Abstract B62: Development of novel chimeric antigen receptor T cells for immunotherapy of hepatocellular carcinoma
Bibliographic record
Abstract
Abstract Background and Aim: Several glypican 3 (hGPC3)-specific chimeric-antigen-receptor modified T cells (CARTs) are in trials for hepatocellular carcinoma (HCC), but most are constructed from one monoclonal antibody (mAb). It is unknown how targeting different hGPC3 epitopes will affect CART’s efficacy. The aim of this study is to develop novel effective CARTs by targeting different regions of hGPC3. Methods: BalB/C mice were immunized with hGPC3 protein to generate novel mAbs that targeted different regions of hGPC3. CARTs were then built from mAbs and their antitumor effect was studied. Results: Twenty-two mAbs were identified by ELISA. Fourteen of them bound HepG2 cells. Five mAbs were further characterized by immunohistochemical staining. Three of them (6G11, 8F8, and 12D7) were found to specifically stain HCC tumors but not adjacent normal tissues. The mAbs’ affinity was in the nanomolar range. 6G11 and 8F8 bound to hGPC3 N-(AA25-39) and C-(AA463-496) epitopes, respectively. 12D7 recognized a conformational epitope in the hGPC3 N-fragment (AA25-358). All CARTs built from the mAbs underwent expansion after GPC3+ cell stimulation. However, their effector function was significantly different. 8F8 CARTs possessed the strongest effector function. 6G11 CARTs experienced the greatest expansion, but with slightly weaker function. In contrast, 12D7 CARTs showed minimal effector function. Soluble hGPC3 did not activate CARTs or block CART activation by tumor cells. Adoptive transfer of 8F8 and 6G11, but not 12D7, CARTs generated complete regression of HCC xenografts in NSG mice. Conclusion: The three novel CARTs that target a membrane-distal N-epitope, a membrane-proximal C-epitope, or a conformational epitope of hGPC3 possessed different effector function and antitumor effects. CARTs targeting the hGPC3 N- or C specific epitope generated potent antitumor effects, while CARTs targeting an hGPC3-N conformational epitope showed minimal effector function. Citation Format: Xiaotao Jiang, Leidy D. Caraballo G., Huajun Zhang, Xiangyang Chi, Yibing Peng, Aiwu R. He, Yanxia Shao, Lun Cai, Yukai He. Development of novel chimeric antigen receptor T cells for immunotherapy of hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B62.
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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) | 0.001 | 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".