Old Dogs, New Tricks: Revisiting Immune Modulatory Approaches for Myelodysplastic Syndromes

Immune modulatory approaches show high promise in the treatment of MDS. Given the heterogeneity of the disease, both in terms of risk stratification as well as highly variable genetic traits and the type of immune dysregulation present, it will be of utmost importance to correctly identify which patients will most likely benefit from which approach. For a small group of carefully selected low-risk MDS patients, IST with ATG shows high response rates with durable remissions and an acceptable toxicity profile. However, more recent efforts are focused on targeting the inflammatory phenotype (in particular the expanding MDSC compartment) in low-risk MDS induced through modulation of the innate immune system by targeting TLR signaling or MDSC directly through inhibition of CD33. By contrast, higher-risk MDS and AML is characterized by an immunosuppressive microenvironment and increased immune escape mechanisms allowing unchecked proliferation of immature progenitor cells. Thus, T cell directed therapies such as checkpoint modulation in combination with HMA or bispecific T cell engager antibody therapies to reverse immunosuppression and activate T cell responses are novel treatment options currently being investigated for this group of patients. The ideal target for bispecific T cell engager antibodies in myeloid disease has yet to be determined, but CD33 as well as CD123 seem to hold promise in patients with AML as well as MDS with high-risk features such as elevated blast counts. As most of the clinical trials are still in their early stages, experience with these approaches for MDS is currently limited. Thus, critical issues such as optimal combination, dosing and scheduling of agents as well as identification of patient populations most likely to benefit from immune modulatory therapies remain to be answered by the currently ongoing clinical trials.