Active immunoprophylaxis and immunotherapy in two mouse lymphoma models.

Injections of appropriate numbers of irradiated tumor cells produced antibodies against tumor cell-surface antigen(s) in both syngeneic tumor models studied: the early transplant generations of the spontaneous L2 lymphoma in AKR/J mice and the chemically induced EL 4 lymphoma in C57BL/6J mice. No antibody was detected in normal or nonimmunized tumor-bearing mice. Tumor inhibitory or enhancing activity was not demonstrated by these antibodies. Immunoprophylaxis or cell-mediated immunity against the L2 lymphoma was not observed after injections of irradiated L2 cells and/or BCG into AKR mice. However, injections of irradiated EL 4 cells alone were effective in immunoprophylaxis against as many as 10(6) EL 4 cells and in immunotherapy against 10(2) EL 4 cells per mouse. The addition of BCG injections made immunotherapy with irradiated EL 4 cells effective against a load of 10(4) EL 4 cells/mouse, though BCG alone was not effective for immunoprophylaxis against EL 4 cells. Resistance to EL 4 could be transferred with viable syngeneic peritoneal or nucleated spleen cells. In both tumor models, an ongoing delayed hypersensitivity reaction to BCG alone apparently did not inhibit bystander tumor cells even when tumor cells were mixed before inoculation with viable BCG. In neither tumor model were concanavalin A-coated tumor cells more potent for immunoprophylaxis than were irradiated tumor cells alone.

Immunochemotherapy of malignant melanoma with chlorambucil-bound antimelanoma globulins: preliminary results in patients with disseminated disease.

Thirteen consecutive patients with inoperable recurrent malignant melanoma were treated by immunochemotherapy with the use of chlorambucil noncovalently bound to goat or rabbit antihuman melanoma globulins. The next consecutive 11 patients fulfilling the criteria for admission into this study were treated with chemotherapy only, i.e., dimethyltriazenoimidazole carboxamide (DTIC). Follow-up was for a minimum of 29 months or until death. Two patients showing an objective response to immunochemotherapy had disease confined to lymph nodes and cutaneous sites; 5 others showed stabilization of cutaneous, nodal, and visceral disease, and 6 patients showed progression of their disease. The median survival of the responders and stabilizers was 20 months, but only 3.5 months for patients with disease progression. None of the 11 patients treated with DTIC had objective tumor regression, and all died within 11 months of the start of treatment with a median survival of 3 months. Immunochemotherapy significantly prolonged the survival compared to that in the DTIC-treated group (P less than 0.05). No hematologic or renal toxicity was detected after immunochemotherapy, but 2 patients in this group developed anaphylactic reactions. Skin reactivity tests to dinitrochlorobenzene and purified protein derivative were of no prognostic value

Imaging of human melanoma xenografts in nude mice with a radiolabeled monoclonal antibody.

External photoscanning with display of radioactivity data as a color-scaled image detected xenografts of human melanoma in male nude inbred mice of BALB/c background 48 hours after injection of 131I-labeled monoclonal IgG 225.28S that is specific for human melanoma. A 131I-labeled polyclonal goat IgG against human melanoma-associated antigens could also image the tumor, but with this preparation there was considerable localization of radioactivity in normal tissues, resulting in less satisfactory tumor definition. Labeled normal mouse IgG did not image the melanoma grafts. Assay of radioactivity in tissues of melanoma-grafted mice confirmed tumor-specific localization of the antimelanoma antibodies. The tumor:blood ratio of radioactivity was 6.55 with the monoclonal antimelanoma IgG and 0.45 with the polyclonal IgG.

Radionuclide imaging of primary renal-cell carcinoma by I-131-labeled antitumor antibody.

A goat antibody against human renal-cell carcinoma reacted on immunofluorescence with renal-cell carcinomas from 20 patients, but not with normal adult human tissues, including kidney. After i.v. administration the I-131-linked antibody showed preferential tumor localization in six of seven patients with primary renal carcinoma. Labeled antitumor antibodies may have the specificity for tumor imaging that current radiopharmaceuticals lack.

Cutaneous malignant melanoma.

In Canada melanoma causes 400 deaths a year, often in young adult patients. Excessive ultraviolet radiation to unprotected skin is an important cause. Certain moles should be removed as a precautionary measure; an experienced clinician can recognize many melanomas. Both microstaging by the pathologist and clinical staging must be carried out before definitive treatment is planned. The only 'curative' treatment is surgical. Any patient so treated requires ten years of careful follow up. The results of chemotherapy for disseminated disease are poor.

Immunochemotherapy of cancer with chlorambucil-carrying antibody.

Cell-surface localizing heterologous antibodies against the mouse EL4 lymphoma and a human malignant melanoma could be bound to chlorambucil without causing the loss of the alkylating activity of chlorambucil or interfering with the reactivity of the antibodies with their respective tumour cells. When given to mice preinoculated with tumour cells 2, 24, 72, and 120 hours before the beginning of treatment the chlorambucil-bound antibody was a much more effective tumour inhibitor than chlorambucil or the antibody alone. In a patient with disseminated malignant melanoma injection of the chlorambucil-bound anti-melanoma antibody first locally into a few metastatic nodules and then by the intravenous route was followed by the regression of all the metastatic nodules.

Prophylactic node dissection for malignant melanoma.

The value of prophylactic node dissection was studied in 147 patients with nonsuperficial malignant melanoma of cutaneous origin; all had clinical stage I disease. Seventy-three patients had prophylactic node dissection and 74 did not. Survival rates were calculated by the actuarial method and were age and sex adjusted. Five-year crude survival rates for these two groups were 62 and 29%, respectively, and the adjusted rates were 70 and 33%, respectively. These significant differences (P less than 0.001) were maintained at 10 years. The difference in survival in the two groups cannot be explained on the basis of age, sex, year of operation, size or location of the primary tumour, or previous incisional biopsy. It is concluded that prophylactic node dissection contributed appreciably to increased survival in this study.

Antibody as carrier of 131I in cancer diagnosis and treatment.

Cell-surface localizing heterologous antibodies against mouse EL4 lymphoma, Ehrlich ascites carcinoma, and several human malignant tumors could be bound to varying amounts of 131I without interfering with the reactivity of these antibodies with their respective tumor cells. Exposure of the mouse tumor cells to radio-iodinated antitumor antibodies in vitro, or the injection of radio-iodinated antitumor antibodies into mice preinoculated with tumor cells resulted in either partial or complete tumor inhibition depending upon the amount of 131I activity carried by the antibodies. Injection of comparable amounts of the immunoglobulin alone or of 131I bound to normal globulin did not cause any tumor inhibition. Intraperitoneally injected radio-iodinated anti-EL4 antibody was found to localize preferentially in the subcutaneous transplants of EL4 lymphoma. Similar localization of intravenously injected radio-iodinated antibodies was observed in the metastases of two cancer patients.