Trametinib for Refractory Chylous Effusions and Systemic Complications in Children with Noonan Syndrome.

OBJECTIVE: To evaluate the effect of the RAS-MAPK pathway inhibitor trametinib on medically refractory chylous effusions in 3 hospitalized patients with Noonan syndrome. STUDY DESIGN: Pharmacologic MEK1/2 inhibition has been used to treat conditions associated with Noonan syndrome, given that activation of RAS-MAPK pathway variants leads to downstream MEK activation. We describe our experience with 3 patients with Noonan syndrome (owing to variants in 3 distinct genes) and refractory chylous effusions treated successfully with MEK inhibition. A monitoring protocol was established to standardize medication dosing and monitoring of outcome measures. RESULTS: Subjects demonstrated improvement in lymphatic leak with additional findings of improved growth and normalization of cardiac and hematologic measurements. Trametinib was administered safely, with only moderate skin irritation in 1 subject. CONCLUSIONS: Improvements in a variety of quantifiable measurements highlight the potential utility of MEK1/2 inhibition in patients with Noonan syndrome and life-threatening lymphatic disease. Larger, prospective studies are needed to confirm efficacy and assess long-term safety.

CD19 CAR T cells for multiple sclerosis: Forging further into the new frontier.

The efficacy of CD19 chimeric antigen receptor (CAR) T cells in B cell malignancies has generated recent interest in their application to other B cell-related pathologies, such as autoimmune diseases. Fischbach et al.1 report on the use of CD19 CAR T cells in two patients with progressive multiple sclerosis, demonstrating feasibility and safety for the first time in this disease process.

Overcoming the challenges of primary resistance and relapse after CAR-T cell therapy.

INTRODUCTION: While CAR T-cell therapy has led to remarkable responses in relapsed B-cell hematologic malignancies, only 50% of patients ultimately have a complete, sustained response. Understanding the mechanisms of resistance and relapse after CAR T-cell therapy is crucial to future development and improving outcomes. AREAS COVERED: We review reasons for both primary resistance and relapse after CAR T-cell therapies. Reasons for primary failure include CAR T-cell manufacturing problems, suboptimal fitness of autologous T-cells themselves, and intrinsic features of the underlying cancer and tumor microenvironment. Relapse after initial response to CAR T-cell therapy may be antigen-positive, due to CAR T-cell exhaustion or limited persistence, or antigen-negative, due to antigen-modulation on the target cells. Finally, we discuss ongoing efforts to overcome resistance to CAR T-cell therapy with enhanced CAR constructs, manufacturing methods, alternate cell types, combinatorial strategies, and optimization of both pre-infusion conditioning regimens and post-infusion consolidative strategies. EXPERT OPINION: There is a continued need for novel approaches to CAR T-cell therapy for both hematologic and solid malignancies to obtain sustained remissions. Opportunities for improvement include development of new targets, optimally combining existing CAR T-cell therapies, and defining the role for adjunctive immune modulators and stem cell transplant in enhancing long-term survival.