Adris S, Chuluyan E, Bravo A, Berenstein M, Klein S, Jasnis M, Carbone C, Chernajovsky Y, Podhajcer O L
Gene Therapy Laboratory, Instituto de Investigaciones Bioquímicas Fundación Campomar, Consejo Nacional de Investigaciones Cientificas y Técnicas (CONICET), Facultad de Ciencias Exactas y Natrurales, Universidad de Buenos Aires, Argentina.
Cancer Res. 2000 Dec 1;60(23):6696-703.
Cell-based gene therapy after cytokine gene transfer is being investigated for autologous and allogeneic vaccination in cancer therapy. Here we show that mice vaccinated with 3-5 x 10(6) interleukin 12 (IL-12) gene-transduced CT26 colon cancer cells developed a long-lasting antitumor immune memory able to reject not only parental cells but also syngeneic, LM3 mammary, and MCE fibrosarcoma tumorigenic cells. In contrast, mice vaccinated with 0.5-1 x 10(6) CT26 cells transduced with pBabe neo IL-12 retrovirus cells (CT26-IL12) were only able to reject parental cells. An increase in the total circulating levels of IgG2a and a clear shift toward a systemic Th1 response developed, regardless of the amount of injected CT26-IL12 cells. On the contrary, a strong increase in anti-CT26-specific IgG2a levels was observed only when 3-5 x 10(6) CT26-IL12 cells were injected. Immunocompetent mice vaccinated with 3-5 x 10(6) CT26-IL12 cells developed local nodules for a few days, which then ceased growing. These nodules comprised mainly blood vessels, suggesting that an angiogenic process was taking place. CD8+ T cells were responsible for the anti-LM3 tumor cell memory, whereas CD4+ T cells were not involved. Splenocytes and lymphocytes obtained from mice immunized against CT26 cells were able to kill LM3 cells in vitro. Adoptive transfer of lymphocytes obtained from animals immunized against CT26 colon cancer cells suppressed LM3 mammary tumor growth in tumor-bearing mice. The present studies raised the possibility of isolating CTL clones and identifying CTL epitopes shared by different tumor cell types, which can be a target for cancer therapy.
细胞因子基因转移后的基于细胞的基因治疗正在癌症治疗的自体和异体疫苗接种方面进行研究。在此我们表明，用3 - 5×10⁶个白细胞介素12（IL - 12）基因转导的CT26结肠癌细胞接种的小鼠产生了持久的抗肿瘤免疫记忆，不仅能够排斥亲本细胞，还能排斥同基因的、LM3乳腺和MCE纤维肉瘤致瘤细胞。相比之下，用pBabe neo IL - 12逆转录病毒细胞（CT26 - IL12）转导的0.5 - 1×10⁶个CT26细胞接种的小鼠仅能排斥亲本细胞。无论注射的CT26 - IL12细胞数量如何，IgG2a的总循环水平都会升高，并且明显向全身性Th1反应转变。相反，仅在注射3 - 5×10⁶个CT26 - IL12细胞时，才观察到抗CT26特异性IgG2a水平的强烈升高。用3 - 5×10⁶个CT26 - IL12细胞接种的免疫活性小鼠在几天内形成局部结节，然后停止生长。这些结节主要由血管组成，表明正在发生血管生成过程。CD8⁺T细胞负责抗LM3肿瘤细胞记忆，而CD4⁺T细胞不参与。从免疫CT26细胞的小鼠获得的脾细胞和淋巴细胞能够在体外杀死LM3细胞。将从免疫CT26结肠癌细胞的动物获得的淋巴细胞进行过继转移，可抑制荷瘤小鼠中LM3乳腺肿瘤的生长。本研究提出了分离CTL克隆并鉴定不同肿瘤细胞类型共有的CTL表位的可能性，这可能成为癌症治疗的靶点。
