Study Design: Human Leukocyte Antigen Class I Molecule A∗02-Chimeric Antigen Receptor Regulatory T Cells in Renal Transplantation

Abstract

Introduction: Cell therapy with regulatory T cells (Tregs) in solid organ transplantation is a promising approach for the prevention of graft rejection and induction of immunologic tolerance. Previous clinical studies have demonstrated the safety of Tregs in renal transplant recipients. Antigen-specific Tregs, such as chimeric antigen receptor (CAR)-Tregs, are expected to be more efficacious than polyclonal Tregs in homing to the target antigen. We have developed an autologous cell therapy (TX200-TR101) where a human leukocyte antigen (HLA) class I molecule A^∗02 (HLA-A^∗02)-CAR is introduced into autologous naive Tregs from a patient with HLA-A^∗02-negative end-stage renal disease (ESRD) awaiting an HLA-A^∗02-positive donor kidney.

Methods: This article describes the design of the STEADFAST study, a first-in-human, phase I/IIa, multicenter, open-label, single-ascending dose, dose-ranging study to assess TX200-TR101 in living-donor renal transplant recipients. Up to 15 transplant recipients will receive TX200-TR101 and will be followed up for a total of 84 weeks post-transplant, alongside a control cohort of up to 6 transplant recipients. All transplant recipients will receive a standard of care immunosuppressive regimen, with the intent of intensified tapering of the regimen in the TX200-TR101 cohort.

Results: The primary end point is the incidence and severity of treatment-emergent adverse events (AEs) within 28 days post-TX200-TR101 infusion. Other end points include additional safety parameters, clinical and renal outcome parameters, and the evaluation of biomarkers.

Conclusion: The STEADFAST study represents the next frontier in adoptive cell therapies. TX200-TR101 holds great potential to prevent immune-mediated graft rejection and induce immunologic tolerance after HLA-A^∗02-mismatched renal transplantation.

Keywords: CAR-Tregs; HLA-A∗02 mismatch; acute and chronic kidney rejection; end-stage renal disease; immunotherapy; living-donor kidney transplantation.

Graphical abstract

Figure 1

Autologous Tregs for generation of antigen-specific CAR-Tregs. Naive Tregs (CD4⁺/CD45RA⁺/CD25⁺/CD127^low/neg) will be isolated from HLA-A^∗02–negative renal transplant recipients designated to receive mismatched HLA-A^∗02–positive organs (1). The isolated Tregs will be transduced with a lentiviral vector encoding the HLA-A^∗02-CAR (2) and expanded ex vivo before cryopreservation (3). After renal transplantation, transplant recipients will receive an intravenous infusion of the autologous HLA-A^∗02-CAR-Tregs (4). CAR, chimeric antigen receptor; CD, cluster of differentiation; HLA-A^∗02, human leukocyte antigen class I molecule A^∗02; Tregs, regulatory T cells.

Figure 2

Proposed mechanism of action of TX200-TR101. HLA-A^∗02-CAR-Tregs are expected to migrate into the HLA-A^∗02-positive allograft tissue (1), where they will interact with their target antigen HLA-A^∗02 (2), leading to their activation and proliferation (3, 4). On the basis of the known mechanism of action of Tregs, HLA-A^∗02-CAR-Tregs are then expected to exert a variety of immunomodulatory functions to dampen effector and cytotoxic T cell activation (5, 7) responsible for transplant rejection. Through the production of immunomodulatory cytokines, HLA-A^∗02-CAR-Tregs are expected to modulate the activation of Teff (5) and antigen-presenting cells. Moreover, the interaction of activated HLA-A^∗02-CAR-Tregs with antigen-presenting cells should lead to the creation of an unfavorable microenvironment for the Teff, leading to their apoptosis (6). HLA-A^∗02-CAR-Tregs might also have a cytolytic activity and induce the apoptosis of Teff (7). Moreover, the HLA-A^∗02-CAR-Tregs may suppress B-cell activation and differentiation into antibody-producing cells, reducing the risk of antibody-dependent cellular cytotoxicity directed against the transplanted tissue (not depicted). CAR, chimeric antigen receptor; DC, dendritic cell; HLA-A^∗02, human leukocyte antigen class I molecule A^∗02; Teff, effector T cell; Tregs, regulatory T cells.

Figure 3

STEADFAST study scheme. SMC, Safety Monitoring Committee.