Abstract B012: Reviving exhausted T cells in pediatric B-cell acute lymphoblastic leukemia
Bibliographic record
Abstract
Abstract Despite significant treatment advances, the poor long-term prognosis for children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) persists. The application of immune cell-based therapies, such as chimeric antigen receptor-expressing T cells and bispecific T-cell engagers, has improved progression-free survival for many B-ALL patients. However, many of these patients still experience disease relapse. While tumours are widely recognized to influence T cell function, this relationship has not been extensively studied in B-ALL. A clinically silent pre-leukemic phase usually precedes childhood B-ALL. Since only a small percentage of children subsequently develop disease, the impact of pre-leukemia on T cell function remains elusive. To address this knowledge gap, we investigated the development of T cell dysfunction in B-ALL and explored ways to restore it using in situ and transplanted leukemia models Using the Emu-Ret transgenic mouse model of hyperdiploid B-ALL, we investigated the induction of exhaustion-associated marker expression (PD-1, CTLA-4 and Tim-3) on T cells. Longitudinal analysis of marker expression revealed that an upregulation of multiple immune checkpoints such as PD-1 and Tim-3, on T cells occurred only in the presence of leukemia cells, not during the extended preleukemia phase. This suggests that T cell exhaustion occurs exclusively during the established malignancy phase, highlighting the evolving nature of T cell responses as disease progresses. Next, we measured exhaustion-associated marker expression in a syngeneic model of transplanted B-ALL. While expression of PD-1 and Tim-3 on T cells correlated with disease progression, a significant increase in these markers was already detectable at low leukemia burden. This indicates that T cell exhaustion is not merely a reflection of high disease burden and highlights the differing impact exerted by preleukemic and leukemic cells on T cells. Phenotypically exhausted T cells from both mouse models showed reduced proliferation, activation, and cytokine secretion. Previously, we have demonstrated the ability of toll-like receptor (TLR) ligands to induce immune control over B-ALL cells. Thus, we investigated the impact of CpG oligodeoxynucleotides (CpG ODN), a ligand for TLR-9, to overcome T cell dysfunction. The treatment of leukemia bearing mice with CpG ODN led to a decrease in PD-1 and Tim-3 expression on T cells, which was also associated with a reduction in leukemia burden. Lastly, the administration of a checkpoint blockade antibodies, with or without TLR agonists as adjuvant therapy led to increased survival of leukemia bearing mice. Overall, this study demonstrates the functional impact of interactions between B-ALL cells and the immune system. The findings from this study may inform therapeutic approaches to overcome B-ALL immune evasion mechanisms and enhance patient outcomes. Citation Format: Tanmaya Atre, Gregor S.D Reid. Reviving exhausted T cells in pediatric B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B012.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".