Here, we show that the virus-infected cells not only proliferate in vitro in the absence of exogenously supplied IL-2 under certain conditions, but also develop tumors (lymphomas) in nude and syngeneic mice.
Culture of human peripheral blood leukocytes with interleukin 2 (IL-2) stimulates their differentiation into lymphokine-activated killer (LAK) cells, with a broad range of cytotoxicity against fresh tumor cells and tumor cell lines (Grimm et al., J. Exp.Med., 155: 1823-1841, 1982).
The results suggest that peritumoral administration of lymphoid cells transformed with IL-2 cDNA and constitutively producing IL-2 in the immediate tumour vicinity is sufficient for the effective activation of local IL-2-dependent tumour defence mechanisms and, therefore, can be considered a novel, genetic approach to the immunotherapy of cancer.
High levels of tumor-specific cytolytic activity could also be detected in parental CMS-5 tumor-bearing animals 18 d after inoculation with tumor cells, if IL-2-producing CMS-5 cells but not unmodified parental tumor cells were used as targets.
IL-2-expanded 444P.3 cells, tested on day 104 in culture, expressed mRNA for tumor necrosis factor (TNF), IL-2 and tumor growth factor beta (TGF-beta) but not for IL-1, lymphotoxin or granulocyte/macrophage-colony stimulating factor (GM-CSF).
Tumor-infiltrating lymphocytes (TILs) are cells generated from tumor suspensions cultured in interleukin 2 that can mediate cancer regression when adoptively transferred into mice or humans.
Twelve autologous mixed peripheral blood (PBL) tumor cell interactions (MLTC) followed by in vitro expansion of the stimulated T cells in recombinant interleukin-2 (IL-2) were analyzed for the potential emergence of oligoclonal or monoclonal T cell populations in the PBL by Southern blot analysis of the T cell receptor (TCR) beta gene.
The detection of an increasing number of cytokines and the demonstration of autocrine and paracrine mechanisms perpetuating tumor growth prompted the investigation of the expression of the cytokines IL-2, IL-3, IL-4, IL-5, IL-6, IFN gamma, Tac, and GMCSF in primary lymph-node biopsies of patients with peripheral T-cell lymphoma (n = 11), Hodgkin's disease (n = 13), and large-cell anaplastic lymphoma (n = 6) by means of Northern blot analysis and in situ hybridization (ISH); 15 of 28 cases had IL-6 message, predominantly in cases of Hodgkin's disease (HD) and large-cell anaplastic lymphomas (LCAL).
Only TIL grown with low dose IL-2 and autologous tumor maintained long-term (over 4 months in culture) specific cytotoxicity against the autologous tumor, even upon cryopreservation and regrowth.
It remains to be established whether IL-2 production occurs in the normal pituitary or is intrinsic to the process of tumor development of these cells.
In those ductal breast carcinomas which contained intracellular or intraductal mucins, up to 30% of lymphoid cells in the tumor stroma were positive for IL-2, TNF alpha, IFN gamma and IL-2R.
The low-dose IL-2 therapy has been studied with an adoptive transfer combined with either autologous lymphokine activated killer cells or autologous tumor infiltrating lymphocytes (TIL).
We also looked for the presence of transcripts for IL-2, leukaemia inhibitory factor (LIF) and transforming growth factor (TGF)beta in cells of tumour samples from the same patients and in HMCL.
The development of immunotherapy with IL-2 and tumor-infiltrating lymphocytes (TIL), which can accumulate at tumor sites in some patients, and of efficient retroviral techniques for gene transfer into eukaryotic cells has allowed new therapeutic approaches using TNF.