An emerging strategy in the treatment of various neoplasms involves the stimulation of an immune response against the malignant cells. Cytokines such as interleukin-2 (IL-2) or interferon-γ (IFN-γ) have been used in both experimental animals and patients to treat malignant disease with inconsistent success. Interleukin-2 has no direct toxic effect on cancer cells; its antitumor activity is mediated by modulation of the host's immunological response to the neoplasm.25 Interferon-γ induces the expression of major histocompatibility complex (MHC) class I determinants and augments the sensitivity of tumor cells to cytotoxic T lymphocyte—mediated lysis.29,32 Whether cytokine treatment is effective in the treatment of intracerebral neoplasms has remained uncertain.
To evaluate the potential of a novel form of cytokine treatment of glioma, in a prior study we first modified a mouse fibroblast cell line, LM, which expresses defined MHC determinants (H—2k) to secrete both IL-2 and IFN-γ.8 The cytokine-secreting cells (LM—IL-2/IFN-γ) were then cotransplanted subcutaneously with Gl261 murine glioma cells (H—2b) into C57BL/6 mice (H—2b) whose cells differed at the MHC from the cytokine-secreting cells. The period of survival in the tumor-bearing mice treated with the IL-2/IFN-γ double—secreting allogeneic cells was significantly prolonged relative to the survival of untreated mice with glioma, or that of mice with glioma treated with nonsecreting LM cells.8
At the present time, we report the effects of intracerebral injection of LM—IL-2/IFN-γ cells on the survival of mice bearing glioma. The results indicate that the survival of mice injected with a mixture of glioma cells and the double cytokine—secreting cells was significantly prolonged, relative to the survival of mice injected with an equivalent number of tumor cells alone. The antitumor immunity was mediated predominantly by natural killer (NK) and lymphokine-activated killer (LAK) cells.
We would like to thank Dr. James L. Stone for his continued encouragement and support of this work. We also thank Drs. George Pappas, Department of Anatomy and Cell Biology, University of Illinois at Chicago, and O. Howard Reichman, Department of Neurosurgery, Loyola University, for their thoughtful advice and careful review of the manuscript.
Gattoni-Celli SWillett CGRhoads DBet al: Partial suppression of anchorage-independent growth and tumorigenicity in immunodeficient mice by transfection of the H-2 class I gene H-2Ld into a human colon cancer cell line (HCT). Proc Natl Acad Sci USA 85:8543–85471988d into a human colon cancer cell line (HCT). Proc Natl Acad Sci USA 85:
Kim TSCohen EP: Immunization of mice with allogeneic fibroblasts genetically modified for interleukin-2 secretion and expression of melanoma-associated antigens stimulates predetermined classes of anti-melanoma effector cells. J Immunother Emphasis Tumor Immunol 16:24–351994J Immunother Emphasis Tumor Immunol 16:
Kim TSCollins MKLCohen EP: Independent cell types are involved in the induction of antimelanoma responses in C57BL/6 mice immunized with interleukin-2-secreting allogeneic mouse fibroblasts expressing melanoma-associated antigens. J Immunother 14:298–3041993J Immunother 14:
Merchant REMcVicar DWMerchant LHet al: Treatment of recurrent malignant glioma by repeated intracerebral injections of human recombinant interleukin-2 alone or in combination with systemic interferon-α. Results of a phase I clinical trial. J Neurooncol 12:75–831992J Neurooncol 12:
Mulé JJYang JCAfreniere RLet al: Identification of cellular mechanisms operational in vivo during the regression of established pulmonary metastases by the systemic administration of high-dose recombinant interleukin 2. J Immunol 139:285–2941988in vivo during the regression of established pulmonary metastases by the systemic administration of high-dose recombinant interleukin 2. J Immunol 139:
Ram ZWalbridge SHeiss JDet al: In vivo transfer of the human interleukin-2 gene: negative tumoricidal results in experimental brain tumors. J Neurosurg 80:535–5401994In vivo transfer of the human interleukin-2 gene: negative tumoricidal results in experimental brain tumors. J Neurosurg 80:
This study was supported by the U.S. Department of Health and Human Services Grants CA 55651-03 awarded to Dr. Cohen and National Institutes of Health Grant K17 NS01777-01 awarded to Dr. Glick.