In Vivo Control of Acute Lymphoblastic Leukemia by Immunostimulatory CpG Oligonucleotides.
Bibliographic record
Abstract
Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. While current therapy is effective for the majority of children, relapsed ALL remains the fifth most common pediatric malignancy and responds very poorly to treatment. In addition, about 50% of ALL cases occur in adults, and while remission is achieved in many patients the majority of these will succumb to relapsed disease. In most cases relapse is treated with more intensive chemotherapy or hematopoietic cell transplantation, therapies that are associated with significant toxicity. In both patient populations, therefore, there is an urgent need for novel approaches to inhibit disease progression. Immunostimulatory DNA oligonucleotides containing CpG motifs (CpG ODN) have been shown to induce strong anti-tumor immune activity in a variety of model systems and are currently being evaluated in clinical trials. We have previously reported that CpG ODN stimulation of ALL cells alters their antigen presentation ability and enhances Th1 responses by allogeneic T cells. In this study, using NOD-SCID mice bearing xenografts of primary human ALL or human ALL cell lines, we demonstrate that CpG ODN stimulate significant immune activity against ALL cells in vivo. A single intravenous injection of 300micrograms Class B CpG ODN induced a significant reduction in percentage of human ALL cells in peripheral blood (P<0.0001), spleen (P=0.0036) and liver (P=0.0004), but not bone marrow (P=0.254), compared to PBS treatment of mice. The reduced leukemia burden in the spleens of CpG ODN treated mice correlated with a significantly higher percentage of Annexin-V positive ALL cells (P=0.008 for PBS vs CpG; P=0.016 for CpG vs control ODN), indicating the induction of leukemia cell death in these mice. In addition, repeated administration of CpG ODN mediated continued disease control, and significantly improved survival of mice with established primary sample or cell line derived human ALL (P=0.002). The death of leukemia cells in vivo was independent of the ability of ALL cells to respond directly to CpG ODN, and correlated with the production of significant amounts of interferon-alpha, interferon-gamma and IL-12 in treated mice. Cell depletion studies implicate natural killer cells in the CpG ODN induced killing of human ALL. Preliminary results obtained using the Emu-ret transgenic mouse model of B cell leukemia indicate that CpG ODN treatment also induces killing of syngeneic leukemia cells, and work is ongoing to identify the immune mechanisms mediating this activity. Based on these results, we hypothesize that CpG ODN will have considerable potential as a novel agent for the prevention of ALL progression.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 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".