Highlights of our translational studies conducted under the UCRC grant and involving intraperitoneal immunotherapy include the following: (A) Twenty-two patients received IP injections of IFN- followed by rIL-2 without significant adverse effects in most patients. One out of 2 patients with minimal residual disease (defined as individual tumors <1cm and absence of multiple metastases in the peritoneum, currently after one year has no clinical or radiologic evidence of disease. Two other patients had stability of their tumors for 6 months. (B) Expression of HLA class I and class II antigens were significantly increased on ovarian tumor cells following the IP treatment with IFN- . However, in certain patients, either HLA class I or class II decreased following the injections of IP IL-2. These changes appear to be correlated with increased concentrations of IL-10 and possibly TGF- B in peritoneal fluids. (C) A graduate student who works in my laboratory has identified and characterized an IL-10 secreting monocyte in the peritoneal fluid of patients (abstract submitted to AACR and American Association of Immunologists). This is an important finding since it provides a possible target for future efforts to control IL-10 production in vivo. (D) We have also shown that IL-2 message is present in 92% of RNA extracts of the PEC, whereas IFN- message was present in only 22% of cases. Our findings suggest that T cells may only be partially activated in vivo. (E) We have therefore looked for other factors that may account for incomplete T cell activation in vivo. We have identified a population of cells that are phenotypically characteristic of dendritic cells, however, these cells lack CD80 or have low expression of CD80 and have other features suggesting immaturity. (F) Based on our findings that MHC antigens can be upregulated by IFN- although expression of the B7.1 costimulatory antigens are deficient, we are exploring the effects of a gene modified autologous tumor vaccine in a new clinical trial. The vaccine is derived from autologous tumor cells that have been infected with a canarypox vector that encodes the gene for CD80. Fresh tumor cells have been pretreated with IFN- and then infected with the ALVAC-hB7.1 vector (Pasteur Merieux). We have observed an increase in MHC, CD80 and ICAM. These characteristics in an autologous vaccine should favor more complete activation of T cells in vivo. The clinical trial design has been approved by the RAC, the NCI and the FDA and accrual has started. It is anticipated that some of the patients will be treated in the UCRC. (G) In a separate trial which is being conducted at the UCRC, we are studying the effects of IP rIL-12, a novel cytokine that can direct immune responses in favor of TH1 effects (this has a potential to drive differentiation of precytotoxic CTL to cytotoxic CTL). We are presently at the second dose level and pharmacologic as well as immunologic studies are being conducted in association with this trial. (H) If both of these trials attain separate objectives, consideration will be given to the combination of IL-12 with ALVAC-hB7.1 in a future clinical trial. (I) We have also initiated several studiess in our laboratory to determine of we can control the production of the immunosuppressive molecules, TGF- and IL-10. These include antisense oligonucleotides combined with liposomal formulation, and secondly the use of small molecules from the aromatic fatty acid group that which we have shown can reduce production of TGF-B . (J) Finally, a clinical program is being developed at M. D. Anderson Cancer Center to address IP therapy issues in general. This program will deal with more fundamental issues such as drug penetration, drug concentration in tissues and its goal is to obtain improved outcomes with IP therapies based on better understanding of pharmacodynamic principles.
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