Systemic mastocytosis (SM) is a mast-cell neoplasm found in the bone marrow and other organs driven primarily by mutations in KIT. This gene codes for the tyrosine kinase KIT and D816V substitution mutation results in constitutive activation of the KIT receptor (CD117) and subsequent overproliferation of mast cells. The accumulation of mast cells in various organs as well as organ damage are characteristic of disease progression to advanced SM (AdvSM), which includes 3 subtypes: SM with an associated hematologic neoplasm, aggressive SM (ASM), and mast-cell leukemia (MCL). AdvSM can be difficult to treat and is associated with decreased overall survival (OS). Patients receiving tyrosine kinase inhibitors such as midostaurin have been shown to respond to treatment but OS is variable depending on AdvSM subtype (median 3.5 years for ASM compared with median 6 months for MCL). For some patients, midostaurin provides no clinical improvement or must be discontinued or reduced because of treatment-induced adverse events. Although stem-cell transplant represents the best option for cure, it is also associated with significant side effects, high rates of relapse, and an OS of 43% for ASM and 17% for MCL after 3 years.
Previous research has demonstrated that CD117+ acute myeloid leukemia can be cured by anti-CD117 CAR T-cell therapy in vitro and in vivo. Mast cells with KIT D816V mutation overexpress CD117, which is the primary mediator of disease course in most patients with SM. Therefore, CD117 may serve as a candidate for more targeted therapy for AdvSM by reducing its activity. In the preliminary study reported here, researchers assessed the effectiveness of anti-CD117 in reducing proliferation of CD117+ malignant mast cells. CD117+ mast-cell cultures with KIT mutations were co-incubated with anti-CD117 CAR T-cells in vitro at 1:1 and 1:4 effector-to-target ratios and observed for 28 days. After 24 hours, anti-CD117 CAR T-cells had eradicated malignant mast cells in both 1:1 and 1:4 conditions. Over the 28-day period, the number of anti-CD117 CAR T-cells increased and malignant mast-cell proliferation remained low.
Although the findings are preliminary, these in vitro results demonstrate potential utility of anti-CD117 CAR T-cells for targeted therapy in AdvSM. However, hematopoietic stem and progenitor cells also express CD117. Albeit at low levels, the efficiency of CAR T-cells may also destroy some healthy cells, and hematopoietic stem- and progenitor-cell transplant may be necessary in some patients. More research is needed to assess possible side effects of anti-CD117 CAR T-cell therapy in the AdvSM setting.
Source Kaiser A, Myburgh R, Volta L, et al. CD117 as an immunotherapeutic target in advanced forms of mastocytosis. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 2538.
