Alteration of macrophage infiltrates in the tumor immune microenvironment following Janus kinase 1 (JAK) inhibition: analysis from a prospective clinical trial in Leiomyosarcoma

JAK1 signaling supports a suppressive tumor-associated macrophage (TAM) state and may also promote tumor-intrinsic oncogenic signaling. Leiomyosarcoma (LMS) is a soft tissue sarcoma (STS) subtype known to have abundant TAM infiltration, which is often polarized to an immunosuppressive M2 phenotype and contributes to immune evasion. We hypothesized that using a JAK1 inhibitor could alter TAM phenotypes in the LMS tumor microenvironment (TME), helping patients and potentially enabling future combination studies. Here, we present results from a pilot study of itacitinib, a JAK1 inhibitor, for LMS. We analyzed patients in the LMS cohort of a pilot study of the selective JAK1 inhibitor itacitinib (started at 300 mg daily in 28-day cycles) (NCT03670069). Serial tumor biopsies and peripheral blood samples were collected for correlative analysis. Despite the heavily pretreated LMS population, PFS rate at 3 and 6 months for LMS was 75% (95% CI: 50%-100%) and 25% (95% CI: 5%-100%), respectively, and the median OS was 101 weeks (range: 70-256). Six of eight patients with LMS achieved stable disease. Serial biopsies demonstrated a decrease in M2 TAM but without a corresponding inflammatory response and with a decrease of inflammatory infiltrates, suggesting that JAK1 inhibition may have direct anti-tumor effects in this subtype and that the impacts of the TAM reduction may be related to their tumor supportive and angiogenic functions, rather than immune inhibitory functions. These data support further investigation of JAK1 inhibition in LMS as part of rational immunotherapeutic combinations.