Submitted April 15, 2006
Accepted July 21, 2006
T-lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B-lymphocyte derived malignant cells
Juan Vera, Barbara Savoldo, Stephane Vigouroux, Ettore Biagi, Martin Pule, Claudia Rossig, Jessie Wu, Helen E Heslop, Cliona M Rooney, Malcolm K Brenner, and Gianpietro Dotti*
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas
* Corresponding author; email: gdotti{at}bcm.tmc.edu.
There has been interest in generating T cells expressing artificial T-cell receptors (CAR) targeting CD19/CD20 antigens to treat B-cell lymphomas. If successful, however, this approach would likely impair humoral immunity, since T cells may persist long-term. Most low-grade-lymphoma and Chronic Lymphocytic Leukemia (B-CLL) cells express monoclonal immunoglobulins (Igs) carrying either kappa (
) or lambda (
) light chains. We therefore explored whether T-lymphocytes could be genetically modified to target the tumor associated light chain, sparing B-lymphocytes expressing the reciprocal light chain, and consequently reduce impairment of humoral immunity. We found that T-lymphocytes expressing the anti--light chain CAR showed cytotoxic activity against Ig+ tumor cell lines and B-CLL cells both in vitro and in vivo. We also found that the incorporation of the CD28 endodomain within the CAR enhanced the in vitro and in vivo expansion of transgenic T cells after tumor associated antigen stimulation. Free Ig+ did not compromise the ability of redirected T-lymphocytes to eliminate Ig+ tumors, since these free Igs served to sustain proliferation of CAR-CD28 transgenic T cells. Thus adoptive transfer of T-lymphocytes targeting the appropriate light chain could be a useful immunotherapy approach to treat B-lymphocyte malignancies that clonally express Ig without entirely compromising humoral immunity.
