Abstract 1424: Preclinical development of TAC01-CD19, a CD19 specific T-cell Antigen Coupler (TAC) therapy for the treatment of CD19-positive B cell malignancies
Bibliographic record
Abstract
Abstract Background: The T cell antigen coupler (TAC) is a chimeric receptor co-opting the natural TCR receptor signaling complex to target tumor antigens in an MHC-independent manner (Helsen et. al., Nat. Comm. 2018). TAC engineered T cells mediate biological effects that are distinct from conventional chimeric antigen receptors (CARs) and may offer safety advantages due to greater target selectivity and no detectable off-target toxicity. Here, we present preclinical data of TAC01-CD19, an autologous CD19-specific TAC-T cell product candidate for clinical testing in patients with CD19-positive B cell malignancies Materials and Methods: T cells from healthy donors and lymphoma patients were engineered with a CD19-specific TAC using lentivirus. Anti-tumor activity, T cell expansion and persistence were measured in the CD19-positive NALM-6 and Jeko-1 mouse tumor xenograft models. We used flow cytometry to determine surface expression of CD19-TAC, cytokine production and in vitro T cell proliferation. Cytotoxicity was evaluated in vitro using luciferase-based killing assay. Results: Cytotoxicity was measured against multiple CD19 positive tumors cells (NALM6/Jeko-1/Raji) showing strong cytotoxicity in all cases. Treatment of established NALM-6 (acute lymphoblastic leukemia) and Jeko-1 xenografts (mantle cell lymphoma) with CD19 TAC-T cells resulted in clearance of tumors within a few weeks of T cell infusion. In vivo efficacy was tested across multiple donors, establishing consistent and reproducible anti-tumor efficacy. Monitoring of TAC T cells post-infusion revealed robust expansion that peaked in the peripheral blood 1-2 weeks post-infusion. Mice that cleared tumors following TAC-T cell treatment were resistant to subsequent challenge with fresh tumor cells demonstrating persistence of TAC-T cells. In contrast, treatment with control TAC-T had no impact on tumor growth. A histological examination of normal mouse tissues failed to detect TAC-T cell induced toxicity. Conclusion: The pre-clinical evaluation of TAC01-CD19 has demonstrated specific anti-tumor responses without signs of toxicity. Results were reproducible across multiple donors demonstrating the robustness of the CD19 TAC system. TAC01-CD19 is expected to enter clinical testing in patients with CD19-positive hematological malignancies in Q2 2019. Citation Format: Christopher W. Helsen, Danielle Hayes, Joanne Hammill, Criag Aarts, Andreas Bader, Donna Rill, Jonathan Bramson. Preclinical development of TAC01-CD19, a CD19 specific T-cell Antigen Coupler (TAC) therapy for the treatment of CD19-positive B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1424.
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".