VEGF Blockade Enables Oncolytic Cancer Virotherapy in Part by Modulating Intratumoral Myeloid Cells

Understanding the host response to oncolytic viruses is important to maximize their antitumor efficacy. Despite robust cytotoxicity and high virus production of an oncolytic herpes simplex virus (oHSV) in cultured human sarcoma cells, intratumoral (ITu) virus injection resulted in only mild antitumor effects in some xenograft models, prompting us to characterize the host inflammatory response. Virotherapy induced an acute neutrophilic infiltrate, a relative decrease of ITu macrophages, and a myeloid cell-dependent upregulation of host-derived vascular endothelial growth factor (VEGF). Anti-VEGF antibodies, bevacizumab and r84, the latter of which binds VEGF and selectively inhibits binding to VEGF receptor-2 (VEGFR2) but not VEGFR1, enhanced the antitumor effects of virotherapy, in part due to decreased angiogenesis but not increased virus production. Neither antibody affected neutrophilic infiltration but both partially mitigated virus-induced depletion of macrophages. Enhancement of virotherapy-mediated antitumor effects by anti-VEGF antibodies could largely be recapitulated by systemic depletion of CD11b⁺ cells. These data suggest the combined effect of oHSV virotherapy and anti-VEGF antibodies is in part due to modulation of a host inflammatory reaction to virus. Our data provide strong preclinical support for combined oHSV and anti-VEGF antibody therapy and suggest that understanding and counteracting the innate host response may help enable the full antitumor potential of oncolytic virotherapy.     

Inhibition of TLR-4/MD-2 signaling by RP105/MD-1

Activation of Toll-like receptor (TLR) signaling by microbial and host molecular signatures is critical to the induction of immune responses. Such signaling is, perforce, kept under tight control. We recently discovered a novel endogenous inhibitor of TLR-4 - RP105. Initially identified as a B-cell-specific molecule with a role in B-cell proliferation in response to RP105 mAb and LPS, RP105 is a TLR-4 homologue. Further, like TLR-4 whose surface expression and signaling depends upon co-expression of the secreted protein MD-2, surface expression of RP105 is dependent upon co-expression of the MD2 homologue, MD-1. Unlike the TLRs, however, RP105 lacks a signaling domain, having the apparent structure of a TLR inhibitor. Further, RP105 is not B-cell-specific; its expression directly mirrors that of TLR-4 on dendritic cells and macrophages. These considerations suggested a role for RP105 as a physiological inhibitor of TLR-4 signaling. Indeed, we have recently found that: (i) RP105 is a specific inhibitor of TLR-4 signaling in HEK293 cells; (ii) RP105/MD-1 interacts directly with TLR-4/MD-2, inhibiting the ability of this signaling complex to bind LPS; (iii) RP105 regulates TLR-4 signaling in dendritic cells and macrophages; and (iv) RP105 regulates in vivo responses to LPS.     

Prenatal heart block screening in mothers with SSA/SSB autoantibodies: Targeted screening protocol is a cost‐effective strategy

Objective: Maternal anti-Ro/SSA and anti-La/SSB antibodies can lead to fetal complete heart block (CHB). Current guidelines recommend weekly echocardiographic screening between 16 and 28 weeks gestation. Given the cost of screening and the rarity of conduction abnormalities in fetuses of mothers with low anti-Ro levels (<50 U/mL), we sought to identify a strategy that optimizes resource utilization.
Design: Decision analysis cost-utility modeling was performed for three screening paradigms: “standard screening” (SS) in which mid-gestation mothers are screened weekly, “limited screening” (LS) in which fetal echocardiograms are avoided unless the fetus develops bradycardia, and “targeted screening by maternal antibody level” (TS) in which only high anti-Ro values warrant weekly screening. A systematic review of existing literature and institutional cost data were used to define model inputs.
Results: The average cost of LS, TS, and SS was $8566, $11 038, and $23 279, respectively. SS was cost-ineffective with an incremental cost-effectiveness ratio (ICER) of $322 756 while TS was cost-effective with an ICER of $43 445.
Conclusion: While the efficacy of fetal intervention for first or second degree AV block remains unclear, this analysis supports utilizing antibody levels to stratify this population for optimized surveillance for CHB. SS is cost-ineffective and results in resource overutilization.     

IFN-γ-driven IDO production from macrophages protects IL-4Rα-deficient mice against lethality during Schistosoma mansoni infection

The balance between alternatively activated macrophages (AAMs)/M2 cells and classically activated macrophages (M1 cells) is largely dependent on the effects of IL-4 and interferon (IFN)-γ, respectively. Although AAM/M2 cells can suppress inflammation and repair damaged tissue, M1 cells produce an array of pro-inflammatory molecules. Macrophage effector functions are critical for host protection against many infectious diseases, but it remains unknown whether lethal immunopathological characteristics, caused by Schistosoma mansoni infection in IL-4 receptor α-deficient mice (IL-4Rα(-/-)), results from the absence of M2 cells or increased numbers of M1 cells. In this study, we generated mice that completely lack IL-4Rα signaling in the context of a macrophage-specific loss of IFN-γ responsiveness (MIIG × IL-4Rα(-/-)). Contrary to what we expected, acute schistosomiasis resulted in greater liver injury and mortality in MIIG × IL-4Rα(-/-) mice compared with IL-4Rα(-/-) mice. Greater tissue injury in MIIG × IL-4Rα(-/-) mice was likely because of a lack of indoleamine 2,3 dioxygenase (IDO), a critical regulator of immunosuppression. Indeed, MIIG × IL-4Rα(-/-) failed to up-regulate IDO expression, and IL-4Rα(-/-) mice treated with an IDO antagonist underwent greater liver damage and mortality compared with mock-treated IL-4Rα(-/-) mice. Thus, we propose that, in the absence of AAM/M2 cells, IFN-γ-induced M1 cells suppress tissue-damaging inflammation during acute schistosomiasis through an IDO-dependent mechanism.