MT-401 multiTAA-specific T cells (zedenoleucel) for the treatment of AML
Introduction
Measurable residual disease (MRD) testing has become more prevalent in AML. MRD positivity is associated with increased relapse risk and shorter survival in AML, and currently, there are no approved therapies for these patients. Zedenoleucel (also known as MT-401) is a non-genetically modified allogeneic multi-tumor associated antigen (mTAA)-specific T cell therapy with selectivity to multiple tumor antigens, specifically preferentially expressed antigen in melanoma (PRAME), Wilms’ tumor 1 (WT1), New York esophageal 1 (NY-ESO-1) and Survivin.
Methods
The Safety Lead-in portion of a multicenter Phase 2 study (ARTEMIS) evaluating the safety, tolerability, and efficacy of zedenoleucel in patients with AML post-HSCT, has been completed. The Safety Lead-in includes patients with active disease (frank relapse or MRD+) in two cohorts with a primary objective to evaluate the safety and tolerability of zedenoleucel manufactured using reagents obtained from two different vendors. Patients may receive up to three consecutive infusions of zedenoleucel as a monotherapy (50 × 106 cells every 2 weeks) at weeks 0, 2 and 4 during the Intervention Period, with a maximum dose of 200 × 106, and enter Follow-up at week 8. Primary endpoints include various safety measurements and incidence of dose-limiting toxicities (DLTs). Efficacy evaluations occur using ELN recommendations for standard AML response criteria.
Results
Six patients were enrolled and treated in the Safety Lead-in portion of ARTEMIS (four patients with frank relapse, one patient with morphologic leukemia-free state [MLFS] and 1 MRD+ patient). No DLTs were observed. Regarding efficacy, one patient had MLFS at baseline but developed increased blast count at week 8 disease assessment. The other four patients had frank relapse with blast counts at baseline ranging from 5-40% and their disease worsened. However, the MRD+ patient with t(8/21)(q22;q22.1)[RUNX1-RUNX1T1] genetic abnormality showed a decrease in MRD by PCR from a starting baseline of 0.8093% to resolution via peripheral blood at approximately 32 weeks post-treatment with zedenoleucel. T cell composition of the product consisted of 71% CD4+ and 24% CD8+ T cells. T cell receptor (TCR) analysis identified 3,117 antigen-specific clones (881 Survivin, 783 NY-ESO-1, 750 PRAME, 709 WT1). Immune monitoring of this patient using biomarker analysis showed T cell specificity not only for the targeted antigens but also for non-targeted antigens over time, thereby demonstrating epitope spreading. Interestingly, the tumor antigen composition by RNASeq identified an antigen expression profile that changes over time and inversely correlates with the presence of antigen-specific T cells, demonstrating the interplay of tumor cell immunogenicity and antigen-specific T cells.
Conclusion
Specifically, the ARTEMIS results showed that administration of zedenoleucel converted an MRD+ patient to MRD- and suggests that AML patients could potentially benefit from administration of zedenoleucel.