Abstract 3763: UCART22: allogenic adoptive immunotherapy of leukemia by targeting CD22 with CAR T-cells

Abstract

Adoptive immunotherapy using autologous T-cells endowed with chimeric antigen receptors (CARs) has given rise to long-term durable remissions and remarkable objective response rates in patients with refractory leukemia, raising hopes that a wider application of CAR technology may lead to a new paradigm in cancer treatment. However, a limitation of the current autologous approach is that CAR T-cells must be manufactured on a "per patient basis". To overcome this limitation, we have developed a standardized platform for manufacturing T-cells from third-party healthy donors to generate allogeneic "off-the-shelf" engineered CAR+ T-cell-based frozen products. Our allogenic platform utilizes the Transcription Activator-Like Effector Nuclease (TALEN) gene editing technology to inactivate the TCRα constant (TRAC) gene, significantly reducing the potential for T-cells bearing alloreactive TCR’s to mediate Graft-versus-Host Disease (GvHD). We have previously demonstrated the precise and efficient disruption of the the TRAC gene by gene editing, yielding up to 85% of TCRαβ-negative cells. This allows the production of TCRαβ-deficient T-cells that no longer mediate alloreactivity in a xeno-GvHD mouse model. In the clinic, the proof of concept of the applicability of our allogeneic platform was achieved with early compassionate use for patients treated with UCART19, an allogeneic engineered CAR T-cell product directed against CD19. UCART19 clinical trials are currently ongoing. Here, we have developed T-cells targeting CD22 which is expressed on tumor cells from the majority of patients with B-cells leukemia. In a first step, we have screened multiple antigen recognition domains in the context of different CAR architectures to identify effective CAR candidates displaying activity against cells expressing variable levels of the CD22 antigen. As a safety feature, T-cells are engineered to co-express a depletion gene, rendering them sensitive to the monoclonal antibody rituximab. Several constructs of depletion genes have been evaluated in the context of the CD22 CAR. In addition, experiments in an orthotopic ALL mouse model using UCART22 cells demonstrated important anti-tumor activity in vivo. The ability to carry out large scale manufacturing of allogeneic, non-alloreactive CD22 specific T-cells from a single healthy donor can offer the possibility of an off-the-shelf treatment that would be immediately available for administration to a large number of leukemic patients. UCART22 could also offer an alternative to patients who may relapse with CD19-negative tumors after CD19 CAR T-cell treatment. Citation Format: Agnès Gouble, Cécile Schiffer-Mannioui, Severine Thomas, Anne-Sophie Gautron, Laurent Poirot, Julianne Smith. UCART22: allogenic adoptive immunotherapy of leukemia by targeting CD22 with CAR T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3763. doi:10.1158/1538-7445.AM2017-3763

CAR T cell therapy: A new era for cancer treatment (Review)

“…Furthermore, multiple clinical investigations have been implemented by Cellectis following UCART19. Cellectis is currently leading with two successful FDA Investigational New Drug (IND)-approved allogeneic CAR T approaches (119): UCART123 for patients with blastic plasmacytoid dendritic cell neoplasm and AML (120) and UCART22 IND for patients with B-ALL (121). Two other ongoing clinical trials are UCARTCS1 for suppressing CS1-expressing hematologic malignancies (122) and UCART38 for CD38-expressing hematologic malignancies.…”