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Intratumoral administration of IL2- and TNF-based fusion proteins cures cancer without establishing protective immunity.

ABSTRACT: AIM:The combination of tumor-targeting IL2- and TNF-based antibody-cytokine fusions has exhibited encouraging results in mouse and men. Here, we studied their combination to assess efficacy and mechanism of action in four different immunocompetent mouse models of cancer. METHODS:Mice receiving a single intratumoral injection of F8-IL2, F8-TNF or the combination were investigated for tumor-infiltrating leukocytes and rechallenged when cured. RESULTS:In three models, a proportion of treated animals could be cured, most probably by infiltrating NK and CD8+ T cells. Most of the cured mice did not acquire protective immunity when rechallenged with the same tumor cell line. CONCLUSION:Immunocompetent mouse tumor models may not be adequate enough to predict the search for more efficacious therapy regimens.

SUBMITTER: Ziffels B

PROVIDER: S-EPMC5850986 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Intratumoral administration of IL2- and TNF-based fusion proteins cures cancer without establishing protective immunity.

Ziffels Barbara B Pretto Francesca F Neri Dario D

Immunotherapy 20180301 3

<h4>Aim</h4>The combination of tumor-targeting IL2- and TNF-based antibody-cytokine fusions has exhibited encouraging results in mouse and men. Here, we studied their combination to assess efficacy and mechanism of action in four different immunocompetent mouse models of cancer.<h4>Methods</h4>Mice receiving a single intratumoral injection of F8-IL2, F8-TNF or the combination were investigated for tumor-infiltrating leukocytes and rechallenged when cured.<h4>Results</h4>In three models, a propor ...[more]

PMID: 29370721

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Project description:Previous studies suggest that protective immunity against Schistosoma haematobium is primarily stimulated by antigens from dying worms. Praziquantel treatment kills adult worms, boosting antigen exposure and protective antibody levels. Current schistosomiasis control efforts use repeated mass drug administration (MDA) of praziquantel to reduce morbidity, and may also reduce transmission. The long-term impact of MDA upon protective immunity, and subsequent effects on infection dynamics, are not known. A stochastic individual-based model describing levels of S. haematobium worm burden, egg output and protective parasite-specific antibody, which has previously been fitted to cross-sectional and short-term post-treatment egg count and antibody patterns, was used to predict dynamics of measured egg output and antibody during and after a 5-year MDA campaign. Different treatment schedules based on current World Health Organisation recommendations as well as different assumptions about reductions in transmission were investigated. We found that antibody levels were initially boosted by MDA, but declined below pre-intervention levels during or after MDA if protective immunity was short-lived. Following cessation of MDA, our models predicted that measured egg counts could sometimes overshoot pre-intervention levels, even if MDA had had no effect on transmission. With no reduction in transmission, this overshoot occurred if protective immunity was short-lived. This implies that disease burden may temporarily increase following discontinuation of treatment, even in the absence of any reduction in the overall transmission rate. If MDA was additionally assumed to reduce transmission, a larger overshoot was seen across a wide range of parameter combinations, including those with longer-lived protective immunity. MDA may reduce population levels of immunity to urogenital schistosomiasis in the long-term (3-10 years), particularly if transmission is reduced. If MDA is stopped while S. haematobium is still being transmitted, large rebounds (up to a doubling) in egg counts could occur.

Dataset Information

Intratumoral administration of IL2- and TNF-based fusion proteins cures cancer without establishing protective immunity.

Publications

Intratumoral administration of IL2- and TNF-based fusion proteins cures cancer without establishing protective immunity.

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