Abstract 2982: TriTCE CPI, next generation trispecific T cell engagers with integrated checkpoint inhibition (CPI) for the treatment of solid tumors
Bibliographic record
Abstract
Abstract CD3-bispecific T cell engager (TCE) therapies have exhibited clinical utility against hematological malignancies, but successes in solid tumor indications have been limited. Compared to heme malignancies, treatment of solid tumors is hindered by immunosuppressed microenvironments that can be refractory to traditional CD3-bispecific TCEs. Immunosuppression in the tumor microenvironment limits treatment responses in part due to the expression of inhibitory immune checkpoints, such as PD-1 on exhausted T cells and PD-L1 on tumor cells. To improve T cell responses and anti-tumor activity in immunosuppressed solid tumors, we generated trispecific TCE antibodies (Abs) that target a tumor associated antigen (TAA), CD3 and PD-L1 (via a PD1 moiety) to stimulate tumor-directed T cell killing and checkpoint blockade at the tumor site. In this engineering approach we harnessed the flexibility of our AzymetricTM technology to screen multiple antibody formats, geometries, paratopes, and PD-1 domain affinities in parallel. We screened the TriTCE CPI antibodies, targeting different TAAs, for tumor-directed T cell cytotoxicity and CPI activity on TAA+PD-L1+ and TAA-PD-L1+ tumor cells. We identified multiple TriTCE CPI Abs that induced potent TAA-dependent T cell killing of TAA+PD-L1+, but not TAA-PD-L1+, tumor cells. Evaluation of CPI using a PD-1/PD-L1 checkpoint reporter gene assay identified antibody formats that stimulated simultaneous TAA dependent T cell engagement and enhanced checkpoint inhibition superior to bispecific Ab plus anti-PD-L1 Ab combination treatments. Additionally, in a human PBMC-engrafted xenograft model, TriTCE CPI Abs showed increased anti-tumor activity compared to a bispecific Ab control +/- anti-PD-L1 Ab treatment. Furthermore, the benefits of increased anti-tumor activity and CPI was observed across multiple TriTCE CPI Abs targeting different TAAs. We generated multiple TriTCE CPI Abs that combine tumor-dependent T cell cytotoxicity with checkpoint blockade, which may translate to improved T cell responses in immunosuppressed solid tumors. The evaluation of multiple Ab formats, geometries and paratope affinities allowed for optimization of TAA-dependent cytotoxicity and CPI to identify Abs with enhanced anti-tumor activity and superior site-specific CPI, key factors that may contribute to a wide therapeutic index and improved clinical outcomes. Citation Format: Maya C. Poffenberger, Meghan M. Verstraete, Anna Von Rossum, Patricia Zwierzchowski, Matteo Zago, Veronica Luu, Sifa Arrafi, Siran Cao, Harsh Pratap, Chayne L. Piscitelli, Nina E. Weisser, Thomas Spreter von Kreudenstein. TriTCE CPI, next generation trispecific T cell engagers with integrated checkpoint inhibition (CPI) for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2982.
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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 | 0.001 |
| 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".