Abstract B052: IKAROS mediates antigen escape following CD19- or CD22-targeted immunotherapies in r/r B-ALL
Bibliographic record
Abstract
Abstract CD19 CAR T cell (CART19) therapy has shown impressive results in relapsed or refractory B cell acute lymphoblastic leukemia (r/r B-ALL). However, 30 – 70% of initial responders will eventually relapse with CD19 loss. Early identification of patients that will respond successfully to CART19 therapy vs. those at risk for CD19neg relapse would support clinical decision making and improve patient care. To address this question, we profiled by CyTOF 25 pre-CART19 samples from patients that achieved an ongoing complete remission (CR, N. = 6), underwent CD19neg (n = 11) or CD19pos relapse (n = 4) or were refractory to CART19 (n = 4). We also analyzed paired post-CART19 samples from CD19neg relapse (n = 8), CD19pos relapse (n = 2), and refractory (n = 4) tumors. In pre-CART19 samples, we observed that low levels of transcription factor IKAROS in a subset of CD19pos pro-B like tumor cells correlate with a higher risk for CD19neg relapse. Through single cell CITE-seq of pre-CART19 samples from CR (n = 3) or CD19neg relapsed (n = 3) tumors, we confirmed that patients that underwent CD19neg relapse bear a subset of pro-B like tumor cells with lower expression of IKZF1, IKAROS gene. Although IKZF1 alterations have been associated with poor response to front-line treatment, IKAROS’ involvement in CART19 failure has not been described. To elucidate how IKAROS modulates CD19 surface expression, we performed CyTOF, RNA-seq and ATAC-seq analysis of isogenic IKAROSWT or IKAROSKD B-ALL cell lines. We found that IKAROS regulates several genes associated with mRNA splicing and that IKAROSKD B-ALL cells resemble multipotent progenitor cells, suggesting a loss in their B cell identity. Moreover, we observed that CD19 mRNA preferentially retains intron 10 in IKAROSKD cells. Interestingly, intron 10 was also more retained in CD19neg relapsed leukemia and lymphoma patients after blinatumomab or CART19 treatments. In addition, we observed that IKAROS also modulates CD22 levels. Performing co-cultured experiments, we confirmed that IKAROSlow B-ALL cells express lower CD19 and CD22 levels, thus conferring resistance against CD19-targeted (blinatumomab, 19.BBz or 19.28z CAR T cells), CD22-targeted (22.BBz CAR T cells) and dual CD19/ CD22-targeted (19-22.BBz CAR T cells) immunotherapies. This work demonstrates a novel role for IKAROS in CD19 and CD22 modulation and CD19 and/or CD22 targeted immunotherapies, identifying it as a potential prognostic target. In addition, given the role of IKAROS in lineage specification and chemotherapy resistance, IKAROS mediated splicing regulation could have broader beyond CD19- or CD22-directed immunotherapies. Citation Format: Pablo Domizi, Jolanda Sarno, Astraea Jager, Milton Merchant, Kaithlen Pacheco, Sean Yamada-Hunter, Maria Caterina Rotiroti, Yuxuan Liu, Reema Baskar, Warren Reynolds, Brian Sworder, Bita Sahaf, Sean Bendall, Charles Mullighan, Ash Alizadeh, Allison Leahy, Regina Myers, Stephan Grupp, Robbie Majzner, David Barrett, Elena Sotillo, Kara Davis. IKAROS mediates antigen escape following CD19- or CD22-targeted immunotherapies in r/r B-ALL [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B052.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".