Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells.
T cells can be engineered to target tumor cells by transduction of tumor-specific chimeric receptors, consisting of an extracellular antigen-binding domain and an intracellular signaling domain. However, the peripheral blood of cancer patients frequently contains an increased number of T regulatory cells, which appear to inhibit immune reactivity. We have investigated the effects of T regulatory cells on chimeric T cells specific for the B-cell antigen CD19, as B-cell malignancies are attractive targets for chimeric T-cell therapy. When a CD19 single-chain Fv antibody was coupled to the CD3 zeta (zeta) chain, there was sharply reduced activity on exposure to T regulatory cells, measured by CD19+ target-induced proliferation and cytotoxicity. By contrast, expression in T cells of a chimeric receptor consisting of the intracellular portion of the CD28 molecule fused to the zeta-chain and CD19 single-chain Fv not only produced a higher proliferative response and an increased nuclear factor kappaB activation but also sustained these activities in the presence of T regulatory cells. These effects are seen whether the chimeric T cells are derived from normal donors or from patients with B-cell chronic lymphocytic leukemia, indicating the potential for clinical application in B cell malignancies.
Loskog
A
A
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. angelica.loskog@klinimm.uu.se
Giandomenico
V
V
Rossig
C
C
Pule
M
M
Dotti
G
G
Brenner
M K
MK
D018941:Antigens, CD19 / Q000235:genetics; D018106:CD28 Antigens / Q000737:chemistry / Q000235:genetics*; D017252:CD3 Complex / Q000235:genetics; D002455:Cell Division / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D020014:K562 Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000628:therapy*; D050506:Mutant Chimeric Proteins / Q000737:chemistry / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000502:physiology*; D014161:Transduction, Genetic
D018941:Antigens, CD19; D018106:CD28 Antigens; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D016207:Cytokines; D050506:Mutant Chimeric Proteins; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell