CAR T cell therapies have achieved substantial improvements in the prognoses of patients fighting advanced hematological malignancies, demonstrating robust efficacy in inducing durable remissions. While the focus has predominantly been on acute adverse events, more research is needed on the long-term consequences of these therapies. The data that have become available thus far reveal a complex landscape of resulting changes in the patient’s immune system.
Immediate adverse events resulting from CAR-T therapies may encompass problems like cytokine-release syndrome (CRS) and neurotoxicity. While research has predominantly focused on these immediate impacts, there is a critical gap in our understanding of the extended consequences, particularly in patients achieving prolonged remission post-infusion.
The prevalent long-term adverse effects include B cell depletion, hypogammaglobulinemia, cytopenias, and infections. Notably, CD19-targeted CAR T cell therapy has been linked to persistent B cell depletion and prolonged immunoglobulin depletion, affecting a considerable percentage of patients even several years after infusion.
Cytopenias, commonly observed as acute toxicity, can persist for more than three months post-infusion. The risk is exacerbated by the presence of factors such as higher-grade CRS, multiple prior lines of therapy, and allogeneic hematopoietic stem cell transplant (HSCT) within a year before CAR T cell infusion.
Despite the alterations in the immune system, the occurrence of severe infections more than a month after CAR T cell therapy remains relatively low. However, the limited data necessitates ongoing research for a comprehensive understanding of the long-term implications.
Concerns regarding potential malignant transformations of transduced cells leading to hematological malignancies, such as myelodysplastic syndrome (MDS), have been explored through follow-up studies. The incidence of secondary malignancies after CAR infusion aligns with anticipated rates in patients with substantial chemotherapy exposure.
Ongoing CAR-T research efforts are mainly focused on closing-off antigen escape mechanisms, optimization of CAR constructs, enabling early administration in the course of malignancy, medication optimization, and advancements in cell manufacturing protocols. Dual antigen targeting, fully human CARs, and modifying T cell composition are also attractive investigational approaches showing promise in preclinical and clinical studies. However, the limited data on long-term negative effects of CAR therapies beckon to researchers in the scientific and medical communities. These therapies promise powerful benefits which they have already begun to deliver, and surely, efforts towards their improvement will only grow.
References
- Cappell, K. M., & Kochenderfer, J. N. (2023). Long-term outcomes following CAR T cell therapy: What we know so far. Nature Reviews Clinical Oncology, 1-13.
- Tan, Y., Shan, L., Zhao, L., Deng, B., Ling, Z., Zhang, Y., … & Pan, J. (2023). Long-term follow-up of donor-derived CD7 CAR T-cell therapy in patients with T-cell acute lymphoblastic leukemia. Journal of Hematology & Oncology, 16(1), 34.