Incorporation of SKI-G-801, a Novel AXL Inhibitor, With Anti-PD-1 Plus Chemotherapy Improves Anti-Tumor Activity and Survival by Enhancing T Cell Immunity

Abstract

A recently developed treatment strategy for lung cancer that combines immune checkpoint inhibitors with chemotherapy has been applied as a standard treatment for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and it has improved the outcomes of chemotherapy. Maintenance treatment with anti-PD-1 antibody (aPD-1) enhances the effect of immunochemical combination therapy and improves therapeutic efficacy, which contributes toward a significant improvement in patient survival rates. The AXL receptor tyrosine kinase (AXL), which is expressed in tumor cells, plays an essential role in the resistance of cancers to chemotherapy and immunotherapy, and stimulates signaling associated with epithelial-mesenchymal transition (EMT) in metastatic cancer. AXL is thus an attractive target for controlling resistance to anti-tumor therapies. In this study, we examined the effect of AXL inhibitors on immune activation and tumor growth in TC1 and C3PQ mouse tumor models, in the context of clinical immunotherapy/chemotherapy and maintenance treatment, using an aPD-1 with/without pemetrexed. To determine the optimal timing for administration of SKI-G-801, an AXL inhibitor, we investigated its anti-tumor effects based on inclusion at the immunochemotherapy and maintenance therapy stages. We also performed flow cytometry-based immune profiling of myeloid cells and lymphoid cells at different points in the treatment schedule, to investigate the immune activation and anti-tumor effects of the AXL inhibitor. The addition of SKI-G-801 to the immune checkpoint inhibitor and chemotherapy stage, as well as the maintenance therapy stage, produced the best anti-tumor results, and significant tumor growth inhibition was observed in both the TC1 and C3PQ models. Both models also exhibited increased proportion of effector memory helper T cells and increased expression of CD86+ macrophages. Especially, regulatory T cells were significantly reduced in the TC1 tumor model and there was an increase in central memory cytotoxic T cell infiltration and an increased proportion of macrophages with high CD80 expression in the C3PQ tumor model. These results suggest increased infiltration of T cells, consistent with previous studies using AXL inhibitors. It is expected that the results from this study will serve as a stepping stone for clinical research to improve the existing standard of care.

Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy

“…In vivo pharmacologic inhibiting pan-TAM Tyrosine Kinases, TYRO3, AXL, and MERTK, diminishes MDSC suppressive capability, promotes CD8 + T cell infiltration, slows tumor growth, and augments anti-PD-1 immunotherapy [ 247 – 249 ]. Consistently, another AXL kinase inhibitor, SKI-G-801, blocks metastasis through inducing anti-tumor immune responses and potentiates anti-PD-1 therapy in multiple mouse cancer models (including B16F10 melanoma, CT26 colon, 4T1 breast, TC1 and C3PQ lung cancer models) [ 250 , 251 ]. Similarly, combining AXL kinase inhibitor R428 with anti–PD-1 in a mouse HER2 + breast cancer model reduces the primary tumor and metastatic burdens [ 171 ].…”

“… [ 246 ] BMS-777607 Murine Model of Triple-Negative Breast Cancer Blocks macrophage efferocytosis and Gas6-PS–opsonized apoptotic cell, and enhances anti-PD-1 mAb efficacy via up-regulating PD-L1 expression [ 249 ] SKI-G-801 B16F10 melanoma, CT26 colon and 4T1 breast model Blocks metastasis through inducing CD8 + T cells, decreasing M2 macrophage and potentiates anti-PD-1 therapy [ 250 ] TC1 and C3PQ mouse tumor models Improves efficiency of anti-PD-1 therapy, exhibiting increased proportion of effector memory helper T cells, CD86+ macrophages. [ 251 ] Enapotamab vedotin (EnaV) Melanoma and lung cancer models Induced ICB benefit and promoted the induction of a memory-like phenotype in cytotoxic T cells. [ 252 ] R428 HER2 + breast cancer Enhances anti-PD-1 responses via increased CD8 + T cells [ 171 ] PDGFR inhibitors Imatinib Gastrointestinal stromal tumors Abrogated the IFN-γ induced upregulation of PD-L1 via STAT1 inhibition.…”

Vimentin expression correlates with immune checkpoint inhibitor efficacy in non–small cell lung cancer

“…Vimentin contributes to the stabilization of focal adhesion kinase, 9 which inhibits CD8 + cellular infiltration and induces T regulatory cell infiltration 43 . Vimentin is also associated with inducing expression of Axl receptor tyrosine kinase, 7,10 which decreases the efficacy of ICI 44,45 . These mechanisms may adversely affect ICI treatment and may be partially related to the poor efficacy of ICI in the vimentin highly positive group (≥50%) in the present study.…”

“…43 Vimentin is also associated with inducing expression of Axl receptor tyrosine kinase, 7,10 which decreases the efficacy of ICI. 44,45 These mechanisms may adversely affect ICI treatment and may be partially related to the poor efficacy of ICI in the vimentin highly positive group (≥50%)…”

Gas6/AXL pathway: immunological landscape and therapeutic potential

“…A recent mouse study demonstrated that AXL inhibitors impact the immune status and tumor growth in lung cancer. Application of AXL inhibitors to treat mice resulted in delayed tumor growth, elevated rate of effector memory helper T cells, enhanced infiltration of central memory cytotoxic T cells, increased amounts of CD86+ macrophages, and elevated proportion of CD80 high-expression macrophages in the tumor model ( 113 ).…”