Multiparametric MRI assessment of response to convection-enhanced intratumoral delivery of MDNA55, an interleukin-4 receptor targeted immunotherapy, for recurrent glioblastoma

Background: Glioblastoma (GBM) is the most common malignant brain tumor and carries a dismal prognosis. Attempts to develop biologically targeted therapies are challenging as the blood–brain barrier can limit drugs from reaching their target when administered through conventional (intravenous or oral) routes. Furthermore, systemic toxicity of drugs often limits their therapeutic potential. To circumvent these problems, convection-enhanced delivery (CED) provides direct, targeted, intralesional therapy with a secondary objective to alter the tumor microenvironment from an immunologically “cold” (nonresponsive) to an “inflamed” (immunoresponsive) tumor. Case Description: We report a patient with right occipital recurrent GBM harboring poor prognostic genotypes who was treated with MRI-guided CED of a fusion protein MDNA55 (a targeted toxin directed toward the interleukin-4 receptor). The patient underwent serial anatomical, diffusion, and perfusion MRI scans before initiation of targeted therapy and at 1, 3-month posttherapy. Increased mean diffusivity along with decreased fractional anisotropy and maximum relative cerebral blood volume was noted at follow-up periods relative to baseline. Conclusion: Our findings suggest that diffusion and perfusion MRI techniques may be useful in evaluating early response to CED of MDNA55 in recurrent GBM patients.

Inactivation of Interleukin‐4 Receptor α Signaling in Myeloid Cells Protects Mice From Angiotensin II/High Salt–Induced Cardiovascular Dysfunction Through Suppression of Fibrotic Remodeling

Background Hypertension‐induced cardiovascular remodeling is characterized by chronic low‐grade inflammation. Interleukin‐4 receptor α (IL‐4Rα) signaling is importantly involved in cardiovascular remodeling, however, the target cell type(s) is unclear. Here, we investigated the role of myeloid‐specific IL‐4Rα signaling in cardiovascular remodeling induced by angiotensin II and high salt. Methods and Results Myeloid IL‐4Rα deficiency suppressed both the in vitro and in vivo expression of alternatively activated macrophage markers including Arg1 (arginase 1), Ym1 (chitinase 3‐like 3), and Relmα/Fizz1 (resistin‐like molecule α). After angiotensin II and high salt treatment, myeloid‐specific IL‐4Rα deficiency did not change hypertrophic remodeling within the heart and aorta. However, myeloid IL‐4Rα deficiency resulted in a substantial reduction in fibrosis through the suppression of profibrotic pathways and the enhancement of antifibrotic signaling. Decreased fibrosis was associated with significant preservation of myocardial function in MyIL4RαKO mice and was mediated by attenuated alternative macrophage activation. Conclusions Myeloid IL‐4Rα signaling is substantially involved in fibrotic cardiovascular remodeling by controlling alternative macrophage activation and regulating fibrosis‐related signaling. Inhibiting myeloid IL‐4Rα signaling may be a potential strategy to prevent hypertensive cardiovascular diseases.

Association of IL-4 and IL-4R Polymorphisms with Litter Size Traits in Pigs

The interleukin-4 (IL-4) and interleukin-4 receptor (IL-4R) are cytokines that are involved in the immune and reproductive systems. This study aimed to verify the polymorphisms in the porcine IL-4 and IL-4R genes and to assess their effects on litter size traits in commercial pigs. Single nucleotide polymorphisms (SNPs) in the porcine IL-4 and IL-4R genes were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. A non-coding SNP of IL-4 g.134993898T > C and a non-synonymous SNP of IL-4R c.1577A > T (amino acid change at position 526, Q526L) were found to be segregating in Landrace sows. The IL-4 g.134993898T > C polymorphism was significantly associated with the number of piglets weaned alive (NWA) trait. The IL-4R c.1577A > T polymorphism was significantly associated with the number born alive (NBA) and NWA traits. Moreover, the accumulation of favorable alleles of these two SNP markers revealed significant associations with the NBA, NWA, and mean weight of piglets at weaning (MWW) traits. These findings indicate that the porcine IL-4 and IL-4R genes may contribute to the reproductive traits of pigs and could be used as candidate genes to improve litter size traits in the pig breeding industry.

Clinical efficacy of dupilumab in the treatment of severe chronic rhinosinusitis

Chronic rhinosinusitis with nasal polyps is a type 2-mediated inflammatory disease associated with significant burden due to symptoms and high recurrence rate after surgery. Dupilumab, a monoclonal antibody against the interleukin-4 receptor subunit α, has demonstrated good clinical efficacy and acceptable safety in phase II and phase III trials.