The extracellular ATP/adenosine axis in the tumor microenvironment (TME) has emerged as an important immune-regulatory pathway. Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), otherwise known as CD39, is highly expressed in the TME, both on infiltrating immune cells and tumor cells across a broad set of cancer indications. CD39 processes pro-inflammatory extracellular ATP to ADP and AMP, which is then processed by Ecto-5'-nucleotidase/CD73 to immunosuppressive adenosine.
View Article and Find Full Text PDFWe explored the mechanism of action of CD39 antibodies that inhibit ectoenzyme CD39 conversion of extracellular ATP (eATP) to AMP and thus potentially augment eATP-P2-mediated proinflammatory responses. Using syngeneic and humanized tumor models, we contrast the potency and mechanism of anti-CD39 mAbs with other agents targeting the adenosinergic pathway. We demonstrate the critical importance of an eATP-P2X7-ASC-NALP3-inflammasome-IL18 pathway in the antitumor activity mediated by CD39 enzyme blockade, rather than simply reducing adenosine as mechanism of action.
View Article and Find Full Text PDFThe dramatic clinical benefit of immune checkpoint blockade for a fraction of cancer patients suggests the potential for further clinical benefit in a broader cancer patient population by combining immune checkpoint inhibitors with active immunotherapies. The anti-tumor efficacy of MVA-BN-HER2 poxvirus-based active immunotherapy alone or in combination with CTLA-4 checkpoint blockade was investigated in a therapeutic CT26-HER-2 lung metastasis mouse model. MVA-BN-HER2 immunotherapy significantly improved the median overall survival compared to untreated controls or CTLA-4 blockade alone (p < 0.
View Article and Find Full Text PDFPoxvirus-based active immunotherapies mediate anti-tumor efficacy by triggering broad and durable Th1 dominated T cell responses against the tumor. While monotherapy significantly delays tumor growth, it often does not lead to complete tumor regression. It was hypothesized that the induced robust infiltration of IFNγ-producing T cells into the tumor could provoke an adaptive immune evasive response by the tumor through the upregulation of PD-L1 expression.
View Article and Find Full Text PDFJ Immunother Cancer
October 2014
Background: PROSTVAC®, an active immunotherapy currently studied for the treatment of metastatic castration-resistant prostate cancer (mCRPC), consists of a heterologous prime-boost regimen with two different poxvirus-based vectors to provoke productive immune responses against prostate specific antigen (PSA) as the target tumor antigen. A Phase 2 study of PROSTVAC immunotherapy showed significantly improved median overall survival by 8.5 months and is currently being validated in a global Phase 3 study (PROSPECT; NCT01322490).
View Article and Find Full Text PDFBackground: Immunostimulatory DNA sequences (ISS) are potent immunomodulators that can drive T(H)1 responses to antigens or allergens. This effect can be dramatically enhanced by direct linkage of ISS to the protein.
Objective: Evaluate the effects of the number of ISS bound to the major ragweed allergen Amb a 1 on immunogenicity and allergenicity.
CpG-C are a novel class of CpG motif-containing immunostimulatory sequences (ISS) that includes both a 5'-TCG element and a CpG-containing palindrome. CpG-C drive all known ISS activities and, in particular, are potent enhancers of IFN-alpha from plasmacytoid dendritic cells (PDCs). In our examination of CpG-C sequence requirements, we determined that optimal IFN-alpha-inducing activity could be achieved with longer palindromes.
View Article and Find Full Text PDFThe immunostimulatory effects of bacterial DNA on mammalian cells have been localized to unmethylated CpG motifs, and synthetic CpG-containing oligodeoxynucleotides that mimic these effects are known as immunostimulatory sequences (ISS). We have found that the polycationic antibiotic, polymyxin B (PMXB), associates with ISS and serum albumin in vitro and forms microparticles that greatly increase the activity of ISS on plasmacytoid dendritic cells (PDCs). Specifically, ISS/PMXB greatly enhanced IFN-alpha production from PDCs and other activities downstream of IFN-alpha, including IFN-gamma secretion, NK lytic activity, and the expression of genes dependent upon IFN-alpha/IFN-gamma.
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