Attempts to increase the antigenicity and immunogenicity of tumors have been made for more than 20 years.
These modifications can be achieved by introducing allogeneic major histocompatibility complex molecules, cytokine genes, viruses, or costimulatory molecules such as B7-1 and B7-2 into tumor cells.
Numerous studies in different tumor and mouse models have established that the transfection of cytokine genes such as interleukin-2 (IL-2), IL-4, IL-7, IL-10, IL-12, GM-CSF, or interferon-gamma (IFN-gamma) into tumor cell lines can protect mice against inoculation with these modified autologous cells.
In some situations, protection against later challenge with unmodified cells or even a rejection of established tumors was achieved.
Although more than 30 clinical protocols worldwide have been designed and initiated to augment the immune response against cancer by cytokine transduction, the administration of cytokine-engineered autologous tumor cells to patients is hampered by several major drawbacks.
The establishment of autologous tumor cell lines and their transfection with cytokines is a time-consuming, laborious, and expensive procedure that is frequently unsuccessful.
In addition, genetically modified tumor cells from different patients may vary in terms of the level and stability of cytokine expression and other molecular properties, making a comparison of clinical and biological effects difficult.
Roth et al. used cytokine-secreting allogeneic and xenogeneic cell lines to overcome these limitations and showed that the coadministration of such cells with syngeneic tumor cells could control tumor growth in several mouse and rat models, mainly through the activation of natural killer (NK) cells.
To test this specific immunotherapy strategy in a situation that mimics more closely the biology of human tumors, scientists have produced a genetically modified monkey fibroblast cell line secreting high levels of human IL-2 (Vero-IL-2) to treat the spontaneous fibrosarcomas and melanomas of domestic animals.
Using these xenogeneic, IL-2-secreting cells, they have demonstrated in a controlled study in >60 cats and dogs that repeated adjuvant injections of the engineered cells into the tumor bed after surgery and local irradiation substantially improved disease-free and overall survival in the treated animals compared with controls treated by standard therapy alone.
In cats with fibrosarcomas, long-term survival and the probably cure of Vero-IL-2 treated animals was 70%, compared with 30% in animals treated with surgery and irradiation alone.
In canine melanomas, Vero-IL-2 treatment more than tripled the median survival of dogs compared with controls treated with standard tumor resection and external beam radiotherapy.
Interestingly, a local injection of either IL-2 or unmodified Vero cells alone led to decreased rather than improved survival in some additional cats and dogs included in this study, supporting the notion that both cytokine stimulation and the nonspecific effects of the xenogeneic cells are necessary to mediate the therapeutic effect.
Scientists injected Vero-IL-2 cells into human patients and it was observed that the intratumoral (i.t.) administration of Vero-IL-2 is safe and shows biological and clinical effects.
Xenogenic cells in cancer therapy are one of optional methods, which can be used to prevent cancer development and help patients to prolong their survival.
Keywords: Cancer gene therapy; interleukin-2; immunotherapy; xenogeneic cells.