Transfer of the interleukin-2 gene into human cancer cells induces specific antitumor recognition and restores the expression of CD3/T-cell receptor associated signal transduction molecules.

Normal peripheral blood mononuclear cells (PBMC) were co-cultured with a human lung cancer cell line (LC89) transduced with the interleukin-2 (IL-2), IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha) genes to evaluate the capacity of the engineered cells to: allow survival of CD3+ and CD56+ cells, generate cytotoxic effectors with HLA class I restricted and unrestricted antitumor activity, and interfere in the molecular organization of the CD3/T-cell receptor associated signal transduction machinery. When PBMC were cultured up to 3 weeks with IL-2 releasing LC89 cells (LC89/IL-2), the number of viable CD3+ and CD56+ lymphocytes was much greater than in cultures with parental cells or with LC89 cells transduced with the other cytokine genes. After 1 week of coculture, a variable degree of restricted and unrestricted killing directed against different targets was observed.

Clinical and immunological studies in advanced cancer patients sequentially treated with anti CD3 monoclonal antibody (OKT3) and interleukin-2.

CD3 engagement has been used as a surrogate for antigen-specific stimulation to trigger T cell effector functions. Exogenous IL-2 has been used to prolong and amplify CD3-induced T cell activation. Previous studies have been shown that CD3 reactivity is increased in cancer patients with preactivated (> 10% HLA-DR+) T cells in the peripheral blood.

CD3-induced T-cell activation in the bone marrow of myeloma patients: major role of CD4+ cells.

A large expansion of activated T cells (CD3+CD25+) with the potential to act as anti-tumour effector cells is inducible in multiple myeloma (MM) patients by culturing bone marrow mononuclear cells (BMMCs) with the anti-CD3 monoclonal antibody (mAb) OKT3. The aim of this study was to provide a greater characterization of CD3-activated T cells. On day 6, most T cells coexpressed the CD11a, CD18, CD54, CD45R0 antigens and consisted of activated (CD25+) CD4+ and CD8+ cells in nearly equal proportions.

Dysregulated Fas and Bcl-2 expression leading to enhanced apoptosis in T cells of multiple myeloma patients.

We have previously reported the presence of activated (HLA-DR+) T cells in multiple myeloma (MM) patients. These cells produce high amounts of interleukin (IL)-2 and interferon (IFN)-gamma and generate a potent antiplasma cell activity after appropriate in vitro stimulation, but they are unable in vivo to hold in check the disease. Activated T cells are highly susceptible to apoptosis, a form of programmed cell death involved in the modulation of immune responses and regulated by molecules such as Fas (CD95) and bcl-2.

Generation of anti-tumour activity by OKT3-stimulation in multiple myeloma: in vitro inhibition of autologous haemopoiesis.

T cells in multiple myeloma (MM) patients are highly susceptible to activation with the anti-CD3 monoclonal antibody (mAb) OKT3. When short-term OKT3 stimulation is carried out on bone marrow mononuclear cells (BMMC), large numbers of CD3+ CD25+ HLA-DR+ cells are rapidly generated and autologous malignant plasma cells are killed. OKT3 may thus be exploited in autologous bone marrow transplantation (ABMT) to purge residual plasma cells and simultaneously activate T cells to induce graft-versus-leukemia-like (GVL-like) activity upon reinfusion.