Differential Response of Human and Mouse Dendritic Cells to VEGF Determines Interspecies Discrepancies in Tumor-Mediated Th1/Th2 Polarity Shift

Block, Matthew S.; Nevala, Wendy K.; Leontovich, Alexey A.; Markovic, Svetomir N.

doi:10.1158/1078-0432.ccr-10-2836

Cited by 19 publications

(15 citation statements)

References 29 publications

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“…Cancer vaccines have been shown to have potent antitumor effects in preclinical models of primary de novo cancers (12,15); however, these results have translated poorly to clinical trials to prevent recurrences after surgery (6). Our studies demonstrate strong vaccine efficacy when treating small (200 mm 3 ) primary tumors.…”

Section: Discussionmentioning

confidence: 79%

“…To date, responses have been infrequent despite the generation of antigen-specific effector T lymphocytes (5,6,14). One potential explanation for the discordance between preclinical studies and postoperative clinical trials is that most evidence was derived from xenograft or transgenic mouse models with primary tumors (12,15). We propose that these studies have not considered the changes in a recurrent tumor.…”

mentioning

confidence: 99%

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Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery

Predina¹,

Eruslanov²,

Judy³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

168

140

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Each year, more than 700,000 people undergo cancer surgery in the United States. However, more than 40% of those patients develop recurrences and have a poor outcome. Traditionally, the medical community has assumed that recurrent tumors arise from selected tumor clones that are refractory to therapy. However, we found that tumor cells have few phenotypical differences after surgery. Thus, we propose an alternative explanation for the resistance of recurrent tumors. Surgery promotes inhibitory factors that allow lingering immunosuppressive cells to repopulate small pockets of residual disease quickly. Recurrent tumors and draining lymph nodes are infiltrated with M2 (CD11b + F4/80 hi CD206 hi and CD11b + F4/80 hi CD124 hi ) macrophages and CD4 + Foxp3 + regulatory T cells. This complex network of immunosuppression in the surrounding tumor microenvironment explains the resistance of tumor recurrences to conventional cancer vaccines despite small tumor size, an intact antitumor immune response, and unaltered cancer cells. Therapeutic strategies coupling antitumor agents with inhibition of immunosuppressive cells potentially could impact the outcomes of more than 250,000 people each year.immunology | tumor macrophages | T regulatory cells

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Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery

Predina¹,

Eruslanov²,

Judy³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

168

140

View full text Add to dashboard Cite

show abstract

“…Many cancer-fighting therapies have shown strong antitumor effects in preclinical models of primary tumors but fail to translate clinically for prevention of disease recurrence after surgery (Block, Nevala 2011, Grinshtein, Bridle 2009, Schreiber, Rowley 2006, Tucker, Laguna 2012). Surgery promotes inhibitory factors that allow lingering immunosuppressive cells to repopulate minute pockets of residual disease quickly (Predina, Eruslanov 2013).…”

Section: Discussionmentioning

confidence: 99%

Ultrasound-Stimulated Drug Delivery for Treatment of Residual Disease after Incomplete Resection of Head and Neck Cancer

Sorace

Korb

Warram

et al. 2014

Ultrasound in Medicine & Biology

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Microbubbles triggered with localized ultrasound (US) can improve tumor drug delivery and retention. Termed US-stimulated drug delivery, this strategy was applied to head and neck cancer (HNC) in a post-surgical tumor resection model. Nude athymic mice (N = 24) were implanted in the flank with luciferase-positive HNC squamous cell carcinoma (SCC) and underwent various degrees of surgical tumor resection (0%, 50% or 100%). Following surgery, animals received adjuvant therapy with cetuximab-IRDye alone, cetuximab-IRDye in combination with US-stimulated drug delivery, or saline injections (control) on days 4, 7, and 10. Tumor drug delivery was assessed on days 0, 4, 7, 10, 14, and 17 with an in vivo fluorescence imaging system, while tumor viability was evaluated at the same time points with in vivo bioluminescence imaging. Tumor caliper measurements occurred two times per week for days. Optical imaging demonstrated that in the 50% tumor resection group, US-stimulated drug delivery resulted in a significant increase in cetuximab delivery compared to drug alone on day 10 (day of peak fluorescence) (p = 0.03). Tumor viability decreased in all groups receiving US-stimulated drug delivery plus drug compared to the drug alone group. After various degrees of surgical resection, this novel study demonstrates positive improvements in drug uptake in the residual cancer cells when combined with US-stimulated drug delivery.

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“…17,35,37 Several studies suggested that targeting VEGFR2 may elicit and improve the immune response directed toward the tumor and its microenvironment trough different mechanisms including direct activation of CD8 C cells and targeting of the FOXP3 high regulatory T cells. [87][88][89][90][91][92][93][94][95] These findings could explain, at least in part, the efficacy of ramucirumab, a mAb IgG1 direct to VEGFR2 and appear of interest taking also into account that GC is a disease in which VEGFR2 expression has not been reported to retain a prognostic weight. 96 Moreover, recent evidence underscored the prognostic roles of both VEGFA and VEGFC expression in GC.…”

Section: Discussionmentioning

confidence: 99%

A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: Evidence does not translate?

Ciliberto

Staropoli

Caglioti

et al. 2015

Cancer Biology & Therapy

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It is still uncertain if targeted therapy-based regimens in advanced gastric cancer actually produce survival benefit. To shed light on this important question, we performed a systematic review and meta-analyses on each relevant targeted-pathway. By searching literature databases and proceedings of major cancer meetings in the time-frame 2005-2014, 22 randomized clinical trials exploring targeted therapy for a total of 7022 advanced gastric cancer patients were selected and included in the final analysis. Benefit was demonstrated for antiangiogenic agents in terms of overall survival (HR 0.759; 95%CI 0.655-0.880; p < 0.001). Conversely no benefit was found for EGFR pathway (HR 1.077; 95%CI 0.847-1.370; p D 0.543). Meta-analysis of HER-2 pathway confirmed improvement in terms of survival outcome, already known for this class of drugs (HR 0.823; p D 0.004). Pooled analysis demonstrated a significant survival benefit (OS: HR 0.823; PFS: HR 0.762) with acceptable tolerability profile for targeted-based therapies as compared to conventional treatments. This finding conflicts with the outcome of most individual studies, probably due to poor trial design or patients selection. In conclusion, our findings demonstrate a significant survival benefit for targeted therapy in its whole, which can be ascribed to anti-angiogenic and anti-HER2 agents.

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Differential Response of Human and Mouse Dendritic Cells to VEGF Determines Interspecies Discrepancies in Tumor-Mediated Th1/Th2 Polarity Shift

Cited by 19 publications

References 29 publications

Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery

Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery

Ultrasound-Stimulated Drug Delivery for Treatment of Residual Disease after Incomplete Resection of Head and Neck Cancer

A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: Evidence does not translate?

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