Next Generation CART MAD will be focused on the following Working Packages:

WP1 (IIS/FJD): Development of new effective and persistent CARs for MM, NHL and OSCC that do not cause loss of the target antigen.

Objective 1. Creation of bicistronic CARs against CD79b and BCMA, and comparison of their efficacy and persistence in NHL and MM vs CARs targeting CD19, CD79b or BCMA or vs a cocktail of CARs.

Objective 2. Creation of a combination therapy for NHL, MM and OSCC based on the combination of CB-NK with the best choice of CARs determined in Objective 1.

WP2 (IIS/FJD): Prevent the development of immunosenescence in CART cells during their expansion and after exposure to tumor cells.

Objective 1. Determine the impact of small molecules during CAR cell production on the emergence of a more differentiated or immunosenescent phenotype.

Objective 2. Determine which compounds secreted by senescent tumor cells enhance the immunosenescence of CARs impacting their anti-tumor activity.

WP4 (BIOC-ISCIII): Study of the clonal evolution of tumors against CAR-T.

Objective 1. To determine the phenotypic and genotypic selection of tumor clones during CAR-T cell therapy.

Objective 2. To determine clonal evolution during combined therapies with CAR-T cells.

WP5 (UAM): Preclinical and clinical validation of novel multitarget CAR-T immunotherapy strategies with NKG2D in memory lymphocytes.

Objective 1. Preclinical and clinical validation of multitarget CAR-T NKG2D in different tumor types.

Objective 2. Preclinical and clinical validation of a 4th generation CAR-T NKG2D.

Objective 3. Preclinical validation of dual CAR-T with NKG2D.

WP6 (IIBm/CSIC): CAR-T and CAR-NK of 4th generation with interleukin expression under the control of NFkB promoters induced by CAR activation in the tumor (IL-armed 4th generation CAR-T and CAR-NK cells).

Objective 1. Generation and characterization of IL12-ARMed-CAR-T cells.

Objective 2. Generation and characterization of IL15-ARMed-CAR NK cells.

WP7 (FIBHNJS): Advanced immunotherapy directed against the tumor microenvironment.

WP8 Generation of singletargeting strategies for immunotherapy of hematological and solid tumors.

Objective 1. Generation of anti-BCMA STAb-T cells for multiple myeloma immunotherapy.

Objective 2. Generation of anti-CEA STAb-T soluble PD-1 receptor secreting (sPD-1) cells for immunotherapy of solid tumors.

WP9 Generation of “dualtargeting” strategies for immunotherapy of hematological and solid tumors.

Objective 1. Generation of anti-BCMA CAR-T/anti-CD19 STAb-T cells.

Objective 2. Generation of anti-CD22 CCR (Chimeric Costimulatory Receptor)-T/anti- CD19 STAb-T cells.

WP10 Intellectual protection and clinical translation of research results.

Objective 1. Intellectual protection of the results.

Objective 2. Clinical translation of research results.