Antigen-Specific TCR-T Cells for Acute Myeloid Leukemia: State of the Art and Challenges

Abstract

The cytogenetic abnormalities and molecular mutations involved in acute myeloid leukemia (AML) lead to unique treatment challenges. Although adoptive T-cell therapies (ACT) such as chimeric antigen receptor (CAR) T-cell therapy have shown promising results in the treatment of leukemias, especially B-cell malignancies, the optimal target surface antigen has yet to be discovered for AML. Alternatively, T-cell receptor (TCR)-redirected T cells can target intracellular antigens presented by HLA molecules, allowing the exploration of a broader territory of new therapeutic targets. Immunotherapy using adoptive transfer of WT1 antigen-specific TCR-T cells, for example, has had positive clinical successes in patients with AML. Nevertheless, AML can escape from immune system elimination by producing immunosuppressive factors or releasing several cytokines. This review presents recent advances of antigen-specific TCR-T cells in treating AML and discusses their challenges and future directions in clinical applications.

The Black Hole: CAR T Cell Therapy in AML

“…The major drawbacks are that TAAs might be expressed by non-malignant cells causing on-target, off-tumor toxicities, dose-related toxicity, limited persistence, and the chance of immune escape [103,104]. The dose optimization of TCR-T cells, combining the treatment with exogenous cytokines (e.g., IL-21, IL-7 and IL-15), or adding genetically engineered signaling during cell expansion and demethylating agents such as decitabine might overcome the disadvantages of TCR-T cell application [105]. One other limitation of TCR transfer is the mispairing of endogenous and exogenous TCR components that impair the function; this limitation might be prevented by swapping the constant regions of mouse and human TCRs or codon-optimized cysteine-modified TCRs in which TCR-α and -β are linked by a T2A sequence [106][107][108].…”

The Black Hole: CAR T cell Therapy in AML

“…The major drawbacks are that TAAs might be expressed by non-malignant cells causing on-target, off-tumor toxicities, dose-related toxicity, limited persistence, and chance of immune escape [98,99]. Dose optimization of TCR-T cells, combining the treatment with exogenous cytokines (e.g., IL-21, IL-7 and IL-15), or adding genetically engineered signaling during cell expansion and demethylating agents such as decitabine might overcome the disadvantages of TCR-T cell application [100]. One other limitation of TCR transfer is the mispairing of endogenous and exogenous TCR components that impair the function; this limitation might be prevented by swapping the constant regions of mouse and human TCRs or codon-optimized cysteine modified TCRs in which TCR-α and β are linked by a T2A sequence [101][102][103].…”

Harnessing the T Cell to Treat Multiple Myeloma: Dawn of a New Therapeutic Paradigm

“…Production of TCR-engineered T cells is a similar process to CAR T production, expensive, and can take approximately 4-6 weeks to produce (102,104). TCR-engineered T cells have shown early promise in leukemia and are being evaluated in a few MM clinical trials in a small number of patients (102,(105)(106)(107). One study, in which TCRs are engineered to target a shared sequence between antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and L-antigen family member 1 (LAGE-1), has reported an objective response rate of 80% at day 42 and median progression free survival of 13.5 months in 25 relapsed/refractory myeloma patients with at least one adverse cytogenetic abnormality (107).…”