Cancer of the uterine cervix affected 15,800 women in the U.S. in 1995, resulting in 4,800 deaths. Cervical carcinoma beyond the scope of definitive radiation therapy or surgery has a poor prognosis and only 20-40% of women with FIGO stage III and 10% with stage IV survive. In addition to high mortality, patients with advanced disease suffer severe morbidities including renal failure, thrombophlebitis, pelvic fistulas and pain. More effective therapies are required. Human papillomavirus (HPV) infection has been shown to be the major risk factor for cervical carcinoma and its precursor lesions. It has recently been shown that regression of cervical intraepithelial neoplasia and resolution of HPV infection are associated with cell-mediated immune (CMI) responses to HPV 16 E6 and/or E7 peptides. It is thought than an effective CMI response involves activation of TH1 lymphocytes with generation of IFN-gamma, resulting in effective T lymphocyte cytotoxicity. Cervical cancers containing HPV genomes have been shown to have a better prognosis than HPV negative tumors. Although little is known of CMI responses to HPV in cancer patients, therapies enhancing anti-tumor or antiviral immune reactivity would be expected to be effective in management of HPV-associated cervical carcinoma. IL-12 is a potent growth factor for activated lymphocytes, an enhancer of cytotoxic T and NK cell activity, and an inducer of TH1 responses with IFN-gamma production. Furthermore, IL-12 has been shown to have antimetastatic activity, including inhibition of tumor cell motility, matrix attachment and basement membrane invasion in vitro and antiangiogenic effects in vitro and in vivo. As there are currently no effective strategies for treating metastatic or recurrent cervical cancer, a promising biologic agent such as IL-12 is worth studying. Since cervical cancer is intimately related to the presence of HPV, it would also be reasonable to correlate the effects of IL-12 with the absence or presence of HPV. The effect of IL-12 treatment on immune responses to HPV would be important and might result in improved immunotherapeutic modalities for advanced cervical cancer. The applicant proposes a phase II clinical trial of IL-12 treatment of women with advanced cervical cancer with correlative HPV and immunologic studies.
The specific aims are 1) To determine whether IL-12 therapy results in clinical improvement of advanced cervical cancer; 2) To determine whether IL-12 effects are associated with HPV status of tumors under treatment; 3) To determine whether IL-12 therapy results in improved or restored CMI responses to HPV16 E6 and/or E7 peptides including lymphoproliferative responses and production of IFN-gamma (i.e., TH1); and 4) To determine whether restored immune responses are associated with improved clinical outcome.
|Wadler, Scott; Levy, Donna; Frederickson, Helen L et al. (2004) A phase II trial of interleukin-12 in patients with advanced cervical cancer: clinical and immunologic correlates. Eastern Cooperative Oncology Group study E1E96. Gynecol Oncol 92:957-64|