Abstract
Background/objectives: MDG1011 is a Preferentially Expressed Antigen in Melanoma (PRAME)-specific autologous T cell receptor (TCR) T cell therapy for HLA-A*02:01-positive patients. Data from the first-in-human (FIH) clinical trial, CD-TCR-001, are reported here regarding treatment feasibility, safety, tolerability, and clinical activity of MDG1011 in patients with relapsed/refractory (r/r) acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM). Methods: Nine of thirteen enrolled patients received MDG1011 at dose levels ranging from 0.1 to 5 × 106 TCR-T cells per kg body weight. In addition to clinical assessments, immune monitoring of cytokines associated with cytokine release syndrome (CRS), presence and persistence of MDG1011, and changes in levels of PRAME mRNA were used to assess safety and potential biological activity at defined time points. Results: The treatment was well tolerated. No dose-limiting toxicities (DLTs) were observed, and the most common serious adverse events were associated with lymphodepleting chemotherapy and/or disease progression. Various parameters, such as measurable clinical responses in two patients, the occurrence of CRS in two additional patients, and reductions in PRAME mRNA levels in bone marrow (BM) or peripheral blood (PB) in seven patients, served as signs of the clinical and biological activity of MDG1011 TCR-T therapy. Conclusions: Patients enrolled in the phase 1 part of CD-TCR-001 displayed signs of potential clinical and biological activity of MDG1011 among the small number of patients studied. Advanced disease stage and rapid progression in the r/r AML patients limited clinical impact. The acceptable safety profile of MDG1011 merits further investigation of this TCR-T therapy, potentially in patients at an earlier stage of their disease and with lower tumor burden.

Simple Summary
Adoptive cell therapy (ACT) using chimeric antigen receptor-engineered T cells (CAR-T) has been highly successful in the long-term clinical control of diverse B cell malignancies and multiple myeloma (MM). Expression of suitable target antigens by cancer cells that direct specific CAR-T recognition underlies this success. ACT for other cancers requires the identification of specific and safe target antigens. T cell receptor-engineered T cells (TCR-T) offer a potential solution based on recognition of peptide epitopes derived from overexpressed or mutated intracellular proteins presented by HLA molecules at the tumor cell surface. Preferentially Expressed Antigen in Melanoma (PRAME) may be well suited for TCR-T therapy of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) through its broad overexpression in leukemic blasts of myeloid origin. MDG1011 TCR-T cell therapy, with specificity for an HLA-A2-presented, PRAME-derived peptide, was developed for first-in-human (FIH) phase 1 safety assessment in HLA-A2+ patients with PRAME+ AML, MDS, and multiple myeloma (MM).