb. Approaches to enhance ADCP in the tumor microenvironment include the repolarization of TAMs to proinflammatory phenotypes or the direct augmentation of ADCP by targeting so-called ‘phagocytosis checkpoints’. Here we review the most promising new strategies targeting the cell surface molecules present on TAMs, which include the inhibition of ‘don’t eat me signals’ or targeting immunostimulatory pathways with agonistic mAb and small molecules to augment tumor-targeting mAb immunotherapies and overcome therapeutic resistance.

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Dendritic cell vaccination and CD40-agonist combination therapy licenses T cell-dependent antitumor immunity in a pancreatic carcinoma murine model

Cited by 43 publications

References 50 publications

Pancreatic Cancer and Immunotherapy: A Clinical Overview

Pancreatic Cancer and Immunotherapy: A Clinical Overview

Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy

Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies

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