Potentiation of electrochemotherapy by intramuscular IL-12 gene electrotransfer in murine sarcoma and carcinoma with different immunogenicity
Background. Electrochemotherapy provides good local tumor control but needs adjuvant treatment for increased local response and action on distant metastasis. In relation to this, intramuscular interleukin-12 (IL-12) gene electrotransfer which provides systemic shedding of IL-12 was combined with local electrochemotherapy with cisplatin. Furthermore, dependence on tumor immunogenicity and immunocompetence of the host on combined treatment response was evaluated.
Materials and methods. Sensitivity of SA-1 sarcoma and TS/A carcinoma cells to electrochemotherapy with cisplatin was tested in vitro. In vivo, intratumoral electrochemotherapy with cisplatin (day 1) was combined with a single (day 0) or multiple (days 0, 2, 4) intramuscular murine IL-12 (mIL-12) gene electrotransfer. The antitumor effectiveness of combined treatment was evaluated on immunogenic murine SA-1 sarcoma in A/J mice and moderately immunogenic murine TS/A carcinoma, in immunocompetent BALB/c and immunodeficient SCID mice.
Results. Electrochemotherapy in vitro resulted in a similar IC50 values for both sarcoma and carcinoma cell lines. However, in vivo electrochemotherapy was more effective in treatment of sarcoma, the more immunogenic of the tumors, resulting in a higher log cell kill, longer specific tumor growth delay and also 17% tumor cures compared to carcinoma where no tumor cures were observed. Adjuvant intramuscular mIL-12 gene electrotransfer increased the log cell kill in both tumor models potentiating the specific tumor growth delay by a factor 1.8 – 2 and increasing tumor cure rate by approximately 20%. In sarcoma tumors the potentiation of response by intramuscular mIL-12 gene electrotransfer was dose dependent and also resulted in a quicker onset of tumor cures. Comparison of carcinoma response to the combined treatment modality in immunocompetent and immunodeficient mice demonstrated that the immune system is needed both for increased cell kill and for attaining tumor cures.
Conclusions. Based on the comparison of the antitumor effectiveness of electrochemotherapy with intratumoral cisplatin administration, we can conclude that the fraction of cells killed and the tumor cure rate is higher in immunogenic sarcoma tumor, compared to moderately immunogenic carcinoma tumor. Tumor cell kill and the cure rate depend on elicited immune response by destructed tumor cells, which depends on the immunogenicity of tumors. The effect of adjuvant intramuscular mIL-12 gene electrotransfer is dependent on the amount of IL-12 in the system and the immune competence of the host, as demonstrated by dose dependent increase in curability rate of SA-1 tumors after multiple intramuscular mIL-12 gene electrotransfer and differential curability rate of TS/A tumors growing in immunocompetent and immunodeficient mice.