Adoptive cellular immunotherapy for the treatment of malignant gliomas

The median survival for adults with recurrent primary malignant gliomas is 56 weeks following surgery, radiation, and chemotherapy. Generally, reoperation can extend the median survival an additional 26-32 weeks. We have developed an aggressive treatment program that utilizes low doses of interleukin-2 (IL-2) combined with ex vivo activated killer cells (LAK) infused via an indwelling catheter placed into the surgical resection cavity. Autologous leukocytes were collected during a standard 3-4 h, outpatient leukapheresis procedure, then activated ex vivo for 4-5 days with high doses of IL-2. The treatment protocol consisted of two 2-week cycles of therapy over a 6-week period. Patients with stable disease or objective response on follow-up MRI scans were retreated at 3-month intervals. Acute and cumulative IL-2-related toxicities were observed, but limited, and included fever, headache and transient neurologic irritation. Corticosteroid levels and usage were strictly controlled during immunotherapy, although higher doses were used intermittently to mitigate toxicity. Biologic changes included lymphocytic infiltration, regional eosinophilia, tumor necrosis, and the localized production of IL-2, IFN-gamma and IL-12, demonstrated by in situ hybridization and immunohistochemistry.

IL-2 plus autogeneic LAK cells can be safely administered intracavitary to treat high grade primary brain tumors with limited toxicity within the central nervous system. Six out of 28 patients had long-term survival of greater than 2 years post-reoperation plus immunotherapy with 2 patients alive over 8 years. The presence of a marked regional eosinophilia appeared to correlate with increased survival and may be predictive of a biologic and therapeutic response. Regional adoptive immune therapy was well tolerated and should be considered an option for patients with high-grade tumors refractive to standard therapeutic approaches.