PF446 EVALUATING EX VIVO EXPANSION OF FUNCTIONALLY COMPETENT MULTI-SPECIFIC T LYMPHOCYTES TO MINOR HISTOCOMPATIBILITY ANTIGEN FOR THE TREATMENT OF HEMATOLOGICAL MALIGNANCIES
Bibliographic record
Abstract
Background: Allogeneic hematopoietic stem cell transplantation represents the sole curative treatment for high risk and relapsing leukemia. The presence of donor T cells in the graft mediates the powerful graft-versus-leukemia (GvL) effect. Recognition of minor histocompatibility antigen (MiHA) by T cells forms the basis of this GvL effect. MiHAs are small major histocompatibility antigen-restricted peptides encoded by germline polymorphism. Their preferential tissue restriction makes them an excellent target for adoptive T cell therapy for hematological malignancies. However, this form of anti-cancer activity is highly toxic due to the induction of detrimental graft-versus-host-disease mediated by donor T cells that recognize MiHAs expressed on non-hematopoietic cells. Thus, there is a scope for improving this form of adoptive T cell therapy by pre-activating and expanding donor-derived-T lymphocytes against specific MiHAs that are predominantly expressed on hematopoietic cells and may lead to improved cancer immunotherapy for hematologic cancers. Aims: The aim of this study was to evaluate the ex vivo expansion protocol of functionally competent MiHA specific CD8+ T cells. As an alternative to clinical studies where monocyte-derived dendritic cells (Mo-DC) are pulsed with single MiHA peptide, we propose an approach where Mo-DC pulsed with several MiHA peptides are used to activate and expand MiHA specific CD8+ T cells. We hypothesized that priming CD8+ T cells with multiple MiHAs may result in a multi-specificity product consisting of an oligoclonal T cell population reactive to multiple MiHAs and/or a dominant T cell response to one of the MiHAs. Further, we aim to understand potentially differential MiHA immunogenicity by quantifying MiHA presentation by dendritic cells using labeled-MiHAs. Methods: Mature Mo-DC were pulsed with single or multiple MiHA peptides, irradiated and co-cultured with autologous peripheral blood mononuclear cells for 21 days. Expansion of MiHA specific T cells was evaluated using dextramer staining. The functionality of antigen-specific T cells was assessed by interferon-γ (IFN-γ) and tumor necrosis factor-α production, CD107a degranulation, and IFN-γ ELISpot. In parallel, labeled-MiHA presentation by Mo-DC was quantified using flow cytometry. Results: In this study, we concluded on the feasibility of using Mo-DC pulsed with multiple peptides to expand MiHA specific T cells. Importantly, in several experiments, we also observed CD8+ T cells reactive to more than one MiHA demonstrating multiple antigen-specific responses within the same culture. However, variability was observed in the magnitude of this response. This variability might rely, in part, on the MiHA presentation by Mo-DC; Mo-DCs pulsed with four or more peptides resulted in higher cell mortality and had lower expression of the costimulatory molecule CD80, thus suggesting that pulsing Mo-DCs with four or more MiHAs may impact the antigen-presenting capacity of these cells. Interestingly, we demonstrated, using labeled-MiHAs that the peptides were presented by Mo-DC at variable levels. Summary/Conclusion: Our results demonstrate that we could generate a multi-specific T cell response using Mo-DC pulsed with multiple MiHA peptides. Ongoing experiments will shed light on the variability seen in the antigen presentation by Mo-DC derived from different donors and peptides used. Understanding the fundamental biology of MiHA specific T cells for cancer immunotherapy will allow us to develop a personalized approach for the treatment of high-risk leukemia patients.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.006 | 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 teacher head, 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".