TY - JOUR
T1 - Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma
AU - White, Michael G.
AU - Szczepaniak Sloane, Robert
AU - Witt, Russell G.
AU - Reuben, Alexandre
AU - Gaudreau, Pierre Olivier
AU - Andrews, Miles C.
AU - Feng, Ningping
AU - Johnson, Sarah
AU - Class, Caleb A.
AU - Bristow, Christopher
AU - Wani, Khalida
AU - Hudgens, Courtney
AU - Nezi, Luigi
AU - Manzo, Teresa
AU - De Macedo, Mariana Pettaccia
AU - Hu, Jianhua
AU - Davis, Richard
AU - Jiang, Hong
AU - Prieto, Peter
AU - Burton, Elizabeth
AU - Hwu, Patrick
AU - Tawbi, Hussein
AU - Gershenwald, Jeffrey
AU - Lazar, Alexander J.
AU - Tetzlaff, Michael T.
AU - Overwijk, Willem
AU - Woodman, Scott E.
AU - Cooper, Zachary A.
AU - Marszalek, Joseph R.
AU - Davies, Michael A.
AU - Heffernan, Timothy P.
AU - Wargo, Jennifer A.
N1 - Publisher Copyright:
© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - MAP-kinase
KW - Melanoma
KW - OX-40
KW - checkpoint blockade
KW - immunotherapy
KW - targeted therapy
KW - toxicity
UR - http://www.scopus.com/inward/record.url?scp=85118827164&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85118827164&partnerID=8YFLogxK
U2 - 10.1080/2162402X.2021.1992880
DO - 10.1080/2162402X.2021.1992880
M3 - Article
C2 - 34777916
AN - SCOPUS:85118827164
SN - 2162-4011
VL - 10
JO - OncoImmunology
JF - OncoImmunology
IS - 1
M1 - 1992880
ER -