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 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 | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.002 | 0.003 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.003 |
| Insufficient payload (model declined to judge) | 0.010 | 0.002 |
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; both teacher heads agree on what is shown here.
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".