Principles and applications of cellular therapy in the setting of hematopoietic cell transplant

Immune recovery after hematopoietic cell transplant (HCT) is delayed and incomplete, increasing risk of infection and malignant relapse, which can limit transplant success. The post-HCT period is characterized by elevated interleukin-7 and interleukin-15 and clonal homeostatic peripheral expansion of CD8+ T cells. However, there is limited T-cell receptor diversity and impaired adaptive immune function. In the context of HCT, cellular therapies aim to exploit the unique immune status of the lymphodepleted host and focus on three key goals: (1) to reduce infectious morbidity and mortality, (2) to enhance graft-versus-tumor effect, and (3) to limit graft-versus-host disease. Ex vivo cultured multivirus-specific cytotoxic lymphocytes (CTLs) have been successfully infused into post-HCT patients and confer immunity against cytomegalovirus, Epstein-Barr virus, and other infections. Similarly, adoptive transfer of CTLs that target minor histocompatibility and tumor-associated antigens can offer antitumor immunity. Chimeric antigen receptor (CAR)-transduced T-cell therapy has shown durable remissions even in aggressive malignancies and may replace conventional donor lymphocyte infusions. Potential issues associated with these cellular approaches are as follows: (1) risk of alloreactivity, (2) poor in vivo persistence of adoptively transferred cells, and (3) CAR-T cell toxicities, notably cytokine release syndrome. These challenges are being addressed in novel ways. For instance, tumor- and virus-specific CTLs and CAR-T cells administered after transplantation can be genetically modified to express inducible “suicide genes” which can be activated in the event of graft-versus-host disease. Other immunomodulatory strategies aim to alter the interplay between immune cell subsets, such as depletion of alpha-beta T cells and infusion of mesenchymal stem cells and T-regulatory cells.