Trivedi, Vrunda

Abstract Current advances in the treatment of melanoma brain metastases through immune checkpoint blockade and targeted therapy has significantly improved outcomes and patient survival. Yet, half of all patients continue to die from brain metastases despite use of these therapies and the addition of localized therapies like surgery and stereotactic radiosurgery. Novel treatments are needed to improve the morbidity and mortality associated with melanoma brain metastases. We have identified the inflammatory myddosomal pathway as a novel potential target of therapy in melanoma brain metastases, with gross upregulation in both tumor tissue and tumor-infiltrating immune cells. These cells display upregulation in MYD88, IRAK-1, IRAK-4, and downstream mediators of inflammatory activation at both the gene and protein level. We have previously shown the ability of the oral IRAK-4 inhibitor emavusertib (CA-4948) to penetrate the blood brain barrier and inhibit the myddosomal pathway in metastatic melanoma and primary CNS lymphoma. In this study we further show the capacity for IRAK-4 inhibition with emavusertib to improve the therapeutic efficacy of anti-PD-1 immune checkpoint blockade in melanoma brain metastases. Emavusertib in combination with anti-PD-1 therapy results in improved tumor-infiltrating lymphocyte recruitment, decreased myeloid derived suppressor cell function, and upregulation of interferon γ signaling resulting in improved survival in aggressive mouse models of melanoma brain metastases. This work supports the development of combination strategies of emavusertib with immune checkpoint blockade in melanoma brain metastases.

Abstract Purpose: An ongoing challenge in cancer is the management of primary and metastatic brain malignancies. This is partly due to restrictions of the blood-brain barrier and their unique microenvironment. These challenges are most evident in cancers such as lymphoma and melanoma, which are typically responsive to treatment in systemic locations but resistant when established in the brain. We propose interleukin-1 receptor-associated kinase-4 (IRAK-4) as a potential target across these diseases and describe the activity and mechanism of oral IRAK-4 inhibitor CA-4948. Experimental Design: Human primary central nervous system lymphoma (PCNSL) and melanoma brain metastases (MBM) samples were analyzed for expression of IRAK-4 and downstream transcription pathways. We next determined the central nervous system (CNS) applicability of CA-4948 in naïve and tumor-bearing mice using models of PCNSL and MBM. The mechanistic effect on tumors and the tumor microenvironment was then analyzed. Results: Human PCNSL and MBM have high expression of IRAK-4, IRAK-1, and nuclear factor kappa B (NF-κB). This increase in inflammation results in reflexive inhibitory signaling. Similar profiles are observed in immunocompetent murine models. Treatment of tumor-bearing animals with CA-4948 results in the downregulation of mitogen-activated protein kinase (MAPK) signaling in addition to decreased NF-κB. These intracellular changes are associated with a survival advantage. Conclusions: IRAK-4 is an attractive target in PCNSL and MBM. The inhibition of IRAK-4 with CA-4948 downregulates the expression of important transcription factors involved in tumor growth and proliferation. CA-4948 is currently being investigated in clinical trials for relapsed and refractory lymphoma and warrants further translation into PCNSL and MBM.