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Enhancement of tumor killing using a combination of tumor immunization and HSV‐tk suicide gene therapy
Author(s) -
Ramesh Rajagopal,
Munshi Anupama,
Marrogi Aizen J.,
Freeman Scott M.
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19990129)80:3<380::aid-ijc8>3.0.co;2-g
Subject(s) - suicide gene , bystander effect , ganciclovir , thymidine kinase , genetic enhancement , tumor necrosis factor alpha , herpes simplex virus , immunology , cytokine , cancer research , medicine , biology , microbiology and biotechnology , virus , gene , human cytomegalovirus , biochemistry
Tumor cells genetically modified with the herpes simplex virus thymidine kinase ( HSV‐tk ) gene in combination with ganciclovir (GCV) demonstrate a “bystander effect”. Previous attempts to enhance the bystander tumor killing by combining cytokine genes with HSV‐tk/GCV have met with varying results. The present study was designed to determine the effects of tumor immunization in combination with HSV‐tk gene‐modified tumor cells and GCV on tumor killing and to determine if the bystander tumor killing could be enhanced. Tumor‐bearing mice immunized with syngeneic tumor (KBALB) prior to treatment with an i.p. injection of xenogeneic HSV‐tk gene‐modified tumor cells (PA‐1STK) had prolonged animal survival (group 4, 56.4 days). In contrast, unimmunized tumor‐bearing mice (group 2) or tumor‐bearing mice immunized to the xenogeneic PA‐1STK tumor cells (group 5) showed a mean survival of about 27 days after receiving an i.p. injection of PA‐1STK cells and GCV. Control groups, which were either not immunized and did not receive HSV‐tk cells (group 1) or immunized but treated only with GCV (group 3) showed short survival (16–18 days). Analysis of tumors for cytokine mRNA expression revealed increased TNF‐α and IL‐1α mRNA expression in group 4 mice. Furthermore, IL‐2 mRNA expression was detectable on days 2 and 4 only in group 4 mice. Immunophenotypic analysis for tumor‐infiltrating lymphocytes demonstrated an increase in macrophage (4%, p = 0.0001) and T cells (1.8%, p < 0.001) in group 4 mice with an enhanced T‐cell response as compared with mice from groups 1, 2 and 3. Our results demonstrate that tumor immunization combined with HSV‐tk/GCV treatment results in increased animal survival with enhanced immune response. Furthermore, the cytokine milieu observed in the present study can modulate the tumor micro‐environment in vivo from one that is immunosuppressive to one that is immune‐stimulatory. Int. J. Cancer 80:380–386, 1999. © 1999 Wiley‐Liss, Inc.