Chimeric antigen receptor T-cell (CAR-T) therapy, one of the more remarkable advances in cancer treatment, is a novel cell-based gene therapy that modifies a patient’s T lymphocytes. The process involves extracting the patient’s T cells, chemically reengineering them to produce CARs on their surface that will bind to a specific protein expressed on malignant cells, and then infusing them back into the patient, with the T cells now programmed to recognize and destroy malignant cells that contain the targeted antigen on their surface. However, though some patients have experienced extraordinary results from this therapy, current therapeutic agents are often unable to differentiate between malignant B-lineage cells and normal B cells. This in turn can lead to long-term immune system dysfunction, subsequent hypogammaglobulinemia, and a need to consider antibody replacement therapy.

In a paper published in Blood Reviews, researchers described CAR-T therapies that target B-lineage lymphocytes and their associated side effects, as well as considerations for the approach to management of hypogammaglobulinemia in patients receiving CAR-T therapy.

“Data regarding the efficacy and cost-effectiveness of prophylactic immunoglobulin replacement in CD19-targeted CAR-T therapy recipients are lacking,” said lead author Joshua Hill, MD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, in an interview with Hematology Advisor. “This issue is even more relevant in light of national shortages of these products.”

The development and clinical administration of CAR-T cells is a complex process requiring multiple steps, and each one is associated with some risk to the patients. Despite these challenges, though, the number of CAR-T agents available on the market is likely to increase in the near future. Currently, 2 products that target CD19+ B-lineage neoplasms (tisagenlecleucel and axicabtagene ciloleucel) have received regulatory approval from the US Food and Drug Administration (FDA). Both products also have on-target, off-tumor activity against normal B cells that leads to depletion of CD19+ B cells, which may result in hypogammaglobulinemia. Because CAR-T cells may proliferate and survive in vivo, B-cell aplasia and gaps in humoral immunity can persist over the long term, sometimes for years after treatment ends. However, polyclonal B cell recovery has been observed in patients who were able to achieve durable complete remissions.

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Risk for infection is also relatively high in this patient population, especially in the first 28 days following treatment. Though this risk is due to any number of factors, antibody deficiency is likely an important contributor. For example, in a study looking at 1-year follow-up after CAR-T infusion in adults with lymphoma treated with axicabtagene ciloleucel, 41 (38%) of 108 patients experienced any type of infection, with 23% of infections being grade 3 or higher. Grade 3 or higher infections caused by an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%.