Abstract
IntroductionCytokine-based products are gaining importance for cancer immunotherapy. L19-TNF is a clinical-stage antibody-cytokine fusion protein that selectively accumulates to tumors and displays potent anticancer activity in preclinical models. Here, we describe an innovative approach to transiently inhibit off-target toxicity of L19-TNF, while maintaining antitumor activity.MethodsGSK’963, a potent small molecule inhibitor of RIPK1, was tested in tumor-bearing mice for its ability to reduce acute toxicity associated with TNF signaling. The biological effects of L19-TNF on tumor cells, lymphocytes and tumor vessels were investigated with the aim to enable the administration of TNF doses, which would otherwise be lethal.ResultsTransient inhibition of RIPK1 allowed to increase the maximal tolerated dose of L19-TNF. The protective effect of GSK’963 did not affect the selective localization of the immunocytokine to tumors as evidenced by quantitative biodistribution analysis and allowed to reach high local TNF concentrations around tumor blood vessels, causing diffused vascular shutdown and hemorrhagic necrosis within the neoplastic mass.ConclusionsThe selective inhibition of RIPK1 with small molecule inhibitors can be used as a pharmaceutical tool to transiently mask TNF activity and improve the therapeutic window of TNF-based biopharmaceuticals. Similar approaches may be applicable to other pro-inflammatory cytokines.
Highlights
Cytokine-based products are gaining importance for cancer immunotherapy
The selective inhibition of Receptor-interacting protein kinase 1 (RIPK1) with small molecule inhibitors can be used as a pharmaceutical tool to transiently mask tumor necrosis factor (TNF) activity and improve the therapeutic window of TNF-based biopharmaceuticals
The therapeutic benefit associated with PD-1 blockade in a growing number of cancer indications [1,2,3] has stimulated the search for alternative immunotherapy strategies, that may be complementary to the use of immune checkpoint inhibitors
Summary
L19-TNF is a clinical-stage antibody-cytokine fusion protein that selectively accumulates to tumors and displays potent anticancer activity in preclinical models. Recombinant interleukin-2 has been shown to eradicate metastatic melanoma or renal cell carcinoma in a small proportion of patients, who are fit enough to tolerate the severe side-effects associated with cytokine treatment [5, 6]. The fusion of cytokine www.oncotarget.com payloads with recombinant antibodies, capable of selective localization to the tumor, may represent a strategy for the improvement of the therapeutic index of cytokine-based biopharmaceuticals [9,10,11,12]. Potent and selective anticancer activity has been observed in mouse models of cancer ( for fusion proteins based on IL2, IL12 and TNF payloads) [13,14,15]. L19-TNF and other TNF-based fusion proteins were found to be potently active against soft-tissue sarcoma and the fullyhuman fusion protein is currently being studied in pivotal trials in this indication, in combination with doxorubicin (NCT03420014, Eudract no. 2016-003239-38)
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