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.

A TLR7 agonist strengthens T and NK cell function during BRAF‐targeted therapy in a preclinical melanoma model

“…39 Preclinical transplantable and transgenic tumor models were used to understand the immunological effects of BRAFi and showed, similar to patients, increased immunogenicity of BRAFi-sensitive tumors. [11][12][13][14]20,21,40 However, very few of these studies investigated the immune infiltrate during resistance development. 21,40 Thus, the rationale of our study was to investigate changes in the immunological landscape during BRAFi therapy in a preclinical melanoma mouse model and to modulate antitumor immunity to delay resistance development.…”

“…[11][12][13][14]20,21,40 However, very few of these studies investigated the immune infiltrate during resistance development. 21,40 Thus, the rationale of our study was to investigate changes in the immunological landscape during BRAFi therapy in a preclinical melanoma mouse model and to modulate antitumor immunity to delay resistance development. We demonstrate that in the early BRAFi treatment phase, tumors from the transplantable D4M model, 25 carrying the BRAF V600E mutation and PTEN loss, are highly immunogenic and infiltrated by activated effector T and NK cells.…”

“…The immunogenic effect of BRAFi is transient as indicated by a loss of tumor‐infiltrating T cells during progression . Due to the immunological effects reported, preclinical studies tested combinations of BRAFi and/or MEK inhibitor (MEKi) with anti‐PD‐1 checkpoint blocking antibody and observed increased ratio of CD8 + effector T cells to Tregs in tumor biopsies . Recently, performed clinical trials with the triple combination of BRAFi, MEKi and checkpoint inhibitor demonstrated promising response rates in subgroups of melanoma patients, but also reported high toxicities .…”

“…16,19 Due to the immunological effects reported, preclinical studies tested combinations of BRAFi and/or MEK inhibitor (MEKi) with anti-PD-1 checkpoint blocking antibody and observed increased ratio of CD8 + effector T cells to Tregs in tumor biopsies. 20,21 Recently, performed clinical trials with the triple combination of BRAFi, MEKi and checkpoint inhibitor demonstrated promising response rates in subgroups of melanoma patients, but also reported high toxicities. [22][23][24] A deeper understanding of the tumor microenvironmental changes during targeted therapy and how the immune system can be manipulated to potentiate responses is crucial for the development of urgently needed, alternative combinations.…”

Effects of Combination of Anti-CTLA-4 and Anti-PD-1 on Gastric Cancer Cells Proliferation, Apoptosis and Metastasis

“…Shah et al found that CTLA-4 was a direct target of Wnt/β-catenin signaling and was expressed in human melanoma tumors [36]. Further, Deken et al demonstrated that targeting the MAPK and PI3K pathways in combination with PD-1 could blockade in melanoma [37]. However, whether β-catenin, MAPK and PI3K/AKT signal pathways could influence the anticancer effect of anti-CTLA-4 and anti-PD-1 antibodies on GC cells remains uninvestigated.…”