Abstract 3972: Carpet bombing with CARs: Influence of dose, timing, lymphodepletion and costimulatory domain on efficacy of mRNA engineered anti-CD19 Chimeric Antigen Receptor T cells in preclinical xenograft models.
Bibliographic record
Abstract
Abstract T cells engineered to express chimeric antigen receptors (CARs), consisting of an anti-tumor targeting domain fused to Signal 1 and 2 activation domains, are a promising approach to cell therapy. We compared T cells engineered to stably express CARs using integrating viral vectors with T cells transiently expressing CARs via direct transduction with non-integrating mRNA. In early clinical testing, this CAR design using lentiviral transduction has been tested in patients with advanced CLL and relapsed ALL. Dramatic clinical responses have been observed in these refractory patients, speaking to the power of this approach. Transient expression has several advantages: i) short-term expression may allow initial clinical testing while limiting toxicity, and ii) RNA is easier to manufacture and modify, expediting manufacturing and scaling to GMP of changing CAR designs, allowing rapid iterative testing of and improvements to CAR design. To evaluate the in vivo efficacy of mRNA CAR+T cells compared to permanently modified (lentiviral transduction) T cells, we used xenograft models of human ALL (Nalm-6 and a primary patient leukemia, both CD19+) and high-level human T cell engraftment. NSG mice were injected with ALL at a dose producing 100% BM engraftment by 5d with 100% mortality by 25d (Nalm-6) or 36d (Primary). T cells were expanded ex vivo using CD3/CD28 beads and underwent lentiviral gene transfer or mRNA electroporation. Short-term efficacy of a single dose of mRNA vs. lentiviral CAR+ T cells was similar, and unlike permanently modified CAR T cells the costimulatory domain (CD28, 41BB or both) in mRNA engineered cells had no effect on efficacy in this model. Interval lymphodepletion with cyclophosphamide (CTX, 60mg/kg1) significantly improved efficacy with subsequent infusions of RNA CAR T cells. Neither CTX nor untargeted repeat CAR T cells infusions alone had an effect on leukemia burden or survival. While lentiviral CAR+ T cells persisted and were able to demonstrate a memory response on leukemia rechallenge, median overall survival was not different between repeat mRNA CARs (80d) and a single dose of lentiviral transduced CARs (77d). Importantly, both models produced long term (>120 days) survivors, suggesting that repeat infusion of RNA CAR T cells with interval lymphodepletion may approximate the efficacy of permanently modified T cells in this liquid tumor model. In our clinical experience with permanently modified cells, disease clearance happens over 14-21 days, which correlates with the window of efficacy of mRNA CARs. This suggests that though they do not persist, mRNA CARs may have significant potential for clinical efficacy. These pre-clinical results demonstrate an important advance in T cell engineering, and are leading directly to clinical trials testing mRNA CAR CTLs. Citation Format: David M. Barrett, Yangbing Zhao, Xiaojun Liu, Shuguang Jiang, Gregor S D Reid, Alix E. Seif, Carl H. June, Stephan A. Grupp. Carpet bombing with CARs: Influence of dose, timing, lymphodepletion and costimulatory domain on efficacy of mRNA engineered anti-CD19 Chimeric Antigen Receptor T cells in preclinical xenograft models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3972. doi:10.1158/1538-7445.AM2013-3972
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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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".