TREATMENT OF ESTABLISHED LONG METASTASES WITH TUMOR-INFILTRATING LYMPHOCYTES DERIVED FROM A POORLY IMMUNOGENIC TUMOR ENGINEERED TO SECRETE HUMAN TNF-ALPHA

The growth of a poorly immunogenic methylcholanthrene (MCA)-induced mu rine (m) sarcoma genetically engineered to secrete human (h) TNF-alpha (MCA-102-hTNF) was studied. MCA-102-hTNF tumor cells were implanted i n animals bearing three- or 7-day pulmonary metastases established wit h the parental line MCA-102-WT (wild type). This model approximates th e clinical situation in which patients with metastatic cancer would be vaccinated with autologous tumor genetically modified to stimulate th e host immune response. Reduction in the number of pulmonary metastase s was occasionally seen but was not consistently reproducible. Other c ytokine-producing tumors had either no effect on distant pulmonary met astases (mIL-4, IFN-gamma) or a mild, inconclusive effect similar to h TNF-alpha (mTNF-alpha). Significant growth inhibition of MCA-102-hTNF was noted in animals bearing pulmonary metastases. This inhibition was : 1)tumor specific (regression occurred only in animals bearing pulmon ary metastases from the same parental line), 2) TNF specific (it was i nhibited by in vivo administration of anti hTNF mAbs), 3) dependent on cellular immunity (immune-depletion with anti-CD4 or CD8 mAbs permitt ed growth). Tumor-infiltrating lymphocytes (TIL) could not be grown fr om MCA-102-WT or MCA-102-hTNF tumors nor from MCA-102-WT subcutaneous implants in mice bearing MCA-102-WT pulmonary metastases. However, TIL could be grown from hTNF-secreting tumors implanted in mice bearing M CA-102-WT metastases. These TIL were therapeutic against established l ung metastases from the parental tumor in adoptive immunotherapy model s. These studies suggest a strategy for using gene modified tumors for the therapy of established cancer.