Characterization of a 3S PRAME VLD-Specific T Cell Receptor and Its Use in Investigational Medicinal Products for TCR-T Therapy of Patients with Myeloid Malignancies
by
, ,
Maja Bürdek
1,*
,
Petra U. Prinz
1,
Kathrin Mutze
1,
Stefanie Tippmer
1,
Christiane Geiger
1,
Giulia Longinotti
1 and
Dolores J. Schendel
1,2,* 1
Medigene Immunotherapies GmbH, 82152 Planegg-Martinsried, Germany
2
Medigene AG, 82152 Planegg-Martinsried, Germany
*
Authors to whom correspondence should be addressed.
Cancers 2025, 17(2), 242; https://doi.org/10.3390/cancers17020242
Submission received: 12 November 2024
/
Revised: 23 December 2024
/
Accepted: 24 December 2024
/
Published: 13 January 2025
(This article belongs to the Special Issue New Insights of Hematology in Cancer)
Simple Summary
TCR-T therapies have the potential to capture the power of adoptive cell therapy, as has been successfully developed for CAR-T therapies for several B cell malignancies and multiple myeloma. CAR-T therapies for myeloid malignancies are hindered by lack of safe target antigens and healthy cell toxicity. Therefore, TCR-T therapies recognizing other targets are explored for these blood cancers. The antigen PReferentially expressed Antigen in MElanoma, PRAME, was shown to be a T cell target for acute myeloid leukemia after stem cell transplantation, without overt toxicity. Therefore, PRAME-specific TCR-T therapies may serve well for treatment of AML and myelodysplastic syndrome. PRAME-specific TCR-T therapy may also be suited for relapsed multiple myeloma after CAR-T therapy, arising from outgrowth of malignant cells due to loss of CAR-T antigens. On this basis, MDG1011, a PRAME-specific TCR-T therapy, was developed to fill an unmet medical need for new treatment options for these myeloid malignancies.
Abstract
Background/Objectives: MDG1011 is an autologous TCR-T therapy developed as a treatment option for patients with myeloid malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM). It is specific for the target antigen PReferentially expressed Antigen in MElanoma (PRAME). The recombinant TCR used in MDG1011 recognizes PRAME100–108 VLD-peptide presented by HLA-A*02:01-encoded surface molecules. Methods: Two preclinical batches of MDG1011, produced from enriched CD8+ T cells of healthy donors, underwent rigorous evaluation of on-target and off-target recognition of tumor cells and test cells representing healthy tissues. MDG1011 investigational medicinal products (IMPs) were produced for 13 patients. VLD-TCR surface expression was assessed using dual-marker flow cytometry using TCR V-beta-specific antibody and VLD/HLA-A2-specific multimer. Functionality was assessed by interferon-gamma (IFN-γ) secretion and cell-mediated cytotoxicity of target cells. Results: Preclinical MDG1011 batches displayed strong VLD-TCR expression, cytokine secretion, and cytotoxicity after antigen-specific activation, while showing no signals of on-target/off-tumor or off-target recognition. All IMPs had good VLD-TCR expression as well as functionality after activation by multiple target cells. Conclusions: Preclinical studies demonstrated that MDG1011 displayed key 3S attributes of high specificity, sensitivity, and safety required for regulatory approval of a first-in-human (FIH) clinical study of patients with myeloid malignancies (CD-TCR-001: ClinicalTrials.gov Identifier: NCT03503968). MDG1011 IMP manufacturing was successful at 92%, even including heavily pretreated elderly patients with very advanced disease. The IMPs applied in nine patients all displayed antigen-specific functionality. Elsewhere, clinical study results for MDG1011 showed no dose-limiting toxicity and signs of biological and/or clinical activity in several patients.
