Potential TH9402-Based ECP Treatment for cGvHD Patients.
Bibliographic record
Abstract
Abstract Although the risk of graft versus host disease (GvHD) can be reduced by improved donor-recipient matching and by the depletion of T cells before transplantation, GvHD still develops in 30–70% of allogeneic hematopoietic stem cell transplantation (HSCT) patients. The chronic phase of the disease (cGvHD), for which the pathogenesis is similar to autoimmune diseases, involves profound immune dysregulation leading to both immunodeficiency and autoimmunity. Standard therapies for cGvHD such as corticosteroids and immunosuppressants are associated with high toxicity and have demonstrated limited efficacy in patients with extensive disease. Extracorporeal photopheresis (ECP) has been shown by others in the clinic as a non-aggressive and beneficial alternative treatment for cGvHD, inducing Th1/Th2 immunomodulation that restores immunological tolerance. Celmed has developed an alternative approach to eliminate immunoreactive T cells using the Theralux™ photodynamic cell therapy (PDT) system based on the use of the rhodamine-123 derivative TH9402 illuminated ex vivo with a visible light source (λ =514nm). It has been suggested that the apoptotic cells, when returned to the patient, may be able to modulate the immune system as seen with other ECP methods. We aimed to evaluate in vivo and in vitro the possibility of also using the Theralux™ system in the ECP setting. A preliminary mouse model suggested that splenic T cells pre-treated with the Theralux™ system were able to induce an improvement of overall survival (p<0.05) in mice with acute GvHD. Additionally, we developed a simplified PDT process and conducted a series of experiments with peripheral blood mononuclear cells (PBMCs) isolated from healthy volunteers. These studies have shown that the intra- and inter-donor variability in TH9402 incorporation are very low (~5% and 10%, respectively). A dose-effect study has shown a relationship of the PDT conditions with the levels of cell death, allowing significant control of the level of apoptosis induced. Phenotypic analyses have shown that this process results in an increase of AnnexinV positive cells as well as a decrease in the absolute number of CD3+ cells, CD19+/CD20+ cells and CD14+ cells and an increase in CD11c+ cells. This would suggest that apoptosis could be induced in both autoreactive T and B cells which could potentially stimulate an immune response against them. Moreover, the increase in CD11c+ cells combined with the decrease in CD14+ cells could reflect the maturation of macrophages into dendritic cells that are very potent antigen presenting cells. The mechanism by which these specific PDT conditions induce cell death is still under investigation but preliminary studies have shown that the cell death in unselected resting PBMCs may be caspase-independent. Finally, the evaluation of the effect of PDT on samples from cGvHD patients also demonstrated the capacity of this treatment strategy to induce apoptosis in these cells. Based on these data, we intend to begin a pilot clinical study evaluating two controlled PDT conditions inducing different levels of apoptosis in order to assess the safety and biological effect of the Theralux™ ECP system to treat patients with cGvHD.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".