Exploring the synergistic effects of cabozantinib and a programmed cell death protein 1 inhibitor in metastatic renal cell carcinoma with machine learning

Abstract

Clinical evidence supports the combination of cabozantinib with an immune checkpoint inhibitor for the treatment of metastatic clear cell renal cell carcinoma (mccRCC) and suggests a synergistic antitumour activity of this combination. Nevertheless, the biological basis of this synergy is not fully characterized. We studied the mechanisms underpinning the potential synergism of cabozantinib combined with a PD1 inhibitor in mccRCC and delved into cabozantinib monotherapy properties supporting its role to partner these combinations. To model physiological drug action, we used a machine learning-based technology known as Therapeutic Performance Mapping Systems, applying two approaches: Artificial Neural Networks and Sampling Methods. We found that the combined therapy was predicted to exert a wide therapeutic action in the tumour and the microenvironment. Cabozantinib may enhance the effects of PD1 inhibitors on immunosurveillance by modulating the innate and adaptive immune system, through the inhibition of VEGF-VEGFR and Gas6-AXL/TYRO3/MER (TAM) axes, while the PD1 inhibitors may boost the antiangiogenic and pro–apoptotic effects of cabozantinib by modulating angiogenesis and T-cell cytotoxicity. Cabozantinib alone was predicted to restore cellular adhesion and hamper tumour proliferation and invasion. These data provide a biological rationale and further support for cabozantinib plus PD1 inhibitor combination and may guide future nonclinical and clinical research.

Cabozantinib combination therapy for the treatment of solid tumors: a systematic review

“…23 A recent study using machine-learning-based technology investigated the potential synergistic effects of cabozantinib and anti-PD1 therapy in the treatment of metastatic RCC (mRCC) and reported that cabozantinib may enhance the impact of anti-PD1 therapy on immunosurveillance via its actions on the innate and adaptive immune system, and that anti-PD1 therapy may enhance the anti-angiogenic and pro-apoptotic effects of cabozantinib via action on angiogenesis and T-cell cytotoxicity. 24 In patients with metastatic urothelial carcinoma (mUC) treated with cabozantinib, reductions in the number of regulatory T cells and myeloidderived suppressor cells were observed after treatment and were associated with clinical responses 21 ; similar associations have been demonstrated in patients with RCC treated with cabozantinib. 25 In addition, cabozantinib has been shown to increase the number of CD8+ T cells in patients with RCC.…”

“… 23 A recent study using machine-learning-based technology investigated the potential synergistic effects of cabozantinib and anti-PD1 therapy in the treatment of metastatic RCC (mRCC) and reported that cabozantinib may enhance the impact of anti-PD1 therapy on immunosurveillance via its actions on the innate and adaptive immune system, and that anti-PD1 therapy may enhance the anti-angiogenic and pro-apoptotic effects of cabozantinib via action on angiogenesis and T-cell cytotoxicity. 24 …”