Abstract PR05: T-cell receptor (TCR)-based immunotherapy in pediatric malignancy: Addressing the challenge of early metastasis and low immunogenicity
Bibliographic record
Abstract
Abstract Pediatric malignancies, in particular Ewing sarcoma (EwS), are characterized by low mutational load, low immunogenicity, and early metastasis. They recapitulate the embryonic immune tolerance setting and remain a challenge for established immunotherapies. These immunotherapies are not sufficient to target metastasis. Ideally, targeted therapies address gene products required for metastasis. We completed in vivo functional analyses for metastasis of 9/37 genes that we had shown to be overexpressed in EwS (Staege at al., Cancer Res 2004) and generated HLA class I restricted cytotoxic T cells against these gene products. All targets were involved in fetal development and 8/9 demonstrated functional relevance for metastasis. Allorepertoire-derived TCRs against 8/9 targets were cloned and sequenced; one target (DKK2) was nonimmunogenic. 7/8 TCRs were crossreactive, caused fratricide, or clonal TCR expansion failed (EZH2, STEAP1, PAPP-A, GPR64, ADRB3, LIPI, HOX-D1). In the tumor microenvironment we found an immunosuppressive (M0 and M2) transcriptomic signature and evidence for an immunosuppressive inflammation-associated activation of endogenous retroviral sequences. Among these most selectively expressed (n=9) and metastasis sustaining (n=8) targets, the BRICHOS chaperon domain containing antiangiogenetic bone protein chondromodulin-I (CHM1) was addressable by a non-crossreactive TCR. CHM1 is a direct downstream target of the oncogenic driver EWS-FLI1. We clinically assessed HLAA* 02:01/CHM1-specific TCR transgenic CD8+ T cells against EwS utilizing a TCR complementary determining region 3 (CDR3) recognition-sequence for the CHM1319 peptide with a Koff half-life of 113.2 ± 38.2 s. The CHM1319 motive was 130 times less homologous as compared to the 9mer ADRB3CHM1295, a crossreactive EwS target identified before. Four refractory HLA-A2+ EwS patients (pts) were treated with CHM1319-specific TCR-CDR3 transgenic T cells. Pt-derived cell lines (PDCL) were established in all cases. Pts received up to 107/kg TCR transgenic CD8+ T cells. All pts were treated with the same TCR-CDR3 recognition-sequence for CHM1. All PDCLs displayed persistent HLA-A2 expression. Transgenic T cells showed specific in vitro lysis of all PDCLs. Therapy was well tolerated and did not cause graft-versus-host disease (GvHD). Pts #1 #3 and #4 showed delayed progression, whereas pt #2, while having bone marrow (BM) involvement and accessible multifocal disease, showed partial metastatic regression associated with T-cell homing to involved lesions. In conclusion, CHM1319-TCR transgenic T cells may home to affected BM and may cause partial remission. CHM1-TCR transgenic T cells address a persistently expressed target required for metastasis, suggesting lack of immunoediting selection pressure. They proliferate in vivo without causing GvHD. This abstract is also being presented as Poster A07. Citation Format: Stefan Burdach, Guenther Richter, David Schirmer, Andreas Kirschner, Sebastian Schober, Valentina Evdokimova, Hendrik Gassmann, Elvira D’Ippolito, Maxim Barenboim, Dirk Busch, Poul Sorensen, Uwe Thiel. T-cell receptor (TCR)-based immunotherapy in pediatric malignancy: Addressing the challenge of early metastasis and low immunogenicity [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr PR05.
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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) | 0.002 | 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".