Intratumoral IL12 mRNA Therapy Promotes TH1 Transformation of the Tumor Microenvironment.

PURPOSE: While immune checkpoint inhibitors such as anti-PD-L1 are rapidly becoming the standard of care in the treatment of many cancers, only a subset of treated patients have long-term responses. IL12 promotes antitumor immunity in mouse models; however, systemic recombinant IL12 had significant toxicity and limited efficacy in early clinical trials. EXPERIMENTAL DESIGN: We therefore designed a novel intratumoral IL12 mRNA therapy to promote local IL12 tumor production while mitigating systemic effects. RESULTS: A single intratumoral dose of mouse (m)IL12 mRNA induced IFNγ and CD8+ T-cell-dependent tumor regression in multiple syngeneic mouse models, and animals with a complete response demonstrated immunity to rechallenge. Antitumor activity of mIL12 mRNA did not require NK and NKT cells. mIL12 mRNA antitumor activity correlated with TH1 tumor microenvironment (TME) transformation. In a PD-L1 blockade monotherapy-resistant model, antitumor immunity induced by mIL12 mRNA was enhanced by anti-PD-L1. mIL12 mRNA also drove regression of uninjected distal lesions, and anti-PD-L1 potentiated this response. Importantly, intratumoral delivery of mRNA encoding membrane-tethered mIL12 also drove rejection of uninjected lesions with very limited circulating IL12p70, supporting the hypothesis that local IL12 could induce a systemic antitumor immune response against distal lesions. Furthermore, in ex vivo patient tumor slice cultures, human IL12 mRNA (MEDI1191) induced dose-dependent IL12 production, downstream IFNγ expression and TH1 gene expression. CONCLUSIONS: These data demonstrate the potential for intratumorally delivered IL12 mRNA to promote TH1 TME transformation and robust antitumor immunity.See related commentary by Cirella et al., p. 6080.

A two one-sided parametric tolerance interval test for control of delivered dose uniformity--part 2--effect of changing parameters.

This article examines the effects of changing parameters in the test which was proposed by the FDA at the October 2005 Advisory Committee meeting for confirming delivered dose uniformity in orally inhaled and nasal drug products. This article is an extension of the characterization study presented in an accompanying article (Part 1). The goal of this study is to understand how parameters of the test affect the test performance. The effects of changing test parameters such as target interval, maximum allowable proportion in the tail area, and sample size are examined. The results show that changing the maximum allowable tail area and/or the target interval have the largest impact on the test outcomes, i.e., probability of acceptance for a given batch mean and standard deviation. The presented information may provide potential users of the test with a set of tools for optimizing the test characteristics for a particular product.

Increased seizure threshold and severity in young transgenic CRND8 mice.

Reports suggest that Alzheimer's disease (AD) patients show a high life-time prevalence of seizure-like disorders. The transgenic CRND8 (TgCRDN8) is a mouse model of AD-like amyloid pathogenesis that expresses a double-mutant form of human amyloid precursor protein 695 (K670N/M671L and V717F). We have previously reported that post-plaque TgCRND8 mice exhibited a lower threshold to seizure with a more severe seizure type when challenged with pentylenetetrazole (PTZ) intravenously. Here, we now report that pre-plaque TgCRND8 mice also demonstrate an increased sensitivity to PTZ-induced seizures with a more severe seizure type over age-matched littermate controls. A lower threshold and more severe seizure type in TgCRND8 mice prior to and after plaque deposition suggest that this genotype difference may be due to beta-amyloid (Abeta) toxicity rather than plaque formation. Thus, the TgCRND8 mice are not only a model for Abeta production and plaque deposition, but may also be useful for AD associated seizure.