Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells

Loskog, AngelicaUppsala universitet,Institutionen för onkologi, radiologi och klinisk immunologi (författare)

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 kappa B 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.

Giandomenico, ValeriaUppsala universitet,Institutionen för onkologi, radiologi och klinisk immunologi(Swepub:uu)valegian (författare)
Rossig, C. (författare)
Pule, M. (författare)
Dotti, G. (författare)
Brenner, M. K. (författare)
Uppsala universitetInstitutionen för onkologi, radiologi och klinisk immunologi (creator_code:org_t)

Ingår i:Leukemia: Springer Science and Business Media LLC20:10, s. 1819-18280887-69241476-5551

Av författaren/redakt...: Loskog, Angelica; Giandomenico, Va ...; Rossig, C.; Pule, M.; Dotti, G.; Brenner, M. K.

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