TRX103: A Latest Hope for Mismatched Hematopoietic Cell Transplants?
A novel off-the-shelf allogeneic CD4 T-cell therapy, TRX103, is showing promising results in improving immune reconstitution for patients undergoing HLA-mismatched hematopoietic cell transplant (HCT). Presented at the 2026 Tandem Meeting, the first-in-human study, led by Monzr M. Al Malki, MD, of City of Hope, demonstrates a potential shift away from traditional immunosuppression and towards fostering a more durable tolerizing environment.
Understanding the Challenge of Mismatched HCT
Hematopoietic cell transplantation offers a potentially curative treatment for many hematologic malignancies. However, finding a perfectly matched donor can be challenging. Mismatched HCTs, while offering a viable option, often leave patients vulnerable to prolonged immune deficiency, increasing the risk of severe infections and relapse. Current standards of care, like post-transplant cyclophosphamide, aim to mitigate these risks, but often involve transient immunosuppression.
How TRX103 Works: Harnessing the Power of Tr1 Cells
TRX103 utilizes CD4 T cells from healthy donors, engineered to express IL-10. This modification grants the cells the properties of Type 1 regulatory (Tr1) cells. These cells play a crucial role in immune regulation, helping to establish tolerance and prevent the immune system from attacking the transplanted cells. The cells also express dNGFR, which aids in tracking their behavior within the patient’s body.
Key Findings from the Phase 1 Study
The Phase 1 dose-escalation study revealed several encouraging findings. Researchers observed accelerated immune reconstitution of donor-derived CD4-positive T cells, with levels reaching higher counts than previously published data from City of Hope using a post-transplant cyclophosphamide platform. Increases were seen in FOXP3-positive T regulatory cells and circulating tolerogenic dendritic cells (DC10), mirroring levels found in healthy donors by day 42 post-transplant.
Importantly, the study completed the dose-escalation phase without any dose-limiting toxicities, paving the way for an expansion phase to confirm safety and evaluate clinical endpoints. These endpoints include graft-versus-host-disease (GVHD) incidence and severity, transplant mortality, and infection rates.
‘Infectious Tolerance’: A Novel Mechanism
The observed increases in regulatory cells suggest an “infectious tolerance” model, where the transplanted cells induce the patient’s own immune system to generate protective regulatory T cells. This differs significantly from the transient suppression achieved with pharmacological agents like cyclophosphamide. Al Malki explained that the combination of donor-derived DC10, FOXP3-positive, and natural Tr1 T-regulatory cells are important for creating a tolerizing environment and improving transplant outcomes.
Beyond Mismatched Transplants: Future Potential
While the initial study focused on HLA-mismatched HCT recipients, researchers believe TRX103’s potential extends beyond this group. The platform’s flexibility may allow for its application in matched and cord blood transplantation, contingent on positive efficacy signals in larger studies.
Looking Ahead: Expansion Phase and Clinical Endpoints
The next phase of investigation will focus on expanding the study at the most biologically active dose level to further confirm safety. The primary endpoints will be GVHD incidence and severity, transplant mortality, and infection rates. Researchers are hopeful that a larger, potentially multi-center, study will demonstrate the efficacy of TRX103 and establish it as a standard of care addition to mismatched HCT.
FAQ
Q: What is HLA mismatching in HCT?
A: HLA (human leukocyte antigen) matching is crucial for successful HCT. Mismatching occurs when the donor and recipient’s HLA types are not identical, potentially leading to immune complications.
Q: What are Tr1 cells and why are they important?
A: Tr1 cells are a type of regulatory T cell that helps suppress the immune response and promote tolerance, preventing the immune system from attacking healthy tissues or transplanted cells.
Q: What is graft-versus-host disease (GVHD)?
A: GVHD is a complication of HCT where the donor’s immune cells attack the recipient’s tissues.
Q: What is the significance of dNGFR in TRX103?
A: dNGFR is a marker used to track the engineered T cells within the patient’s body, allowing researchers to monitor their persistence and function.
Did you know? TRX103 represents the first demonstration that an engineered, allogeneic cell therapy can induce a patient’s own immune system to generate protective regulatory T cells.
Pro Tip: Understanding the role of regulatory T cells is key to appreciating the potential of therapies like TRX103 in improving transplant outcomes.
Stay informed about the latest advancements in hematopoietic cell transplantation. Explore more articles on CancerNetwork.com and follow the progress of TRX103 as it moves through clinical trials.
