Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma

Hodi, F. Stephen; Lawrence, Donald P.; Lezcano, Cecilia; Wu, Xinqi; Zhou, Jun; Sasada, Tetsuro; Zeng, Wanyong; Giobbie‐Hurder, Anita; Atkins, Michael B.; Ibrahim, Nageatte; Friedlander, Philip; Flaherty, Keith T.; Murphy, Gëorge F.; Rodig, Scott J.; Velázquez, Elsa F.; Mihm, Martín C.; Russell, Sara E.; DiPiro, Pamela J.; Yap, Jeffrey T.; Ramaiya, Nikhil H.; Abbeele, Annick D. Van den; Gargano, Maria; McDermott, David F.

doi:10.1158/2326-6066.cir-14-0053

Cited by 503 publications

(413 citation statements)

References 36 publications

(39 reference statements)

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“…Future work will be aimed at understanding the mechanisms underlying this augmented response, including any synergistic effects of combined therapy. Previous studies in non-CNS solid tumors have shown the ability of VEGF inhibition to enhance CD8+ T-cell responses [58,59]. While not reaching statistical significance, our data also revealed a trend toward increased CD8+ T-cell infiltration into the CNS following treatment with aflibercept, suggesting that vascular normalization could, in fact, promote immune cell infiltration.…”

Section: Discussioncontrasting

confidence: 78%

“…The GL261-Quad cell line is engineered to express the model antigens human gp100 [25][26][27][28][29][30][31][32][33] , chicken OVA 257-264 , chicken OVA [323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339] , and mouse alloantigen I-Ea [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] . Female 6-8-week-old C57BL/6 mice (The Jackson Laboratory, Bar Harbor, ME, USA) were inoculated by stereotactic injection of 6.0×10 4 -1.0×10 5 GL261 or GL261-Quad cells into the right striatum.…”

Section: Gl261 Tumor Implantationmentioning

confidence: 99%

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Improved Treatment Efficacy of Antiangiogenic Therapy when Combined with Picornavirus Vaccination in the GL261 Glioma Model

et al. 2016

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The addition of antiangiogenic therapy to the standard-of-care treatment regimen for recurring glioblastoma has provided some clinical benefits while also delineating numerous caveats, prompting evaluation of the elicited alterations to the tumor microenvironment. Of critical importance, given the steadily increasing incorporation of immunotherapeutic approaches clinically, is an enhanced understanding of the interplay between angiogenic and immune response pathways within tumors. In the present study, the GL261 glioma mouse model was used to determine the effects of antiangiogenic treatment in an immune-competent host. Following weekly systemic administration of aflibercept, an inhibitor of vascular endothelial growth factor, tumor volume was assessed by magnetic resonance imaging and changes to the tumor microenvironment were determined. Treatment with aflibercept resulted in reduced tumor burden and increased survival compared with controls. Additionally, decreased vascular permeability and preservation of the integrity of tight junction proteins were observed. Treated tumors also displayed hallmarks of anti-angiogenic evasion, including marked upregulation of vascular endothelial growth factor expression and increased tumor invasiveness. Aflibercept was then administered in combination with a picornavirusbased antitumor vaccine and tumor progression was evaluated. This combination therapy significantly delayed tumor progression and extended survival beyond that observed for either therapy alone. As such, this work demonstrates the efficacy of combined antiangiogenic and immunotherapy approaches for treating established gliomas and provides a foundation for further evaluation of the effects of antiangiogenic therapy in the context of endogenous or vaccine-induced inflammatory responses.

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Section: Discussioncontrasting

confidence: 78%

Section: Gl261 Tumor Implantationmentioning

confidence: 99%

Improved Treatment Efficacy of Antiangiogenic Therapy when Combined with Picornavirus Vaccination in the GL261 Glioma Model

et al. 2016

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“…31,52 Recent clinical studies combining anti-angiogenic therapy and immune therapies based on checkpoint blockade inhibitors revealed promising preliminary results supporting the notion that anti-angiogenic therapy may reduce immunosuppression. 57 How this is mechanistically achieved remains to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model independently of the immunomodulatory and anti-metastatic effects of VEGFR-2 blockade

et al. 2017

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Tumor angiogenesis promotes tumor growth and metastasis. Anti-angiogenic therapy in combination with chemotherapy is used for the treatment of metastatic cancers, including breast cancer but therapeutic benefits are limited. Mobilization and accumulation of myeloid-derived suppressor cells (MDSC) during tumor progression and therapy have been implicated in metastasis formation and resistance to antiangiogenic treatments. Here, we used the 4T1 orthotopic syngenic mouse model of mammary adenocarcinoma to investigate the effect of VEGF/VEGFR-2 axis inhibition on lung metastasis, MDSC and regulatory T cells (Tregs). We show that treatment with the anti-VEGFR-2 blocking antibody DC101 inhibits primary tumor growth, angiogenesis and lung metastasis. DC101 treatment had no effect on MDSC mobilization, but partially attenuated the inhibitory effect of mMDSC on T cell proliferation and decreased the frequency of Tregs in primary tumors and lung metastases. Strikingly, DC101 treatment induced the expression of the immune-suppressive molecule arginase I in mMDSC. Treatment with the arginase inhibitor N v -hydroxy-nor-Arginine (Nor-NOHA) reduced the inhibitory effect of MDSC on T cell proliferation and inhibited number and size of lung metastasis but had little or no additional effects in combination with DC101.In conclusion, DC101 treatment suppresses 4T1 tumor growth and metastasis, partially reverses the inhibitory effect of mMDSC on T cell proliferation, decreases Tregs in tumors and increases arginase I expression in mMDSC. Arginase inhibition suppresses lung metastasis independently of DC101 effects. These observations contribute to the further characterization of the immunomodulatory effect of anti-VEGF/VEGFR2 therapy and provide a rationale to pursue arginase inhibition as potential anti-metastatic therapy.

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“…Bevacizumab, which targets VEGF, is often added to first-line chemotherapy, and combination with immunotherapy is being tested clinically (34). Because VEGF inhibits DC maturation, anti-VEGF strategies may also enhance the induction and potency of immune responses.…”

Section: Pd-(l)1 Inhibitor Nonrespondersmentioning

confidence: 99%