Abstract LB203: Targeted inhibition of IRAK-4 with CA-4948 (emavusertib) sensitizes metastatic brain melanoma to anti-PD-1 immune checkpoint blockade
Authors: von Roemeling Christina A. , Doonan Bently P. , Russell Rylynn A. , Elliott Tyler V. , Matich Erica , Archibald Vincent , Hoang-Minh Lan , von Roemeling Reinhard W. , Ferrari Dora , Hoffman Jamison , Mitchell Duane A. 
Published: April 2023

Abstract
Introduction: The unique microenvironment within the brain alongside restrictions imparted by the blood brain barrier (BBB) create a sanctuary site for tumors to thrive. Melanoma is often responsive to therapy when present in peripheral tissue, but becomes recalcitrant when sequestered beyond the BBB. An estimated 40-60% of metastatic melanoma patients will develop a brain lesion, even while receiving treatment. Stereotactic radiosurgery (SRS) is the gold standard in intervention for metastatic brain melanoma (MBM), often given with anti-PD1 immune checkpoint blockade (ICB). While this therapy is initially effective, resistance occurs rapidly and ~50% of patients will develop new brain lesions within a year. Treatments at this stage are limited, necessitating the discovery of new therapies. Recent studies have shown that myeloid differentiation primary response protein 88 (MyD88) is activated in melanoma in tumor-associated myeloid cells where chronic myddosome signaling results in defective immunological responses. We have found that myddosome signaling is also prevalent in MBM, likely protecting brain metastases against effector immune detection. We recently identified that CA-4948, a small molecule inhibitor of interleukin (IL)-1 receptor-associated kinase (IRAK-4) and rate-limiting step in the myddosome cascade, can reach therapeutic levels in the brain and demonstrates on-target inhibition in preclinical models of MBM. These data highlight a unique therapeutic opportunity where selective inhibition of pro-tumorigenic cells in the MBM tumor microenvironment (TME) via targeted IRAK-4 inhibition may recondition the immunological landscape of these tumors, sensitizing these difficult-to-treat tumors to immunotherapy.
Hypothesis: Selective inhibition of pro-tumorigenic cells via targeted inhibition of IRAK-4 with CA-4948 will recondition the immunological landscape of MBM, improving anti-tumor response to anti-PD-1 ICB.
Methods: Patient MBM samples were assessed by IHC to define the distribution of myddosome signaling. Preclinical syngeneic MBM tumor models were treated with CA-4948 alone and in combination with anti-PD-1 ICB. Tumors were examined by flow cytometry and IHC to characterize the composition of the immune TME and evaluate the distribution of T lymphocytes. Overall survival was compared between control, single agent, and combination treated animals.
Results: Tumor-associated immune cells and astrocytes comprise the majority of active myddosome signaling in patient MBM. Preclinical models corroborate these findings, with targeted inhibition of IRAK-4 through CA-4948 treatment effective at reducing activation and validating anti-tumor activity in the CNS. Analysis of treated tumors reveal decreased expression of Programmed Death Ligand 1 (PD-L1), and increased numbers of tumor-infiltrating T lymphocytes. Combination CA-4948 with anti-PD-1 ICB resulted in reduced tumor growth, and improved survival over single agent therapy.
Conclusions: Therapeutic inhibition of IRAK-4 in MBM mitigates immune suppression mediated by tumor-associated cells, allowing for improved immune surveillance and tumor infiltration by effector T lymphocytes, resulting in enhanced anti-tumor activity. Thus, CA-4948 may be an effective treatment alongside anti-PD-1 ICB for patients with MBM.
Citation Format: Christina A. von Roemeling, Bently P. Doonan, Rylynn A. Russell, Tyler V. Elliott, Erica Matich, Vincent Archibald, Lan Hoang-Minh, Reinhard W. von Roemeling, Dora Ferrari, Jamison Hoffman, Duane A. Mitchell. Targeted inhibition of IRAK-4 with CA-4948 (emavusertib) sensitizes metastatic brain melanoma to anti-PD-1 immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB203.