Enhanced binding of necrosis-targeting immunocytokine NHS-IL12 after local tumour irradiation in murine xenograft models

Eckert, Franziska; Schmitt, Julia; Zips, Daniel; Krueger, Marcel A.; Pichler, Bernd J.; Gillies, Stephen D.; Strittmatter, Wolfgang; Handgretinger, Rupert; Schilbach, Karin

doi:10.1007/s00262-016-1863-0

Cited by 27 publications

(17 citation statements)

References 28 publications

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“…Combining NHS-IL12 with an anti-PD-L1 antibody, one would anticipate enrichment of the known immune-related actions of this strong T H 1 cytokine while blocking the immune suppression within the tumor microenvironment through the interruption of the PD-1/PD-L1 axis. In addition, NHS-muIL12 is rather promiscuous in that it has the ability to be used in combination with radiation, sunitinib, gemcitabine, and docetaxel, resulting in additive and/or synergistic antitumor effects [1, 25]. The present study reports that treatment with an anti-PD-L1 antibody is also an effective monotherapy against subcutaneous as well as intravesical bladder murine tumors in syngeneic hosts.…”

Section: Introductionmentioning

confidence: 92%

Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody

et al. 2017

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The combined therapeutic potential of an immunocytokine designed to deliver IL-12 to the necrotic regions of solid tumors with an anti-PD-L1 antibody that disrupts the immunosuppressive PD-1/PD-L1 axis yielded a combinatorial benefit in multiple murine tumor models. The murine version of the immunocytokine, NHS-muIL12, consists of an antibody (NHS76) recognizing DNA/DNA-histone complexes, fused with two molecules of murine IL-12 (NHS-muIL12). By its recognition of exposed DNA, NHS-muIL12 targets IL-12 to the necrotic portions of tumors; it has a longer plasma half-life and better antitumor efficacy against murine tumors than recombinant murine IL-12. It is shown here that NHS-muIL12, in an IFN-γ‒dependent mechanism, upregulates mPD-L1 expression on mouse tumors, which could be construed as an immunosuppressive action. Yet concurrent therapy with NHS-muIL12 and an anti-PD-L1 antibody resulted in additive/synergistic antitumor effects in PD-L1‒expressing subcutaneously transplanted tumors (MC38, MB49) and in an intravesical bladder tumor model (MB49). Antitumor efficacy correlated with (a) with a higher frequency of tumor antigen-specific splenic CD8+ T cells and (b) enhanced T cell activation over a wide range of NHS-muIL12 concentrations. These findings suggest that combining NHS-muIL12 and an anti-PD-L1 antibody enhances T cell activation and T cell effector functions within the tumor microenvironment, significantly improving overall tumor regression. These results should provide the rationale to examine the combination of these agents in clinical studies.

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Section: Introductionmentioning

confidence: 92%

Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody

et al. 2017

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“…FcIL-7 is a fusion of interleukin-7 and an Fc fragment while IL-2MAB602 is a fusion of IL-2 and a monoclonal antibody against IL-2, MAb602. Separately, the combination of NHS-IL12 with local tumor irradiation was shown to increase treatment efficacy (114,115).…”

Section: Targeting Tumor Necrosismentioning

confidence: 99%

Localized Interleukin-12 for Cancer Immunotherapy

et al. 2020

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Interleukin-12 (IL-12) is a potent, pro-inflammatory type 1 cytokine that has long been studied as a potential immunotherapy for cancer. Unfortunately, IL-12's remarkable antitumor efficacy in preclinical models has yet to be replicated in humans. Early clinical trials in the mid-1990's showed that systemic delivery of IL-12 incurred dose-limiting toxicities. Nevertheless, IL-12's pleiotropic activity, i.e., its ability to engage multiple effector mechanisms and reverse tumor-induced immunosuppression, continues to entice cancer researchers. The development of strategies which maximize IL-12 delivery to the tumor microenvironment while minimizing systemic exposure are of increasing interest. Diverse IL-12 delivery systems, from immunocytokine fusions to polymeric nanoparticles, have demonstrated robust antitumor immunity with reduced adverse events in preclinical studies. Several localized IL-12 delivery approaches have recently reached the clinical stage with several more at the precipice of translation. Taken together, localized delivery systems are supporting an IL-12 renaissance which may finally allow this potent cytokine to fulfill its considerable clinical potential. This review begins with a brief historical account of cytokine monotherapies and describes how IL-12 went from promising new cure to ostracized black sheep following multiple on-study deaths. The bulk of this comprehensive review focuses on developments in diverse localized delivery strategies for IL-12-based cancer immunotherapies. Advantages and limitations of different delivery technologies are highlighted. Finally, perspectives on how IL-12-based immunotherapies may be utilized for widespread clinical application in the very near future are offered.

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“…The challenges of combination therapies are manifold. The cellular effects of the combination of IR and immunotherapy are at least in part different than the combinatorial effects of IR and chemotherapy [40] , [114] . Thus, “common knowledge” in radiation biology might have to be reconsidered.…”

Section: Discussionmentioning

confidence: 99%

“…Dogs with malignant melanoma treated with NHS-IL12 showed signs of clinical response [113] . In addition to the described immunological effects of radiation the rationale for combining necrosis targeting immunocytokines with IR also includes necrosis induction and enhanced intratumoural bioavailability of the compound through IR [114] . Unpublished data revealed additive effects of the combination as well as abscopal effects by combining NHS-IL12 with local tumour IR (Eckert et al, unpublished data).…”

Section: Immunocytokines In Combination With Irradiationmentioning

confidence: 99%

Beyond checkpoint inhibition – Immunotherapeutical strategies in combination with radiation

Eckert¹,

Gaipl

Niedermann

et al. 2017

Clinical and Translational Radiation Oncology

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Enhanced binding of necrosis-targeting immunocytokine NHS-IL12 after local tumour irradiation in murine xenograft models

Cited by 27 publications

References 28 publications

Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody

Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody

Localized Interleukin-12 for Cancer Immunotherapy

Beyond checkpoint inhibition – Immunotherapeutical strategies in combination with radiation

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