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EBMT 2021 Annual Meeting - New developments in CAR therapy

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Plenary Session P4: New developments in the field of CAR T cell therapy

Wednesday, March 17, 16:15 - 17:30, Auditorium 1

This three-part plenary session on new developments in CAR therapy will be opened by Dr Marcela Maus of Harvard Medical School, Boston, MA, USA. Her talk will be on CAR T-cells to prevent antigen escape.

“One of the main mechanisms of relapse from CAR T-cells in all indications is antigen escape, or loss of expression of the protein target of the CAR T-cell; this has been observed in leukaemia, lymphoma, multiple myeloma, and solid tumors such as glioblastoma,” says Dr Maus. 

“I’m going to describe the different ways that multi-targeted T cells are being engineered, and then focus on our work for dual-targeted CAR T-cells in multiple myeloma, which is based on our TriPRIL (trimeric APRIL) CAR, which targets both BCMA and TACI, and also on our technology using CAR T-cells to secrete T cell engager antibody molecules, like BiTEs ® or TEAMs. We will present our work on this application in glioblastoma.”

The second presentation in this session is “Anti-CD123 CAR T-cells for plasmacytoid dendritic leukaemia (BPDCN)” and will be given by Professor Francine Garnache-Ottou, Université Bougogne Franche-Comté, France.

She will discuss that BPDCN is an aggressive haemopathy characterised by constant overexpression of the CD123 antigen on the entire blastic population, identifying CD123 as a good target for CAR therapy development.

She says: “We obtained very good results on efficacy of CAR123 against BPDCN cells in vitro and in vivo, but the evaluation of the potential cytotoxicity of CAR-T is a major issue for further clinical development. Cytotoxicity of CAR-T against healthy cells expressing low level of CD123 (CSH, monocytes, endothelial cells) is a very important issue to be taken into account.”

Her team has therefore developed and evaluated the functionality of four third-generation CD123 CAR-T (CD28/4-1BB/CD3) with different recognition domains (scFv: single chain fragment variable) in the same backbone in-vitro and in-vivo to determine if one of the scFv induce lower “on-target/off-tumour” effects while maintaining efficacy on CD123+ BPDCN cells. Prof Garnache-Ottou concludes: “These results lead us to go to the transfer phase of a CAR123 for BPDCN treatment.”

Also in this session, a talk entitled “CRISPR-Case to engineer CAR T-cells” will be presented by Edward Stadtmauer, Chief of the Hematologic Malignancies Section and Professor of Medicine at the University of Pennsylvania Abramson Cancer Center, Philadelphia , PA, USA.

He explains: “T cells engineered with chimeric antigen receptors (CARs) have revolutionised the field of cell therapy and changed the paradigm of treatment for many patients with relapsed or refractory B-cell malignancies. Despite this progress, there are limitations to CAR T-cell therapy in both the autologous and allogeneic settings, including practical, logistical, and toxicity issues.”

He will outline how gene editing with such systems as CRISPR-Cas9 offers great potential to enhance the natural ability of immune effector cells to eliminate refractory cancers and to allow ‘off the shelf’ allogeneic cells to function without inducing graft vs host disease or rapid destruction.

He concludes: “We have demonstrated feasibility and safety as well as in vivo expansion and persistence of multiplexed gene editing of lenti-viral transformed antigen directed T-cells. Ongoing studies of gene edited allogeneic T-cells have the potential for increasing the availability and efficacy of CAR T-cell approaches for our patients with advanced cancers.”