Advancing Immune Reconstitution in Mismatched HCT with TRX103

At the 2026 Tandem Meeting, Monzr M. Al Malki, MD, shared compelling findings from a first-in-human study of TRX103, a novel off-the-shelf allogeneic CD4 T-cell therapy. Designed to improve immune reconstitution in HLA-mismatched hematopoietic cell transplant (HCT) recipients, TRX103 utilizes cells from healthy donors engineered to express IL-10, granting them the properties of Type 1 regulatory (Tr1) cells.

In an interview with CancerNetwork®, Al Malki, director of the Unrelated Donor Bone Marrow Transplant and Haploidentical Transplant Programs and associate professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, detailed how this approach induces "infectious tolerance," significantly accelerating the recovery of donor-derived CD4-positive and FOXP3-positive T-regulatory cells. Unlike the transient suppression often associated with standard pharmacological agents, TRX103 appeared to foster a durable tolerizing environment, with regulatory cell levels reaching those of healthy donors by day 42 post-transplant.

Moreover, the dose-escalation phase concluded with no dose-limiting toxicities, allowing the team to move into an expansion phase. This upcoming research will focus on primary end points like graft-versus-host-disease (GVHD) incidence, mortality, and infection rates. By mitigating potential adverse effects while enhancing immune health, TRX103 may represent a promising proof-of-concept that could eventually broaden donor options to include both matched and cord blood transplants, ultimately setting a new benchmark for standard of care in mismatched HCT.

CancerNetwork: Could you elaborate on which specific biomarkers show the most significant correlation with the escalating dose levels of TRX103?

Al Malki: TRX103 is an off-the-shelf allogenic CD4 T cells… that are collected from 3 healthy donors and infected with lentivirus system to transduce cells with IL-10 and dNGFR. The IL-10 will give the cell the Tr1 cell property, while dNGFR will help with tracking. The goal here is to provide a T-regulatory–based approach to help improve the immune reconstitution after transplant.

The data suggests that TRX103 may induce the patient’s own immune system to generate de novo FOXP3-positive and Tr1 regulatory cells. How does this infectious tolerance mechanism differ from the transient suppression seen with pharmacological agents like post-transplant cyclophosphamide?

Based on the data that we presented in at the [2026 Tandem Meetings,] we saw significant accelerated immune reconstitution of donor derived CD4-positive T cells. Those will reach higher levels compared with historical control that we already published in City of Hope data. This was also the same for FOXP3-positive T regulatory cells.

We also saw increasing numbers of circulating, tolerogenic dendritic cells. We call them DC 10, which usually express CD14 and CD16, in parallel to the natural Tr1 cells increasing. The prompt increase reached the level that we see in even healthy donor in the 42 days post-transplant. A combination of donor-derived DC 10, FOXP3-positive and natural Tr1 T-regulatory cells are usually important to tolerizing environment and improve the outcome of transplant.

How did the recovery of absolute lymphocyte count and specific T-cell subsets in TRX103-treated patients compare with historical cohorts of HLA-mismatched HCT recipients?

[With] absolute lymphocytes, CDK4 recovery was faster than what we published before for patients undergoing transplant using a post-transplant cyclophosphamide platform, without the cellular therapy; [it was a] faster and healthier recovery of those subsets of cells. It was the main secondary objective for this study.

Considering the study specifically targeted HLA mismatched HCT, do you see TRX103 eventually enabling the use of even further mismatched owners?

Definitely. The way that we designed this study is that we start with a mismatched donor, related or unrelated, as they could have the highest risk of GVHD and immune dysregulation. This therapy is not restrictive, and could be extended later to match donor, even cord blood transplants.

As you move toward subsequent phases of investigation, what will the primary end point(s) be, and what benchmarks do you anticipate aiming for to consider TRX103, a standard of care addition to mismatched HCT?

We have now completed the dose escalation phase with no dose-limiting toxicity. The goal here is to expand on the most biological active dose level to confirm safety. Secondary end points in the study will include GVHD incidence and severity, mortality from transplant and immune recovery with reflection of infection-on-infection rates. Hopefully, we will have a larger study soon to determine the efficacy of this approach as the next step.

Is there anything else that you would like to highlight that we might not have discussed?

The main highlights here are that the novelty of this first-in-human study using off-the-shelf T cells from third party [donors] will be hopefully improving our understanding of tolerance [and] induction of the transplant. This study was also a proof of concept with a nice illustration of biology with elegant correlatives. If this will be tolerated… we are excited, and we are hopeful to complete the expansion phase soon, so we are able to evaluate the efficacy of this approach in a larger, hopefully multi-center, study.

Reference

Al Malki MM, Juckett M, Perales MA, et al. Off-the-shelf engineered Tr1 cells (TRX103) in patients with hematological malignancies undergoing HLA-mismatched hematopoietic cell transplantation (HCT) show safety and dose dependent effects. Presented at: 2026 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; February 4-7, 2026; Salt Lake City, UT. Abstract 8