Seminar "From chemo to immunotherapy: CAR-T cells"
Antonio Pérez-Martínez, Head of Paediatric Haemato-Oncology and Stem Cell Transplantation at University Hospital La Paz, Madrid. Director of Paediatric Department at Universidad Antónoma de Madrid Spain
Salón de Grados, Edificio Politécnico, Wednesday January 15, 2020, 11:00
Leukaemia relapse is the most significant cause of mortality and hematopoietic stem cell transplantation failure. Any salvage chemotherapy had not shown any impact in overall survival from decades. In the early 1990´s an Israeli group led by Dr. Eshhar reported how a chimeric T cells expressing an antibody, the T-body approach, could kill leukaemia cells combining the antibody recognition and T cell effector function. It is based on T cells expressing chimeric receptors composed of antibody-derived variable fraction (Fv) or single chain variable fraction (scFv) as their extracellular recognition elements joined to lymphocyte triggering molecules. Most important, this chimeric receptor can redirect the specificity of T cells in an MHC unrestricted manner. T cells expressing chimeric receptors made of antitumor antibodies are able to discriminate between a tumour and normal cell with negligible bystander cytotoxicity. Structural features of chimeric antigen receptors. In a first generation CAR, the targeting moiety is coupled via a hinge and transmembrane domain to an intracellular T cell signalling domain, typically the CD3z chain of the TCR complex. Second and third generation CARs contain an additional one or two costimulatory endodomains, respectively. While CAR-T cell therapy redirected against CD19+ cells has shown impressive clinical benefits in B cell malignancies, it is sometimes associated with toxicities that can be life threatening. Several death cases have been reported to date.
To overcome this limitation, the recognition domain can become from NK cell receptors instead of monoclonal antibodies, the T-NK cell approach. NKG2D receptor is expressed in NK and in some T cell subsets. The NKG2D CAR is constituted by the extracellular domain of NKG2D receptor linked to the CD8a TM domain coupled with 41BB co-stimulatory molecule and CD3ζ signalling domain. The group has lead clinical trials focused in non B cell malignancies and solid tumours (high grade refractory sarcoma and central nervous system tumours) as Gaby, CAR4SAR and CINK trials.