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

Introduction

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).

Challenges with Current Therapies

However, despite initial impressive complete response (CR) rates, many patients relapse a 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.

Proposed Therapeutic Strategy

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.

1. CD19/CD22-directed dual CARs have been proposed to overcome B-ALL immunoediting during CAR T-cell therapy.
2. 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.

Advantages of BiTEs

In contrast to CAR T-cells, BiTEs-secreting T-cells represent a unique strategy capable of redirecting bystander T-cells to tumor cells. This is 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 Innovative Approach

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 as BiTECAR).

This strategy harnesses the biological advantages of both CARs and BiTEs while minimizing their limitations. It 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.