Human vaccination against Plasmodium vivax Duffy-binding protein induces strain-transcending antibodies.

BACKGROUND: Plasmodium vivax is the most widespread human malaria geographically; however, no effective vaccine exists. Red blood cell invasion by the P. vivax merozoite depends on an interaction between the Duffy antigen receptor for chemokines (DARC) and region II of the parasite's Duffy-binding protein (PvDBP_RII). Naturally acquired binding-inhibitory antibodies against this interaction associate with clinical immunity, but it is unknown whether these responses can be induced by human vaccination. METHODS: Safety and immunogenicity of replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and modified vaccinia virus Ankara (MVA) viral vectored vaccines targeting PvDBP_RII (Salvador I strain) were assessed in an open-label dose-escalation phase Ia study in 24 healthy UK adults. Vaccines were delivered by the intramuscular route in a ChAd63-MVA heterologous prime-boost regimen using an 8-week interval. RESULTS: Both vaccines were well tolerated and demonstrated a favorable safety profile in malaria-naive adults. PvDBP_RII-specific ex-vivo IFN-γ T cell, antibody-secreting cell, memory B cell, and serum IgG responses were observed after the MVA boost immunization. Vaccine-induced antibodies inhibited the binding of vaccine homologous and heterologous variants of recombinant PvDBP_RII to the DARC receptor, with median 50% binding-inhibition titers greater than 1:100. CONCLUSION: We have demonstrated for the first time to our knowledge that strain-transcending antibodies can be induced against the PvDBP_RII antigen by vaccination in humans. These vaccine candidates warrant further clinical evaluation of efficacy against the blood-stage P. vivax parasite. TRIAL REGISTRATION: Clinicaltrials.gov NCT01816113. FUNDING: Support was provided by the UK Medical Research Council, UK National Institute of Health Research Oxford Biomedical Research Centre, and the Wellcome Trust.

Therapeutic inhibition of Jak activity inhibits progression of gastrointestinal tumors in mice.

Aberrant activation of the latent transcription factor STAT3 and its downstream targets is a common feature of epithelial-derived human cancers, including those of the gastrointestinal tract. Mouse models of gastrointestinal malignancy implicate Stat3 as a key mediator of inflammatory-driven tumorigenesis, in which its cytokine/gp130/Janus kinase (Jak)-dependent activation provides a functional link through which the microenvironment sustains tumor promotion. Although therapeutic targeting of STAT3 is highly desirable, such molecules are not available for immediate clinical assessment. Here, we investigated whether the small-molecule Jak1/2 inhibitor AZD1480 confers therapeutic benefits in two mouse models of inflammation-associated gastrointestinal cancer, which are strictly dependent of excessive Stat3 activation. We confirm genetically that Cre-mediated, tumor cell-specific reduction of Stat3 expression arrests the growth of intestinal-type gastric tumors in gp130(F/F) mice. We find that systemic administration of AZD1480 readily replicates this effect, which is associated with reduced Stat3 activation and correlates with diminished tumor cell proliferation and increased apoptosis. Likewise, AZD1480 therapy also conferred a cytostatic effect on established tumors in a colitis-associated colon cancer model in wild-type mice. As predicted from our genetic observations in gp130(F/F) mice, the therapeutic effect of AZD1480 remains fully reversible upon cessation of compound administration. Collectively, our results provide the first evidence that pharmacologic targeting of excessively activated wild-type Jak kinases affords therapeutic suppression of inflammation-associated gastrointestinal cancers progression in vivo.

Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically.

Among the cytokines linked to inflammation-associated cancer, interleukin (IL)-6 drives many of the cancer "hallmarks" through downstream activation of the gp130/STAT3 signaling pathway. However, we show that the related cytokine IL-11 has a stronger correlation with elevated STAT3 activation in human gastrointestinal cancers. Using genetic mouse models, we reveal that IL-11 has a more prominent role compared to IL-6 during the progression of sporadic and inflammation-associated colon and gastric cancers. Accordingly, in these models and in human tumor cell line xenograft models, pharmacologic inhibition of IL-11 signaling alleviated STAT3 activation, suppressed tumor cell proliferation, and reduced the invasive capacity and growth of tumors. Our results identify IL-11 signaling as a potential therapeutic target for the treatment of gastrointestinal cancers.

mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice.

Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs). Furthermore, in a preclinical mouse model of IGC, GP130 ligand administration simultaneously activated mTORC1/S6 kinase and STAT3 signaling. We therefore investigated whether mTORC1 activation was required for inflammation-associated gastrointestinal tumorigenesis. Strikingly, the mTORC1-specific inhibitor RAD001 potently suppressed initiation and progression of both murine IGC and colitis-associated colon cancer. The therapeutic effect of RAD001 was associated with reduced tumor vascularization and cell proliferation but occurred independently of STAT3 activity. We analyzed the mechanism of GP130-mediated mTORC1 activation in cells and mice and revealed a requirement for JAK and PI3K activity but not for GP130 tyrosine phosphorylation or STAT3. Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis. These findings advocate clinical application of PI3K/mTORC1 inhibitors for the treatment of corresponding human malignancies.