TCL1A Is Associated with Blinatumomab Response and Immune Activation in Pediatric B-ALL
Notice bibliographique
Résumé
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.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».