We conducted a Phase I, first-in-human open label study to evaluate the safety and tolerability of TRX103 cell infusion in patients with hematological malignancies undergoing hematopoietic cell transplantation (HCT). Patients received either reduced intensity or myeloablative conditioning regimens, followed by HLA-mismatched related (haploidentical) or unrelated peripheral blood stem cell (PBSC) grafts. Post-transplant Cyclophosphamide (PTCy), Mycophenolate and Sirolimus were administered for graft versus host disease (GvHD) prophylaxis. IL-10 producing type 1 regulatory T (Tr1) cells are a subset of regulatory T cells (Tregs) with anti-inflammatory and immunomodulatory properties. Donor derived Tr1 cells have proven to be safe and effective in patients receiving ab T- and B-cell depleted haploidentical HSCT (Bertaina A. et al., Transplantation and Cellular Therapy, 30.S13.2024). However, the many challenges related to the use of autologous Treg cells have limited their broader clinical use. We have developed a novel off-the-shelf third party engineered T cell product called TRX103, which mimics the regulatory functions and cytokine secretion profile of naturally occurring Tr1 cells. TRX103 is generated by transducing CD4+ T cells from healthy donors with a bi-directional lentiviral vector that encodes the human lL-10 gene and a non-signaling truncated form of the human of Nerve Growth Factor Receptor (ΔNGFR). In addition to the safety and tolerability primary endpoints, secondary and exploratory endpoints of this Phase I trial include GvHD prevention, overall survival, GvHD relapse free survival (GRFS) and TRX103 pharmacokinetics (PK) and pharmacodynamics (PD). Twelve subjects have been enrolled in 4 escalating dose cohorts to determine the maximum tolerated dose, and the “optimal biologic dose” of TRX103 for further evaluation in later-phase studies. Nine subjects dosed with TRX103 in Cohort 1 (DL1, n=3) Cohort 2 (DL2, n=3) and Cohort 3 (DL3, n=3) have a follow up of more than 150 days. Safety and tolerability have been observed in all 9 patients. No SAE related to TRX103 infusion and no DLT at day 28 post TRX103 infusion were observed. All 9 subjects have engrafted, the median time of neutrophil engraftment was day 17 (range 14-31) with median chimerism of 100% donor by day 32 (range 28-34) post-HCT. Patient characteristics and clinical outcome will be presented after completion of dose escalation. A dose dependent PK of TRX103 has been observed in peripheral blood with a non-linear exposure and a persistence for > 14 days in Cohort 3 (Figure 1). Preliminary PD studies show associated immunomodulatory activity, including downregulation of inflammatory biomarkers and upregulation of donor derived Tr1 and FOXP3+ Tregs. In conclusion, TRX103 is a novel off-the shelf Treg cell product which shows safety and promising immunoregulatory properties in HLA-mismatched HCT.
Malki et al. (Sun,) studied this question.