Local targets for immune therapy to cancer: Tumor draining lymph nodes and tumor microenvironment

Fransen, Marieke F.; Arens, Ramon; Melief, Cornelis J.M.

doi:10.1002/ijc.27755

Cited by 71 publications

(48 citation statements)

References 70 publications

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“…Importantly, B cell lines did not undergo additional proliferation as a result of treatment with anti-CD20:CD40L. These findings are in agreement with earlier reports on therapeutic exploitation of CD40 and highlight our approach as a means of achieving loco-regional maturation of DC in the tumor micro-environment [13]. Furthermore, rational incorporation of scFv fragments into these fusion proteins can be used to confer additional anti-cancer effects.…”

Section: Discussionsupporting

confidence: 89%

“…Indeed, dose-limiting toxicity using sCD40L or agonistic CD40 antibodies has been reported in humans [10-12]. Importantly, whereas systemic treatment with agonistic CD40 Abs in pre-clinical mouse models was associated with significant liver toxicity, local administration of agonistic CD40 Abs proved equally effective, yet without the associated toxicity [13,14]. …”

Section: Introductionmentioning

confidence: 99%

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Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death

et al. 2014

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BackgroundStimulation of CD40 can augment anti-cancer T cell immune responses by triggering effective activation and maturation of antigen-presenting cells (APCs). Although CD40 agonists have clinical activity in humans, the associated systemic activation of the immune system triggers dose-limiting side-effects.MethodsTo increase the tumor selectivity of CD40 agonist-based therapies, we developed an approach in which soluble trimeric CD40L (sCD40L) is genetically fused to tumor targeting antibody fragments, yielding scFv:CD40L fusion proteins. We hypothesized that scFv:CD40L fusion proteins would have reduced CD40 agonist activity similar to sCD40L but will be converted to a highly agonistic membrane CD40L-like form of CD40L upon anchoring to cell surface exposed antigen via the scFv domain.ResultsTargeted delivery of CD40L to the carcinoma marker EpCAM on carcinoma cells induced dose-dependent paracrine maturation of DCs ~20-fold more effective than a non-targeted control scFv:CD40L fusion protein. Similarly, targeted delivery of CD40L to the B cell leukemia marker CD20 induced effective paracrine maturation of DCs. Of note, the CD20-selective delivery of CD40L also triggered loss of cell viability in certain B cell leukemic cell lines as a result of CD20-induced apoptosis.ConclusionsTargeted delivery of CD40L to cancer cells is a promising strategy that may help to trigger cancer-localized activation of CD40 and can be modified to exert additional anti-cancer activity via the targeting domain.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death

et al. 2014

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“…Unfortunately, TDLNs are directly influenced by tumor-derived immunosuppressive factors, which lead to decreased DC population and impaired DC maturation. Previous studies have shown that increasing mature DCs in TDLNs is crucial for eliciting effective anti- tumor immune responses and tumor eradication [33]. We therefore investigated the effect of different vaccines on DC population in TDLNs.…”

Section: Immunization Of Pmp/ova/sirna Increased Mature DC But Decreamentioning

confidence: 99%

Nanovaccine loaded with poly I:C and STAT3 siRNA robustly elicits anti-tumor immune responses through modulating tumor-associated dendritic cells in vivo

et al. 2015

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“…23 As antitumor T cell priming occurs in tumor draining lymph nodes, 24 we first examined IFN-g-expressing T cells in tumor draining lymph nodes. Compared to the animals receiving the blank hydrogel treatment, the treatments using the hydrogels carrying either celecoxib or anti-PD-1 mAb did not significantly increase the percentage of IFN-g-expressing CD4…”

Section: Dual Delivery Of Celecoxib and Anti-pd-1 Mab Elicits A Synermentioning

confidence: 99%

Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity

et al. 2015

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Two major challenges facing cancer immunotherapy are the relatively low therapeutic efficacy and the potential side effects. New drug delivery system and efficient drug combination are required to overcome these challenges. We utilize an alginate hydrogel system to locally deliver 2 FDA-approved drugs, celecoxib and programmed death 1 (PD-1) monoclonal antibody (mAb), to treat tumor-bearing mice. In two cancer models, B16-F10 melanoma and 4T1 metastatic breast cancer, the alginate hydrogel delivery system significantly improves the antitumor activities of celecoxib (CXB), PD-1 mAb, or both combined. These effects are associated with the sustained high concentrations of the drugs in peripheral circulation and within tumor regions. Strikingly, the simultaneous dual local delivery of celecoxib and PD-1 from this hydrogel system synergistically enhanced the presence of CD4 C inteferon (IFN)-g C and CD8C IFN-g C T cells within the tumor as well as in the immune system. These effects are accompanied with reduced CD4 C FoxP3 C regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) in the tumor, reflecting a weakened immuosuppressive response. Furthermore, this combinatorial therapy increases the expression of two anti-angiogenic chemokines C-X-C motif ligand (CXCL) 9 and CXCL10, and suppresses the intratumoral production of interleukin (IL)-1, IL-6, and cycloxygenase-2 (COX2), suggesting a dampened pro-tumor angiogenic and inflammatory microenvironment. This alginate-hydrogel-mediated, combinatorial therapy of celecoxib and PD-1 mAb provides a potential valuable regimen for treating human cancer.

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Local targets for immune therapy to cancer: Tumor draining lymph nodes and tumor microenvironment

Cited by 71 publications

References 70 publications

Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death

Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death

Nanovaccine loaded with poly I:C and STAT3 siRNA robustly elicits anti-tumor immune responses through modulating tumor-associated dendritic cells in vivo

Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity

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