title: Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma.
abstract: Immunotherapy of advanced melanoma with CTLA-4 or PD-1/PD-L1 checkpoint blockade induces in a proportion of patients long durable responses. In contrast, targeting the MAPK-pathway by selective BRAF and MEK inhibitors induces high response rates, but most patients relapse. Combining targeted therapy with immunotherapy is proposed to improve the long-term outcomes of patients. Preclinical data endorsing this hypothesis are accumulating. Inhibition of the PI3K-Akt-mTOR pathway may be a promising treatment option to overcome resistance to MAPK inhibition and for additional combination with immunotherapy. We therefore evaluated to which extent dual targeting of the MAPK and PI3K-Akt-mTOR pathways affects tumor immune infiltrates and whether it synergizes with PD-1 checkpoint blockade in a BRAFV600E/PTEN-/--driven melanoma mouse model. Short-term dual BRAF + MEK inhibition enhanced tumor immune infiltration and improved tumor control when combined with PD-1 blockade in a CD8+T cell dependent manner. Additional PI3K inhibition did not impair tumor control or immune cell infiltration and functionality. Analysis of on-treatment samples from melanoma patients treated with BRAF or BRAF + MEK inhibitors indicates that inhibitor-mediated T cell infiltration occurred in all patients early after treatment initiation but was less frequent found in on-treatment biopsies beyond day 15. Our findings provide a rationale for clinical testing of short-term BRAF + MEK inhibition in combination with immune checkpoint blockade, currently implemented at our institutes. Additional PI3K inhibition could be an option for BRAF + MEK inhibitor resistant patients that receive targeted therapy in combination with immune checkpoint blockade.
authors.affiliation: Department of Immunology, Netherlands Cancer Institute , Amsterdam, the Netherlands.
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Deken
authors.affiliation: Department of Immunology, Netherlands Cancer Institute , Amsterdam, the Netherlands.
authors.forename: Jules
authors.initials: J
authors.lastname: Gadiot
authors.affiliation: Center for Gynecologic Oncology, VU University Medical Center , Amsterdam, the Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.affiliation: Department of Immunology, Netherlands Cancer Institute , Amsterdam, the Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: Lacroix
authors.affiliation: Department of Immunology, Netherlands Cancer Institute , Amsterdam, the Netherlands.
authors.forename: Melissa
authors.initials: M
authors.lastname: van Gool
authors.affiliation: Department of Immunology, Netherlands Cancer Institute , Amsterdam, the Netherlands.
authors.forename: Paula
authors.initials: P
authors.lastname: Kroon
authors.affiliation: Department of Immunology, Netherlands Cancer Institute , Amsterdam, the Netherlands.
authors.forename: Cristina
authors.initials: C
authors.lastname: Pineda
authors.affiliation: Department of Medical Oncology, Netherlands Cancer Institute , Amsterdam, the Netherlands.
authors.forename: Marnix H
authors.initials: MH
authors.lastname: Geukes Foppen
authors.affiliation: Melanoma Institute Australia, The University of Sydney, and Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital , NSW, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Scolyer
authors.affiliation: Department of Animal Pathology, Netherlands Cancer Institute , Amsterdam, the Netherlands.
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.affiliation: Department of Immunology, Netherlands Cancer Institute , Amsterdam, the Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: Verbrugge
authors.affiliation: Department of Dermatology, Medical University of Vienna , Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hoeller
authors.affiliation: Department of Dermatology, University Hospital Zurich , Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
authors.affiliation: Melanoma Institute Australia, The University of Sydney, and Royal North Shore Hospital , Sydney, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Department of Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Christian U
authors.initials: CU
authors.lastname: Blank
keywords: Anti-PD-1; BRAF; MAPK; MEK; PI3K; checkpoint blockade; immunotherapy; mTOR; melanoma; targeted therapy