Abstract
Chimeric antigen receptor (CAR) T cell therapy represents a breakthrough in immunotherapy with the potential of ushering in a new era in cancer treatment. Remarkable therapeutic response and complete remission of this innovative management have been observed in patients with relapse/refractory acute lymphoblastic leukemia. With CAR-T cell therapy becoming widely used both in multicenter clinical trials and as a commercial treatment, therapeutic efficacy monitoring and management of toxicities will be indispensable for ensuring safety and improving overall survival. Biomarkers can act not only as effective indicators reflecting patients’ baseline characteristics, CAR-T cell potency, and the immune microenvironment, but can also assess side effects during treatment. In this review, we will elaborate on a series of biomarkers associated with therapeutic response as well as treatment-related toxicities, and present their current condition and latent value with respect to the clinical utility. The combination of biomarker research and CAR-T cell therapy will contribute to establishing a safer and more powerful monitoring system and prolonging the event-free survival of patients.
Highlights
Acute lymphoblastic leukemia (ALL) is a hematological malignancy that originates from clonal expansion of malignant B or T cell
The results indicated that high expression of LAG-3 combined with low secretion of tumor necrosis factor (TNF)-a were associated with early therapeutic failure, and low frequency of TNF-a+/TIM-3- CD8+ T cells in CD19 Chimeric antigen receptor (CAR)-T cell products may be a risk factor for short persistence of CAR-T cells and early relapse [46]
Hay et al studied 53 patients with Refractory or relapse (RR) B-ALL followed by CD19 CAR-T cell therapy and suggested that the absence of leukemia clone of IGH by high-throughput sequencing (HTS) 3 weeks after CAR-T cell infusion in patients with minimal residual disease (MRD)-negative complete remission (CR) is associated with improved event free survival (EFS) and overall survival (OS) [20]. These findings revealed that patients’ baseline disease status, T cell differentiation degrees, expression levels of PD-1, LAG-3 and TIM-3, immunological microenvironment combined with the CAR copy numbers and MRD monitoring were significant predictor factors associated with the clinical response to CAR-T cell therapy
Summary
Acute lymphoblastic leukemia (ALL) is a hematological malignancy that originates from clonal expansion of malignant B or T cell. Conventional treatments for patients with ALL include high-dose combined chemotherapy, targeted therapy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT). We generalize biomarkers associated with therapeutic response and toxicities correlated with CAR-T cell therapy, which may be beneficial for evaluating the expansion and persistence of CAR-T cells, identifying adverse events, and predicting prognosis in RRALL patients (Figure 1). Previous studies indicated that disease burden, high risk cytogenetic and molecular biology phenotype are major factors that may lead to poor response in RR-ALL patients after CAR-T cell therapy [8, 31]. Biomarkers for Immune Checkpoints The assessment of the expression levels of PD-1, LAG-3, TIM-3, and their receptors indicated that high levels of these inhibitory molecules were associated with T cell exhaustion and poor response to CD19 CAR-T therapy [17].
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