| In recent years, the incidence of RCC has increased dramatically (54% from 1975 to 1990), and in 1996,approximately 30,000 new cases were djanosed in the United States . In the same year, an estimated 12,000 RCC-related deaths occurred in the United States The prognosis for later Stage RCC remains highly unfavorable. nearly one-third of patients present with metastatic disease when they come to see doctor at the first time ,In addition, as many as 10% of all patients treated for local tumors will ultimately relapse with metastatic disease. The prognosis of untreated patients with metastatic disease is unfavorable, with a 3-year survival rate of less than5%. Among patients who develop metastases within I year of nephrectomy, the 2-year survival rate is likewise very poor. A major challenge to the development of effective therapies for the treatment of metastatic RCC is its resistance to both chemotherapy and radiotherapy. RCCs typically exhibit a multidrug-resistance gene(MIDR- 1 ),and objective responses to chemotherapy occur in<10% of treated patients. The immune system has demonstrated the potential to play a protective role in RCC. but the vast majority of RCCs arise in immunocompetent hosts. This observation suggests that tumor cells escaPe normal host defenses and aPpropriate immune stimulation mayprovide theraPeutic effects. Several aPproaches have been usedpreviously to augment the natUrally occutring inunune response to RCC.These include the stimulation ofcytotoxic T cells that demonstrate class Imajor histocomPatibility complex (MHC)-restricted lysis; tUmor-infiltrating lymphocytes, which selectively lyse the tUmor from whichthey were derived. and Dendritic ce1l .Despite considerable progress,many RCCs remain unresponsive to immnotheraPy or other treatments.ImmunotheraPy by gene transfer has traditionally relied upongenetic modification of cells in vitro and ce1l-mediated introduction ofrecombinant genes in vivo. Because this aPproach requires establishxnentof cel1s in tissue cultUre and clonal selection in vitro, its aPplication totumors in vivo and its adaPtation to common clinical practice haveremained difficult. The introduction ofrecombinant genes directly intomalignant tumors in vivo could eliminate the need to establish cell linesfrom each patient in the laboratory and could minimize delays in the timeto treatment. This advance facilitates application to human disease andwill allow further insigh into the mechanisms ofimmunosurveillance inVlvoDirectal transfer of the MHC-I gene into RCC has produced clinicalresponses in some patients,However, to date, no clinical responses havebeen observed in RCC .The injection of the MHC-I gene into RCC of l4RCC patients resulted in unC-I RNA and protein expression in themajority of tumor samples. Although tUmor infiltration by CD8+ T cellsindicated induction of a cellular immune response, no clinical responseswere observed.Most RCC toor cells exPress MHC class I but not class IImolecules. As a result, tUInor cells could effectively present Ags to CTLs,but cannot simultaneously stimulate Th cells and thus may fail to induceeffective CTL responses. But if tUmor ce1ls could be induced to expressMHC class II molecules, they might directly activate Th cells to providenecessary helper factors fOr protective CTL responses. some data alsodemonstrate that allogeneic MHC class II Ag+tumor cells can bedestroyed by CD4+ T cells in the absence of CD8+CTLs.The simplestexplanation for this observation is that, in these mice, the primareinoculum is destroyed by CD4+CTLs. As described in other systems,This is a particularly interesting possibility, because such tumor cell...
|
PDF Full Text Request