Real-world CAR T therapy in older DLBCL patients, monoclonal antibody blocking APC for hemophilia therapy, and targeting the epichaperome in AML
In this week’s episode, we discuss real-world evidence for CAR T cell therapy in older patients with diffuse large B-cell lymphoma, inhibiting endogenous anticoagulant pathways in congenital factor deficiencies, and finally targeting the HSP90 epichaperome in acute myeloid leukemia.
Real-world experience of CAR T-cell therapy in older patients with relapsed/refractory diffuse large B-cell lymphoma
Almost one-half of patients diagnosed with diffuse large B-cell lymphoma are at least 65 years old, and historically their prognosis has been poor after failure of first-line therapy. CD19-directed autologous chimeric antigen receptor (CAR) T-cell therapy has changed outcomes for younger patients. In this month’s CME article, Chihara and colleagues analyzed real-world data for CAR T-cell therapy in older patients from the United States. They report encouraging long-term efficacy but low uptake for patients aged 65 to 75 years and very low utilization for those >75 years of age.
Safety and efficacy of an anti–human APC antibody for prophylaxis of congenital factor deficiencies in preclinical models
Activated protein C (APC) inhibits both thrombin generation and inflammation. Jiang et al describe the development and characterization of an engineered humanized monoclonal antibody (SR604) designed to target the APC protease domain, which is critical for anticoagulant activity but dispensable for anti-inflammatory signaling, thereby reducing the risk of promoting thrombosis. In vivo, SR604 limits bleeding in hemophilic mice to a similar extent to recombinant factor VIII, suggesting that it warrants clinical investigation for restoration of hemostasis in patients with hemophilia and other rare bleeding disorders.
Epichaperome inhibition targets TP53-mutant AML and AML stem/progenitor cells
Epichaperome complexes, comprising heat shock protein 90 (HSP90) and associated proteins, act to maintain malignant phenotypes and are enriched in acute myeloid leukemia (AML) stem cells. After identifying HSP90 inhibitors as top hits in a high-throughput drug screen, Carter et al found that targeting the epichaperome with the HSP90 inhibitor PU-H71 boosts the effectiveness of venetoclax in treating AML, inhibiting the outgrowth of venetoclax-resistant TP53-mutant AML in vivo in murine models. These data support clinical investigation of PU-H71 with venetoclax in patients with TP53-mutant AML, where prognosis has remained dismal despite the introduction of targeted therapies.
Antibody-mediated antigen loss switches augmented immunity to antibody-mediated immunosuppression
Anti-RhD immunoprophylaxis works because of antibody-mediated immunosuppression (AMIS), but the mechanisms governing AMIS are poorly understood. Using an established murine model of red blood cell (RBC) alloimmunization, Jajosky et al demonstrate that passive immunization with RBC antibodies can remove target antigens from RBCs without affecting RBC clearance or CD4+ T-cell proliferation, thereby converting an augmented RBC alloimmune response to AMIS. These data have implications for how immunoprophylaxis is approached for non-RhD hemolytic disease of the fetus and newborn.
Platelet count threshold for hemorrhage in patients with immune thrombocytopenia treated with antiplatelet agents
A significant proportion of older patients with immune thrombocytopenia (ITP) also have clinical indications for treatment of cardiovascular disease with antiplatelet agents. Ollier and colleagues sought to determine the frequency of bleeding in patients with ITP on aspirin therapy, finding that the pattern of bleeding, segregated by platelet count, is similar to that observed in other adults with ITP not on aspirin. They show that a platelet count of <20 × 109/L is associated with most bleeding in ITP patients on antiplatelet agents.
