TCL1A Is Associated with Blinatumomab Response and Immune Activation in Pediatric B-ALL
Bibliographic record
Abstract
Background: The safety and efficacy of the bispecific T-cell engaging antibody blinatumomab (blina) was compared to intensive chemotherapy for the treatment of relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) at first relapse treated on the phase 3 international Children's Oncology Group trial AALL1331. Patients treated with blina had improved survival and lower toxicity (Brown JAMA 2021, Hogan JCO 2023). Blina is now FDA-approved for pediatric B-ALL. However, blina was not universally effective, and disease-free survival on the high-risk blina arm was only 54% at two years. A deeper understanding of the mechanism of action of blina may allow us to further improve outcomes. We hypothesize that blina response and resistance are driven by endogenous T-cell function in addition to cellular and secreted factors that influence T-cell activity. Methods: Bone marrow (BM) and peripheral blood (PB) samples were collected at pre-defined timepoints and separated into cell and plasma components for cryopreservation. We classified patients as responders (R) and non-responders (NR) based on clinical outcome (second relapse). The Olink platform was used to quantify 3072 secreted proteins from the plasma samples of each patient. Protein quantities were compared between response groups by differential expression analysis. Bulk mononuclear cell mRNA expression was measured in a subset of patients by Nanostring, and multiparameter flow cytometry was employed to identify cellular subpopulations. Single cell RNA sequencing (scRNA-seq) was performed on a cohort of cases to further characterize cell subpopulations and their gene expression signatures. Results: Comprehensive secreted protein analysis on 19 patients revealed elevated levels of T-cell leukemia/lymphoma protein 1A (TCL1A) in R (n=11) vs NR (n=8) in pre-infusion BM plasma (5.5 fold increase (5.5x); p=5.6E-5). TCL1A was also increased in PB plasma of R compared to NR during blina infusion, most pronounced at hour 48 (4.5x;p=1.5E-3). Pro-inflammatory cytokines were elevated in PB of R vs NR, including CXCL9 (1.7x;p=9.8E-3), IL-2 (2.6x;p=1.8E-2), and IL-2RA (1.9x,p=8.9E-3) while the immune checkpoint associated protein CTLA4 was found to be elevated in NR vs R (2.2x,p=2.1E-2) at hour 48 of blina infusion. Analysis of mRNA confirmed upregulation of inflammatory cytokines in the plasma of R compared to NR at hour 48 including CXCL9 (19x;p=6.6E-2). scRNA-seq of pre-blina bone marrow samples from 4 R and 3 NR identified a relative abundance of hematopoietic stem and progenitor cells (HSPC) in the bone marrow of responders (12% vs 3%). In comparing proportions of T cell and myeloid-derived suppressor cells (MDSC), we identified a preponderance of MDSC in NR (T:MDSC ratio 1.1 vs 1.6). Multiparameter flow cytometry from 25 R and 9 NR identified an increased abundance of naïve CD8+ T cells in R (21% vs 14% of CD3+ cells), whereas increased expression of inhibitory receptors CTLA-4, LAG-3, and TIM-3 on CD8+ T-cells was observed in NR (~1% vs ~5%). Conclusions: In comparing patients with relapsed B-ALL treated with blinatumomab and chemotherapy on the Phase III clinical trial AALL1331, we made the novel observation that the protein TCL1A is significantly higher in responders compared to non-responders, both before and during blina infusion. This is distinct from proinflammatory cytokine elevation which is only seen after blina initiation. We are investigating TCL1A as a candidate pre-treatment predictor of blina response in a validation cohort. Interestingly, TCL1A is known to be expressed in early stages of lymphocyte development. Taken together with identification of increased naïve cells and fewer MDSCs, this may suggest that responders have a more activating immune phenotype. As blina is being integrated into frontline treatment, it is paramount that we understand the factors that influence response and resistance. Ultimately, these data will help guide risk allocation and treatment interventions to improve responses to blina with the overall goal of reducing toxicities and improving survival for patients with B-ALL.
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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 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".