Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/28017
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dc.contributor.authorWhite, Michael G-
dc.contributor.authorSzczepaniak Sloane, Robert-
dc.contributor.authorWitt, Russell G-
dc.contributor.authorReuben, Alexandre-
dc.contributor.authorGaudreau, Pierre Olivier-
dc.contributor.authorAndrews, Miles C-
dc.contributor.authorFeng, Ningping-
dc.contributor.authorJohnson, Sarah-
dc.contributor.authorClass, Caleb A-
dc.contributor.authorBristow, Christopher-
dc.contributor.authorWani, Khalida-
dc.contributor.authorHudgens, Courtney-
dc.contributor.authorNezi, Luigi-
dc.contributor.authorManzo, Teresa-
dc.contributor.authorDe Macedo, Mariana Pettaccia-
dc.contributor.authorHu, Jianhua-
dc.contributor.authorDavis, Richard-
dc.contributor.authorJiang, Hong-
dc.contributor.authorPrieto, Peter-
dc.contributor.authorBurton, Elizabeth-
dc.contributor.authorHwu, Patrick-
dc.contributor.authorTawbi, Hussein-
dc.contributor.authorGershenwald, Jeffrey-
dc.contributor.authorLazar, Alexander J-
dc.contributor.authorTetzlaff, Michael T-
dc.contributor.authorOverwijk, Willem-
dc.contributor.authorWoodman, Scott E-
dc.contributor.authorCooper, Zachary A-
dc.contributor.authorMarszalek, Joseph R-
dc.contributor.authorDavies, Michael A-
dc.contributor.authorHeffernan, Timothy P-
dc.contributor.authorWargo, Jennifer A-
dc.date2021-
dc.date.accessioned2021-11-16T23:15:45Z-
dc.date.available2021-11-16T23:15:45Z-
dc.date.issued2021-11-
dc.identifier.citationOncoimmunology 2021; 10(1): 1992880en
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/28017-
dc.description.abstractTargeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (>4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten-/- ). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies.en
dc.language.isoeng
dc.subjectMAP-kinaseen
dc.subjectMelanomaen
dc.subjectOX-40en
dc.subjectcheckpoint blockadeen
dc.subjectimmunotherapyen
dc.subjecttargeted therapyen
dc.subjecttoxicityen
dc.titleShort-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma.en
dc.typeJournal Articleen
dc.identifier.journaltitleOncoimmunologyen
dc.identifier.affiliationTranslational Sciences Oncology, MedImmune, Gaithersburg, MD, USAen
dc.identifier.affiliationOlivia Newton-John Cancer Research Instituteen
dc.identifier.affiliationSchool of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australiaen
dc.identifier.affiliationDepartment of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USAen
dc.identifier.affiliationDepartment of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USAen
dc.identifier.affiliationDepartment of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USAen
dc.identifier.affiliationDepartment of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USAen
dc.identifier.affiliationOncology Research, Nektar Therapeutics, San Francisco, CA, USAen
dc.identifier.affiliationDepartment of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USAen
dc.identifier.affiliationTranslational Research to AdvanCe Therapeutics and Innovation in ONcology (TRACTION), University of Texas MD Anderson Cancer Center, Houston, TX, USAen
dc.identifier.affiliationDepartment of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USAen
dc.identifier.affiliationDepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USAen
dc.identifier.doi10.1080/2162402X.2021.1992880en
dc.type.contentTexten
dc.identifier.orcid0000-0003-4510-0382en
dc.identifier.orcid0000-0001-8312-7485en
dc.identifier.orcid0000-0003-4519-5369en
dc.identifier.orcid0000-0002-6395-4499en
dc.identifier.orcid0000-0002-0977-0912en
dc.identifier.pubmedid34777916
item.languageiso639-1en-
item.grantfulltextnone-
item.openairetypeJournal Article-
item.cerifentitytypePublications-
item.fulltextNo Fulltext-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
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