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Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma

SIMPLE SUMMARY: Adoptive cell transfer (ACT) is a potentially robust treatment option for patients with advanced melanoma that is resistant to immune checkpoint inhibitors. The addition of cyclin-dependent kinase 4/6 inhibitors to combination BRAF-MEK inhibitors can also greatly improve the duration...

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Autores principales: Lau, Peter Kar Han, Cullinane, Carleen, Jackson, Susan, Walker, Rachael, Smith, Lorey K., Slater, Alison, Kirby, Laura, Patel, Riyaben P., von Scheidt, Bianca, Slaney, Clare Y., McArthur, Grant A., Sheppard, Karen E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699814/
https://www.ncbi.nlm.nih.gov/pubmed/34944961
http://dx.doi.org/10.3390/cancers13246342
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author Lau, Peter Kar Han
Cullinane, Carleen
Jackson, Susan
Walker, Rachael
Smith, Lorey K.
Slater, Alison
Kirby, Laura
Patel, Riyaben P.
von Scheidt, Bianca
Slaney, Clare Y.
McArthur, Grant A.
Sheppard, Karen E.
author_facet Lau, Peter Kar Han
Cullinane, Carleen
Jackson, Susan
Walker, Rachael
Smith, Lorey K.
Slater, Alison
Kirby, Laura
Patel, Riyaben P.
von Scheidt, Bianca
Slaney, Clare Y.
McArthur, Grant A.
Sheppard, Karen E.
author_sort Lau, Peter Kar Han
collection PubMed
description SIMPLE SUMMARY: Adoptive cell transfer (ACT) is a potentially robust treatment option for patients with advanced melanoma that is resistant to immune checkpoint inhibitors. The addition of cyclin-dependent kinase 4/6 inhibitors to combination BRAF-MEK inhibitors can also greatly improve the duration of response against melanoma. The aim of our study was to investigate adoptive cell transfer with combination BRAF-MEK and CDK4/6 inhibitors. We show triplet targeted therapy is highly efficacious against BRAF(V600) melanoma in YOVAL1.1 and the BRAFi resistant SM1WT1 model. Combination ACT with BRAF-MEK-CDK4/6i led to prolonged and deep anti-tumor responses in YOVAL1.1. This work provides additional evidence for BRAF-MEK-CDK4/6i in clinical trials and in combination with ACT. ABSTRACT: Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic.
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spelling pubmed-86998142021-12-24 Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma Lau, Peter Kar Han Cullinane, Carleen Jackson, Susan Walker, Rachael Smith, Lorey K. Slater, Alison Kirby, Laura Patel, Riyaben P. von Scheidt, Bianca Slaney, Clare Y. McArthur, Grant A. Sheppard, Karen E. Cancers (Basel) Article SIMPLE SUMMARY: Adoptive cell transfer (ACT) is a potentially robust treatment option for patients with advanced melanoma that is resistant to immune checkpoint inhibitors. The addition of cyclin-dependent kinase 4/6 inhibitors to combination BRAF-MEK inhibitors can also greatly improve the duration of response against melanoma. The aim of our study was to investigate adoptive cell transfer with combination BRAF-MEK and CDK4/6 inhibitors. We show triplet targeted therapy is highly efficacious against BRAF(V600) melanoma in YOVAL1.1 and the BRAFi resistant SM1WT1 model. Combination ACT with BRAF-MEK-CDK4/6i led to prolonged and deep anti-tumor responses in YOVAL1.1. This work provides additional evidence for BRAF-MEK-CDK4/6i in clinical trials and in combination with ACT. ABSTRACT: Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic. MDPI 2021-12-17 /pmc/articles/PMC8699814/ /pubmed/34944961 http://dx.doi.org/10.3390/cancers13246342 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lau, Peter Kar Han
Cullinane, Carleen
Jackson, Susan
Walker, Rachael
Smith, Lorey K.
Slater, Alison
Kirby, Laura
Patel, Riyaben P.
von Scheidt, Bianca
Slaney, Clare Y.
McArthur, Grant A.
Sheppard, Karen E.
Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma
title Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma
title_full Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma
title_fullStr Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma
title_full_unstemmed Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma
title_short Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma
title_sort enhancing adoptive cell transfer with combination braf-mek and cdk4/6 inhibitors in melanoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699814/
https://www.ncbi.nlm.nih.gov/pubmed/34944961
http://dx.doi.org/10.3390/cancers13246342
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