T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells.
There has been interest in generating T cells expressing chimeric artificial receptors (CARs) targeting CD19/CD20 antigens to treat B-cell lymphomas. If successful, however, this approach would likely impair humoral immunity because T cells may persist long-term. Most low-grade lymphoma and chronic lymphocytic leukemia (B-CLL) cells express monoclonal immunoglobulins 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-kappa light chain CAR showed cytotoxic activity against Igkappa(+) 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 Igkappa(+) did not compromise the ability of redirected T lymphocytes to eliminate Igkappa(+) tumors because these free immunoglobulins 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 immunoglobulin without entirely compromising humoral immunity.
Vera
Juan
J
Center for Cell and Gene Therapy, Baylor College of Medicine, Fannin St, MC 3-3320, Houston, TX 77030, USA.
Savoldo
Barbara
B
Vigouroux
Stephane
S
Biagi
Ettore
E
Pule
Martin
M
Rossig
Claudia
C
Wu
Jessie
J
Heslop
Helen E
HE
Rooney
Cliona M
CM
Brenner
Malcolm K
MK
Dotti
Gianpietro
G
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D018951:Antigens, CD20 / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D015973:Gene Expression Regulation, Leukemic / Q000276:immunology; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000276:immunology*; D007146:Immunoglobulin lambda-Chains / Q000276:immunology; D020014:K562 Cells; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000276:immunology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D018941:Antigens, CD19; D018951:Antigens, CD20; D018106:CD28 Antigens; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins