Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma
Targeted 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 r...
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2021
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oai:doaj.org-article:e6152b9f5495402183474ea2dacf70222021-11-11T14:23:43ZShort-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma2162-402X10.1080/2162402X.2021.1992880https://doaj.org/article/e6152b9f5495402183474ea2dacf70222021-01-01T00:00:00Zhttp://dx.doi.org/10.1080/2162402X.2021.1992880https://doaj.org/toc/2162-402XTargeted 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.Michael G. WhiteRobert Szczepaniak SloaneRussell G. WittAlexandre ReubenPierre Olivier GaudreauMiles C. AndrewsNingping FengSarah JohnsonCaleb A. ClassChristopher BristowKhalida WaniCourtney HudgensLuigi NeziTeresa ManzoMariana Pettaccia De MacedoJianhua HuRichard DavisHong JiangPeter PrietoElizabeth BurtonPatrick HwuHussein TawbiJeffrey GershenwaldAlexander J. LazarMichael T. TetzlaffWillem OverwijkScott E WoodmanZachary A. CooperJoseph R. MarszalekMichael A. DaviesTimothy P. HeffernanJennifer A. WargoTaylor & Francis Grouparticlemelanomaimmunotherapytargeted therapytoxicitycheckpoint blockadeox-40map-kinaseImmunologic diseases. AllergyRC581-607Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncoImmunology, Vol 10, Iss 1 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
melanoma immunotherapy targeted therapy toxicity checkpoint blockade ox-40 map-kinase Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
melanoma immunotherapy targeted therapy toxicity checkpoint blockade ox-40 map-kinase Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Michael G. White Robert Szczepaniak Sloane Russell G. Witt Alexandre Reuben Pierre Olivier Gaudreau Miles C. Andrews Ningping Feng Sarah Johnson Caleb A. Class Christopher Bristow Khalida Wani Courtney Hudgens Luigi Nezi Teresa Manzo Mariana Pettaccia De Macedo Jianhua Hu Richard Davis Hong Jiang Peter Prieto Elizabeth Burton Patrick Hwu Hussein Tawbi Jeffrey Gershenwald Alexander J. Lazar Michael T. Tetzlaff Willem Overwijk Scott E Woodman Zachary A. Cooper Joseph R. Marszalek Michael A. Davies Timothy P. Heffernan Jennifer A. Wargo Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma |
| description |
Targeted 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. |
| format |
article |
| author |
Michael G. White Robert Szczepaniak Sloane Russell G. Witt Alexandre Reuben Pierre Olivier Gaudreau Miles C. Andrews Ningping Feng Sarah Johnson Caleb A. Class Christopher Bristow Khalida Wani Courtney Hudgens Luigi Nezi Teresa Manzo Mariana Pettaccia De Macedo Jianhua Hu Richard Davis Hong Jiang Peter Prieto Elizabeth Burton Patrick Hwu Hussein Tawbi Jeffrey Gershenwald Alexander J. Lazar Michael T. Tetzlaff Willem Overwijk Scott E Woodman Zachary A. Cooper Joseph R. Marszalek Michael A. Davies Timothy P. Heffernan Jennifer A. Wargo |
| author_facet |
Michael G. White Robert Szczepaniak Sloane Russell G. Witt Alexandre Reuben Pierre Olivier Gaudreau Miles C. Andrews Ningping Feng Sarah Johnson Caleb A. Class Christopher Bristow Khalida Wani Courtney Hudgens Luigi Nezi Teresa Manzo Mariana Pettaccia De Macedo Jianhua Hu Richard Davis Hong Jiang Peter Prieto Elizabeth Burton Patrick Hwu Hussein Tawbi Jeffrey Gershenwald Alexander J. Lazar Michael T. Tetzlaff Willem Overwijk Scott E Woodman Zachary A. Cooper Joseph R. Marszalek Michael A. Davies Timothy P. Heffernan Jennifer A. Wargo |
| author_sort |
Michael G. White |
| title |
Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma |
| title_short |
Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma |
| title_full |
Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma |
| title_fullStr |
Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma |
| title_full_unstemmed |
Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma |
| title_sort |
short-term treatment with multi-drug regimens combining braf/mek-targeted therapy and immunotherapy results in durable responses in braf-mutated melanoma |
| publisher |
Taylor & Francis Group |
| publishDate |
2021 |
| url |
https://doaj.org/article/e6152b9f5495402183474ea2dacf7022 |
| work_keys_str_mv |
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