Researchers have successfully demonstrated the use of engineered human plasma B cells to treat leukemia in a humanized animal model for the first time. This breakthrough paves the way for utilizing engineered plasma cells (ePCs) as therapies for cancer, autoimmune disorders, and protein deficiency disorders. The study’s outcomes were published on July 2 in the journal Molecular Therapy.
“This proof-of-concept study represents the potential of engineered plasma B cells to revolutionize therapy, aiming towards a single-shot treatment option,” explained senior researcher Richard James (@ScienceRicker) from the Seattle Children’s Research Institute. “With engineered plasma B cells capable of long-term survival of over 10 years, they could serve as a sustainable source for various biologic drugs.”
Current immunotherapies like bispecific antibodies that activate cytotoxic T cells have improved survival rates for B cell acute lymphoblastic leukemia (B-ALL) patients. However, medications like blinatumomab, a bispecific antibody approved by the FDA in 2014 for relapsed/refractory B-ALL treatment, require continuous high-dose intravenous infusions for sustained effectiveness. This treatment regimen comes with challenges for patients due to inconvenience and infection risks associated with its administration.
James expressed, “Non-immunoglobulin bispecific therapies face stability issues, necessitating frequent 20-day steady-state infusions, impacting patient compliance. Innovations in drug delivery methods can enhance treatment adherence and effectiveness.”
The study focused on demonstrating the feasibility and efficacy of engineered B cell therapies by developing a gene-editing strategy to create ePCs that produce significant amounts of bispecific antibodies targeting B-ALL and acute myeloid leukemia. The research findings indicated that ePCs producing bispecifics effectively enabled T cell-mediated killing of human primary cells and leukemic cell lines.
One challenge faced during the research was the binding of the bispecific antibody used for killing tumor cells to the engineered plasma B cells since they share the same target protein. To overcome this obstacle, the researchers deleted the target protein CD19 during cell engineering without hindering the production of engineered plasma B cells.
The study also found that plasma cells secreting anti-CD19 bispecific antibodies exhibited anti-tumor activity in mouse models bearing acute lymphoblastic leukemia patient-derived xenografts, alongside autologous T cells. Notably, the serum concentration of anti-CD19 bispecifics one month post-cell delivery and tumor elimination was equivalent to that achieved through continuous infusion of blinatumomab in patients.
Based on these results, the researchers suggested that ePC strategies could extend the functional half-life of bispecific antibodies in acute leukemia patients and other diseases where treatment duration is a limiting factor or where localized plasma cell delivery could enhance therapeutic efficacy.
The study indicated that sustained levels of bispecific antibodies and other biologics could be achieved through a single administration of ePCs, displaying higher levels compared to other bispecific-secreting cell products. The authors recommended further exploration of ePCs as a durable drug delivery system for acute leukemias and potentially other cancers.
“Our engineered plasma B cells, post a single injection, continuously produce bispecific antibodies through the treatment period, effectively eliminating tumors to a similar extent as standard clinical drugs. The key insight is that engineered plasma B cells can provide sustained drug production within living organisms,” highlighted James.
The study did caution that ePC bispecifics need thorough evaluation for potential toxicities if employed clinically. On-target, off-tumor toxicity towards normal bystander B cells is common in patients receiving B cell-targeted treatments. Also, there might be challenges in using a patient’s own engineered B cells for therapy in B cell malignancies due to cancerous cell risks, requiring further investigation into using allogeneic products.
Further studies in humanized mice and non-human primates are recommended to fully comprehend the activity, longevity, and tissue localization of ePCs. Future plans involve testing the effectiveness of engineered plasma B cells producing bispecific antibodies in other B cell-related diseases, initially in animal models. Additionally, there are ongoing efforts to develop engineered plasma B cells for producing therapeutic drugs in protein deficiency diseases like hemophilia, as well as exploring other applications to modify immune cells for immune system modulation.
