CD22/CD19 dual redirection Dual targeting of CD22 and CD19 with BiTE-secreting and CAR-expressing bispecific T-cells for adoptive Cellular ImmunoTherapy in advanced B-cell Acute Lymphoblastic Leukemia

Anti-CD19 immunotherapies based on Bi-specific T-cell Engagers (BiTE) or chimeric antigen receptor (CAR)-expressing T-cells have revolutionized the treatment of refractory/relapse (R/R) B-cell acute lymphoblastic leukemia (B-ALL).

However, despite initial impressive complete response (CR) rates, many patients relapse few months after anti-CD19 immunotherapy; in many cases with CD19 antigen loss. Such relapses are devastating, and patients are left with virtually no further treatment options.

Dual targeting of the pan-B antigens CD19 and CD22 has been proposed as a therapeutic strategy to distribute the antigenic pressure over two molecules and to reduce immune escape by covering practically all B-ALL blast subclones.

CD19/CD22-directed dual CARs have in fact been proposed to overcome B-ALL immunoediting during CAR T-cell therapy but, unfortunately CD19/CD22 dual CAR-treated R/R B-ALL patients showed CR rates not sustained over time and relapse with limited CAR T-cell expansion.

In contrast to CAR T-cells, BiTEs-secreting T-cells represent a unique strategy capable of redirecting bystander T-cells to tumor cells because T-cell-produced BiTEs will be continuously secreted and will decorate, through the CD3scFv, the cell surface of practically all circulating and ex vivo manufactured bystander T-cells.

Our overarching goal is to provide a novel and innovative T-cell redirecting immunotherapy for the treatment of R/R B-ALL by dual targeting both CD22 and CD19 with T-cells modified to simultaneously secrete CD22xCD3 BiTEs and express CD19 CAR (referred to BiTECAR).

This strategy harnesses the biological advantages of both CARs and BiTEs while minimizing their limitations and will circumvent the potential low transduction efficiencies of the BiTECAR construct because the CD22-BiTE secreted by transduced T-cells will decorate the bystander (untransduced) T-cells boosting the durability and strength of T-cell responses.