Contributions
Abstract: EP727
Type: E-Poster Presentation
Session title: Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research
Background
Hematopoietic cell transplantation (HCT) can potentially cure pediatric patients with acute myeloid leukemia (AML). However, a large proportion of transplanted patients eventually die due to relapse.
Aims
To improve overall survival, we propose a combined strategy based on the use of cord blood (CB) derived cells for cellular therapy and HCT.
Methods
We generated CB-CD8+ T cells expressing a recombinant T cell receptor (TCR) against Wilms tumor 1 (WT1) lacking endogenous TCR expression in order to avoid mispairing and competition. These cells were created through a highly efficient CRISPR-Cas9 multiplexing approach (up to 95% gene-editing efficiency) targeting the endogenous TCR alpha and beta chain. Next to this strategy, high lentiviral transduction efficiency resulted in high WT1126-TCR expression levels with transduction enhancer LentiBOOST.
Results
By combining these approaches, we developed a tumor antigen-specific T cell product with robust expression of a WT1126-specific TCR and very efficient elimination of endogenous TCR expression. TCR engineered T cells (TCR-T 2.0) show enhanced proliferation rate and cytokine production upon antigen recognition and express low levels of exhaustion markers (such as PD1, LAG3 and TIM3). Of note, TCR-T 2.0 show killing capacity when in coculture with AML blasts, but not in the presence of healthy cord-blood derived CD34+ hematopoietic stem cells.
Conclusion
Further drug product development could provide a potent off-the-shelf immune cell therapy approach to increase overall survival chances in pediatric relapse patients.
Keyword(s): Acute myeloid leukemia, Cellular therapy, Cord blood, WT1
Abstract: EP727
Type: E-Poster Presentation
Session title: Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research
Background
Hematopoietic cell transplantation (HCT) can potentially cure pediatric patients with acute myeloid leukemia (AML). However, a large proportion of transplanted patients eventually die due to relapse.
Aims
To improve overall survival, we propose a combined strategy based on the use of cord blood (CB) derived cells for cellular therapy and HCT.
Methods
We generated CB-CD8+ T cells expressing a recombinant T cell receptor (TCR) against Wilms tumor 1 (WT1) lacking endogenous TCR expression in order to avoid mispairing and competition. These cells were created through a highly efficient CRISPR-Cas9 multiplexing approach (up to 95% gene-editing efficiency) targeting the endogenous TCR alpha and beta chain. Next to this strategy, high lentiviral transduction efficiency resulted in high WT1126-TCR expression levels with transduction enhancer LentiBOOST.
Results
By combining these approaches, we developed a tumor antigen-specific T cell product with robust expression of a WT1126-specific TCR and very efficient elimination of endogenous TCR expression. TCR engineered T cells (TCR-T 2.0) show enhanced proliferation rate and cytokine production upon antigen recognition and express low levels of exhaustion markers (such as PD1, LAG3 and TIM3). Of note, TCR-T 2.0 show killing capacity when in coculture with AML blasts, but not in the presence of healthy cord-blood derived CD34+ hematopoietic stem cells.
Conclusion
Further drug product development could provide a potent off-the-shelf immune cell therapy approach to increase overall survival chances in pediatric relapse patients.
Keyword(s): Acute myeloid leukemia, Cellular therapy, Cord blood, WT1