GENERATION AND STUDY OF IL-1-SECRETING TIL CELLS

CONVENTIONAL CANCER TREATMENTS HAVE BEEN UNABLE TO ELIMINATEMALIGNANT CELLS IN A SIGNIFICANT NUMBER OF CANCER PATIENTS DESPITE CONTINUTE IMPROVEMENTS IN THE CLINICAL PROTOCOLS UTILIZED. ADOPTIVE IMMUNOTHERAPY WITH LYMPHOKINE-ACTIVATED KILLER (LAK) CELLS AND RIL-2 HAS PROVIDED AN ADDITIONAL THERAPY THAT HAS SHOWN EVIDENCE OF EFFECT IN SITUATIONS WHERE CONVENTIONAL THERAPIES HAVE FAILED. TUMOR-INFILTRATING LYMPHOCYTES (TIL'S) HAVE SHOWN INCREASED EFFECTIVENESS IN ELIMINATING MALIGNANT CELLS IN ANIMALS AND HUMANS WHEN COMPARED WITH LAK CELLS. TO FURTHER INCREASE THE EFFECTIVENESS OF ADOPTIVE IMMUNOTHERAPY, GENETIC THERAPY, INC., WILL USE RETROVIRALLY MEDIATED GENE TRANSFER TO GENERATE TIL-SECRETING BIOLOGICALLY ACTIVE MOLECULES THAT MIGHT ENHANCE THE ANTITUMOR EFFECT OF TIL THERAPY. IN PARTICULAR, BECAUSE OF THE CENTRAL ROLE OF IL-1 IN THE INFLAMMATORY PROCESS, IT IS PLANNED TO GENERATE TIL-SECRETING IL-1 BY TRANSDUCING TIL'S WITH A RETROVIRAL VECTOR CONTAINING IL-1 CDNA SEQUENCES. THE EFFECT OF IL-1 PRODUCTION BY TIL'S WILL BE STUDIED IN VITRO WITH HUMAN AND MOUSE TIL'S AND IN VIVO WITH MURINE MODELS TO DETERMINE IF THERE IS AUGMENTATION OF THE EFFICACYOF TUMOR KILLING. IF SIGNIFICANT THERAPEUTIC RESPONSES WITHACCEPTABLE TOXICITIES ARE SEEN WITH THE IN VIVO MURINE MODELS, THEN APPLICATIONS FOR CLINICAL TRIALS FOR HUMAN MALIGNANCIES WILL BEGIN.