Thus, a novel approach to gene therapy is being developed using direct tumor injection of cDNA, with a tumor specific promoter ligated to the IL-2 gene.
The antitumor activities of G129R-IL2 were demonstrated in vivo using a syngeneic model system with BALB/c mice and EMT6-hPRLR breast cancer cells.After daily injection (i.p.) of G129R-IL2 (100 microg/mouse) for 18 days, the tumor growth in the G129R-IL2-treated group was only one-third the size as compared with that of the control group.
Transforming activity was further demonstrated by the ability of the FBXW7 D510E mutant to provide IL-2-independent growth of Tax-immortalized human T cells and increase the tumor formation in a xenograft mouse model of ATL.
These results indicate that Thujone can inhibit the lung metastasis of B16F-10 cells through inhibition of tumor cell proliferation, adhesion, and invasion, as well as by regulating expression of MMPs, VEGF, ERK-1, ERK-2, TIMPs, nm23, and levels of proinflammatory cytokines and IL-2 in metastatic animals.
Current standard treatments for patients with metastatic (stage IV) renal cell carcinoma involve both surgical removal of tumors and treatment with biological agents such as interleukin 2 or IFN-α.
In this pilot study we sought to determine the prognostic value of epigenetic and genetic inactivation of tumour suppressor genes (TSGs) among BC patients treated with IL-2.
Clinical trials based on these observations have begun in which patients are immunized against their own autologous tumors that were transduced with the genes for TNF or interleukin-2.
These results demonstrated that the combined use of IL-2 gene-transfected tumor vaccine and IL-6 gene-transfected tumor vaccine could achieve more potent antitumor effect via more effective activation of specific and non-specific antitumor immune responses.
Drug targeting, efficient stimulation of immune cell infiltration, and specific elimination of tumor or fibroblast spheroid areas were demonstrated following treatment with a novel immunocytokine (interleukin-2 variant; IgG-IL2v) and tumor- or fibroblast-targeted T cell bispecific antibody (TCB).
Ongoing clinical trials for renal cell carcinoma are encouraging, in that IL-2 gene therapy using non-viral vector systems can reduce the tumor burden.
Sodium stibogluconate (SSG), an inhibitor of SHP-1 that negatively regulates cytokine signaling and immunity, suppressed growth of murine Renca tumors in combination with interleukin-2 (IL-2) via a T-cell-dependent mechanism.
F42K therapy in vivo also induced a dramatic reduction in the expansion of ICOS<sup>+</sup> Tregs, promoted NK cell expansion, and inhibited melanoma tumor growth more efficiently than WT IL2 and more effectively than anti-CTLA-4.
While NXS2 tumors are susceptible to in vivo destruction following either hu14.18-IL2 or Flt3-ligand immunotherapies, these results suggest that some tumor cells may be selected to survive and progress by expressing either higher or lower levels of MHC class I antigen in order to resist either NK- or T-cell-mediated antitumor responses, respectively.
In an orthotopic PDX model, animals receiving chemoimmunotherapy with an anti-GD2 antibody, GM-CSF, and a soluble IL15/IL15Rα complex had greater tumor regression than did those receiving chemotherapy alone (<i>P</i> = 0.012) or combined with anti-GD2 antibody and GM-CSF with (<i>P</i> = 0.016) or without IL2 (<i>P</i> = 0.035).
The 2nd gen dTc can be optimally activated to secrete larger amounts of cytokines such as IL2 and IFNγ than 1st gen and to proliferate more vigorously on PSMA-expressing tumor contact.
These results indicate that vaccination with cells releasing IL-2 locally can expand a T cell response against antigen(s) of autologous, untransduced tumor, although this response occurred in a minority of the melanoma patients studied.
Tumour cell survival is supported by IL-2 and there is a skew towards CD8-positive T cells in the tumour environment, while the immune check-point protein PD-L1 is upregulated in the tumours.
The relationship between local treatment and tumour regression was supported by replacement of tumour cells by inflammatory cells in regressing lesions and marked induction of T and natural killer cell derived cytokines (IL-2, IL-4, IFNg ...) in post-therapeutic lesions analysed 28 days after the start of Vero-IL-2 administration.
Additionally, we found that coadministration of IL2 DNA with pcDNA3-CRT/E7 modified the tumor microenvironment by decreasing the population of regulatory T cells and myeloid-derived suppressor cells relative to that of CTLs.
There was a non-significant trend towards dose-dependent tumor uptake, with higher uptake at doses ≥20 mg. Biodistribution was dose- and CEA-independent with major accumulation in lymphoid tissue compatible with IL-2R binding.
Tumor cells genetically engineered to secrete IL-2 may therefore be promising candidates for tumor vaccines and may provide a new mode of cancer immunotherapy.