Selected Articles from This Issue

Abstract

Expression of TIM-3, an immune checkpoint molecule, has been identified as a resistance mechanism to anti-PD1/PD-L1 therapy. Harding and colleagues performed a clinical trial assessing LY3321367, a first-in-class, humanized monoclonal antibody to TIM-3, with or without an anti-PD-L1 antibody (LY3300054) in patients with advanced cancer. Both LY3321367 monotherap. and combination therapy were well tolerated. In patients with lung cancer previously responding to checkpoint inhibition, modest antitumor activity was observed, with an ORR and DCR of 7% and 50%, respectively. Further study is necessary to understand the ultimate clinical utility of LY3321367.In the Phase III COG ANBL0032 trial, dinutuximab, an anti-GD2 monoclonal antibody, combined with isotretinoin, GM-CSF, and IL-2 improved survival for children with high-risk neuroblastoma, and dinutuximab was subsequently approved by the FDA. Yu and colleagues conducted an extended follow-up of patients in this trial to assess the long-term benefits of this treatment combination. Patients were followed for a median of 9.97 years. Over this extended period, 5-year overall and event-free survival remained significantly improved in children receiving the immunotherapy combination compared to isotretinoin alone. Moving forward, biomarker studies are needed to better identify children who would benefit from immunotherapy in neuroblastoma.CD47 is overexpressed by many cancer cells and activates a “don't eat me” signal upon interaction with macrophages; therefore, CD47 is considered a potential target for immunotherapy. Ansell and colleageus conducted a Phase I trial assessing TTI-621, a CD47 inhibitor, in patients with relapsed/refractory lymphoma. TTI-621 was considered safe. The ORR for TTI-621 monotherap. was 29% in patients with diffuse large B-cell lymphoma and 25% for T-cell non-Hodgkin lymphoma. When combined with rituximab, the ORR of TTI-621 was 21% in diffuse large B-cell lymphoma. This preliminary efficacy of TTI-621 indicates that further study of this agent to inhibit CD47 in cancer, either as monotherapy or in combination with other therapeutics, is warranted.Follicular Lymphoma (FL) is the second most common non-Hodgkin's lymphoma in the United States. However, the development of targeted therapies in FL is a continuing effort. Hu and colleagues identified novel somatic mutations in BTK in FL that inactivate or destabilize BTK, indicating that BTK is not necessary for FL cells in a subset of cases and that BTK inhibition is not an appropriate therapeutic strategy in these patients. B cell receptor-induced phosphorylation of AKT was increased in the setting of mutant BTK, suggesting that inhibition of this pathway may be an effective strategy in FL. These findings provide critical clues for the development of therapeutics in FL, and further study of AKT inhibition in this context is warranted.