HPK1 Inhibition and Venetoclax Combination Suppressed AML By Enhancing Cytotoxic T-Cell Response to Leukaemia
Bibliographic record
Abstract
Background: Immune escape is one of the major causes of treatment failure in cancer therapy and modulation of immune cell function has become an emerging therapeutic strategy. Haematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T cell signaling and its inhibition promotes T cell function. Venetoclax, a BCL2 inhibitor, has become a standard of care for unfit or elderly patients with acute myeloid leukaemia (AML) and may enhance anti-leukaemic effector T-cell function. We hypothesize that HPK1 inhibitor (HPK1i) may synergize with venetoclax and improve treatment outcome in AML by co-activating cell-death pathway and T cell immunity. Methods: Human T cells were activated by anti-CD3/CD28 antibodies in vitro. Proliferation, cytokine production, T-cell subsets and exhaustion were examined by flow cytometry after 3-day treatment of HPK1i. Recipient mice engrafting with MLL-AF9 AML were treated with HPK1i singly or in combination with venetoclax. Leukaemic burden, apoptosis and T cell functions and exhaustion were examined. Results: In vitro, HPK1i treatment of activated human T-cells induced cellular proliferation and expression of TNF-α and INF-γ. It increased effector memory T-cell (CD62L-CD45RA-) and decreased naïve T-cell population (CD62L+CD45RA+). Furthermore, it reduced exhaustion markers including PD-1 and TIM3. In vivo, HPK1i and venetoclax combination significantly decreased the burden and induced apoptosis of leukaemic cells on 18th DPT (days post transplantation), and prolonged survival of non-irradiated mice that were transplanted with donor mouse MLL-AF9 AML cells. Cytotoxic T-cells were activated, associated with increase in TNF-α and INF-γ expression and increase in the effector memory T cell subset. There was a decrease in naïve T cell population and T cell exhaustion marker PD-1. Single cell transcriptomes of serial bone marrow samples from mice treated with the combination were being analyzed and will be presented in the meeting. Conclusion: HPK1i and venetoclax reduced the leukaemic burden and enhanced the anti-leukemic ability of T cells in MLL-AF9 AML mouse model. Acknowledgements This research is supported by the Centre for Oncology and Immunology under the Health@InnoHK Initiative funded by the Innovation and Technology Commission, Theme-based Research Scheme (T12-702/20-N), Hong Kong Jockey Club Charities Trust, Li Shu Fan Medical Foundation, Croucher Foundation, S.K.Yee Medical Foundation (260940161, 260940149, 260940187), Tang King Yin Research Fund, Mr. Ying Wan Leung Research Fund, Madam Madeline Tong Lai-Sheung Cancer Research Fund (A.Y.H.L), The Government of Hong Kong SAR, China.
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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) | 0.002 | 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".