Systemic Inhibition of Transforming Growth Factor-β in Glioma-Bearing Mice Improves the Therapeutic Efficacy of Glioma-Associated Antigen Peptide Vaccines

Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Clinical Cancer Research (Impact Factor: 8.19). 11/2009; 15(21):6551-9. DOI: 10.1158/1078-0432.CCR-09-1067
Source: PubMed

ABSTRACT A variety of cancers, including malignant gliomas, overexpress transforming growth factor-beta (TGF-beta), which helps tumors evade effective immune surveillance through a variety of mechanisms, including inhibition of CD8(+) CTLs and enhancing the generation of regulatory T (T(reg)) cells. We hypothesized that inhibition of TGF-beta would improve the efficacy of vaccines targeting glioma-associated antigen (GAA)-derived CTL epitopes by reversal of immunosuppression.
Mice bearing orthotopic GL261 gliomas were treated systemically with a TGF-beta-neutralizing monoclonal antibody, 1D11, with or without s.c. vaccinations of synthetic peptides for GAA-derived CTL epitopes, GARC-1 (77-85) and EphA2 (671-679), emulsified in incomplete Freund's adjuvant.
Mice receiving the combination regimen exhibited significantly prolonged survival compared with mice receiving either 1D11 alone, GAA vaccines alone, or mock treatments alone. TGF-beta neutralization enhanced the systemic induction of antigen-specific CTLs in glioma-bearing mice. Flow cytometric analyses of brain-infiltrating lymphocytes revealed that 1D11 treatment suppressed phosphorylation of Smad2, increased GAA-reactive/IFN-gamma-producing CD8(+) T cells, and reduced CD4(+)/FoxP3(+) T(reg) cells in the glioma microenvironment. Neutralization of TGF-beta also upregulated plasma levels of interleukin-12, macrophage inflammatory protein-1 alpha, and IFN-inducible protein-10, suggesting a systemic promotion of type-1 cytokine/chemokine production. Furthermore, 1D11 treatment upregulated plasma interleukin-15 levels and promoted the persistence of GAA-reactive CD8(+) T cells in glioma-bearing mice.
These data suggest that systemic inhibition of TGF-beta by 1D11 can reverse the suppressive immunologic environment of orthotopic tumor-bearing mice both systemically and locally, thereby enhancing the therapeutic efficacy of GAA vaccines.

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Available from: Xinmei Zhu, Aug 22, 2014
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    • "The multiple targets and sources of this cytokine makes interpretation of its therapeutic modulation complex, since of TGF-β acts directly on tumour cells, as well as on pro-and anti-tumoural myeloid and other immune cells. TGF-β inhibition through systemic application of neutralizing antibody (1D11) enhanced efficacy of therapeutic vaccination in mouse GL261 glioma, and promoted a type 1 immune response, although it was not effective as a single modality treatment (Ueda et al., 2009). In a further study, the same 1D11 antibody was tested on both subcutaneous and intracranial GL261; in the former site, there was total tumour regression, whereas the orthotopic glioma merely showed reduced invasion (Hulper et al., 2011) These results suggest that it will be challenging to achieve full efficacy with systemic use of blocking antibodies for tumours localised in the brain. "
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    • "Antibodies (1D11 and 13C4) were suspended in 0.2 ml of distilled water and administered intraperitoneally at a dose of 25 mg/kg. Once begun, antibodies were given three times per week for three weeks [10] [11]. "
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    ABSTRACT: Nearly 30% of cancer patients undergoing curative surgery succumb to distant recurrent disease. Despite large implications and known differences between primary and recurrent tumors, preclinical adjuvant therapy evaluation frequently occurs only in primary tumors and not recurrent tumors. We hypothesized that well characterized and reproducible models of postoperative systemic recurrences should be used for preclinical evaluation of adjuvant approaches. We examined traditional animal models of cancer surgery that generate systemic cancer recurrences. We also investigated models of systemic cancer recurrences that incorporate spontaneously metastatic cell lines and surgical resection. For each model, we critiqued feasibility, reproducibility and similarity to human recurrence biology. Using our novel model, we then tested the adjuvant use of a novel systemic inhibitor of TGF-β, 1D11. Traditional surgical models are confounded by immunologic factors including concomitant immunity and perioperative immunosuppression. A superior preclinical model of postoperative systemic recurrences incorporates spontaneously metastatic cell lines and primary tumor excision. This approach is biologically relevant and readily feasible. Using this model, we discovered that "perioperative" TGF-β blockade has strong anti-tumor effects in the setting of advanced disease that would not be appreciated in primary tumor cell lines or other surgical models. There are multiple immunologic effects that rendered previous models of postoperative cancer recurrences inadequate. Use of spontaneously metastatic cell lines followed by surgical resection eliminates these confounders, and best resembles the clinical scenario. This preclinical model provides more reliable preclinical information when evaluating new adjuvant therapies.
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    • "Recent studies have shown that TGF-β is up-regulated in glioma cell clones that are resistant to the cytotoxic effects of allogeneic cytotoxic T-cells (CTLs), suggesting the significance of TGF-β in glioma immune escape mechanisms (Gomez et al., 2007; Ueda et al., 2009). "
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