A retroviral vector-mediated gene transfer system was used to introduce m gamma-IFN and h gamma-IFN genes into mouse and human tumor cells, respectively. Murine tumor cell lines and primary human melanoma tumor cells were successfully transduced with gamma-IFN vector, and these transduced cells secreted measurable levels of biologically active m gamma-IFN and h gamma-IFN, respectively. Both murine and human tumor cell lines that expressed gamma-IFN exhibited increased surface expression of HLA class I antigens when tested by Western blot and FACS analysis. gamma-IFN--transduced human melanoma cells were more active in stimulating tumor-specific cytolytic activity of CTLs from melanoma patients in vitro. m gamma-IFN--transduced tumor cells were substantially less tumorigenic than the corresponding parent tumor cell lines in immune-competent mice. In addition, injection of m gamma-IFN--transduced tumor cells resulted in activation of tumor-specific CTL in vivo. We plan to use gamma-IFN--transduced autologous tumor cells to boost host immune responses as a potential therapy for human melanoma.
We examined the human anti-mouse antibody (HAMA) response in 61 cancer patients following a single, diagnostic injection of any one of ten 111In conjugated murine monoclonal antibodies. Between 1 and 22 mg of antibody containing 1-5 mCi 111In was administered. The populations studied included 30 patients with colorectal carcinoma (four different antibodies), 22 with malignant melanoma (four antibodies), and nine with prostate cancer (two antibodies). Forty-one percent of the patients developed HAMA within 14 days. Three patients (5%) developed an IgM response, five patients (8%) developed an IgG response, and 17 patients (28%) developed both IgM and IgG. Only 27% of the patients with colon cancer developed HAMA, compared to 55% of the melanoma patients and 56% of the prostate cancer patients. There were no correlations among injected dose, various clinical parameters, and HAMA response. There were variations in the HAMA response to different monoclonal antibodies, but population samples were too small to infer significance. Most of the HAMA responses had a significant proportion of idiotypic or isotypic specificity. Only 1/6 patients who were HAMA negative after the first infusion developed HAMA following subsequent infusions of the same monoclonal antibody. Our data demonstrate that a significant percent of cancer patients develop HAMA following a single, low-dose injection of a radiolabeled monoclonal antibody for diagnostic purposes. This may have important implications for the future therapeutic use of monoclonal antibodies in such patients.
The emergence of new therapeutic modalities frequently requires development of relevant laboratory assays. This is especially true for the clinical uses of newly developed reagents such as murine monoclonal antibodies. We have described immunofluorescence, immunohistochemical, and enzyme‐linked immunosorbent assays (ELISA) for monitoring anticancer therapy with monoclonal antibodies. Immunofluorescence assays performed on single cell suspensions and immunohistochemical assays performed on freshly frozen biopsy tissue have confirmed tissue reactivity of the monoclonal antibody prior to infusion and have been used to measure in vivo antibody binding to target cells as well as antigenic modulation during therapy. An ELISA has been used to measure the serum concentrations of monoclonal antibodies; another ELISA has been used to detect the presence of human antibodies reactive with murine monoclonal antibody. These reproducible assays can be performed with commercially available reagents and provide an important data base for making clinical decisions concerning therapy with monoclonal antibodies.
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