“First-In-Human” Clinical Trial Employing Adoptive Transfer of Autologous Thymus-Derived Treg Cells (thyTreg) to Prevent Graft Rejection in Heart-Transplanted Children
Bibliographic record
Abstract
Immune allograft rejection remains the main obstacle to reach successful transplants. Transfer of regulatory T cells (Treg) has acquired growing interest in attempts to prevent rejection. However, the limited number and the differentiated phenotype of Tregs isolated from blood constitute important drawbacks for the effectiveness of this strategy. In collaboration with several teams, we have explored the use of the thymic tissue, which is routinely discarded during pediatric cardiac surgery, as an alternative source of Tregs to be used as cellular immunotherapy in heart-transplanted children. Material and Methods We developed a novel GMP-compatible protocol to obtain massive amounts of thymus-derived Tregs (thyTreg) from thymuses discarded from infants (<3 years old). Several quality tests were performed on the final thyTreg cell product. A “first-in-human” clinical trial (phase 1/2a) will be initiated in January 2018 to test the safety, feasibility and effectiveness of the adoptive transfer of autologous thyTregs in heart-transplanted children. Results/Discussion ThyTreg purified from thymuses were activated and cultured ex-vivo for 7–10 days with our protocol, and the final product showed a very high purity, with >95% of CD25+Foxp3+ cells, and a viability >90% (Fig 1). Importantly, the number of thyTreg cells obtained from one single thymus reached values of more than 13x109 (billions) cells. Considering the Treg doses employed in previous clinical trials (1–10 x106 Treg/kg), in the case of transplanted infants, this amount will be enough to prepare more than 1000 doses of thyTreg treatment. The final product of thyTreg showed great expression of CTLA-4, CD39, HLA-DR and Helios. In comparison to blood-derived Tregs, the frequency of IL-10-secreting cells was markedly higher in thyTregs (Fig 2). Besides, the final thyTreg product showed a very high suppressive capacity, decreasing the proliferation of CD4+ and CD8+ T cells by more than 80% (Fig 3). The thyTreg product will be employed as immunotherapy to prevent rejection in a clinical trial. Infants younger than 3 years old included in the waiting list for a heart transplant will be enrolled. A single dose of autologous thyTreg cells purified from the thymus discarded in the surgery will be infused back to the children at day +10 post-transplant, when doses of immunosuppressants are reduced (Fig 4). The rest of the thyTreg doses will be cryopreserved in a Biobank for potential reinfusions in the future to the patient. Conclusion Massive quantities of highly suppressive and pure Thy-Tregs obtained with our novel GMP-compatible protocol are suitable to be employed as cellular immunotherapy to prevent rejection in heart-transplanted children. At the beginning of 2018, we will initiate the first clinical trial to test the safety of the procedure, the feasibility and the effect of the thyTreg therapy in the context of solid organ transplantation.Grant from Instituto de Salud Carlos III (ISCIII) co-financed by FEDER funds (PI15/00011). Grant from Instituto de Salud Carlos III (ISCIII) co-financed by FEDER funds (ICI14/00282).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".