Purpose To determine the ability to induce tumor-specific immunity with individual mutant K-ras- or p53-derived peptides and to monitor clinical outcome.Patients and Methods Patients in varying stages of disease underwent genetic analysis for mutations in K-ras and p53. Thirty-nine patients were enrolled. Seventeen-mer peptides were custom synthesized to the corresponding mutation. Baseline immunity was assessed for cytotoxic T-lymphocyte (CTL) response and interferon gamma (IFN-gamma) release from mutant peptide-primed lymphocytes. Patients' peripheral-blood mononuclear cells were pulsed with the corresponding peptide, irradiated, and applied intravenously. Patients were observed for CTL, IFN-gamma, interleukin (IL)-2, IL-5, and granulocyte-macrophage colony-stimulating factor responses, for treatment-related toxicity, and for tumor response.Results No toxicity was observed. Ten (26%) of 38 patients had detectable CTL against mutant p53 or K-ras, and two patients were positive for CTL at baseline. Positive IFN-gamma responses occurred in 16 patients (42%) after vaccination, whereas four patients had positive IFN-gamma reaction before vaccination. Of 29 patients with evident disease, five experienced a period of stable disease. Favorable prognostic markers were detectable CTL activity and a positive IFN-gamma reaction but not IL-5 release. Median survival times of 393 v 98 days for a positive versus negative CTL response (P = .04), respectively, and of 470 v 88 days for a positive versus negative IFN-gamma response (P = .02), respectively, were detected.Conclusion Custom-made peptide vaccination is feasible without any toxicity. CTL and cytokine responses specific to a given mutation can be induced or enhanced with peptide vaccines. Cellular immunity to mutant p53 and K-ras oncopeptides is associated with longer survival.

Adult T-cell leukemia/lymphoma (ATL) is frequently a very aggressive malignancy with a poor survival despite aggressive multiagent chemotherapy. The combination of the antiretro-viral drug zidovudine (AZT) and interferon alpha (IFNα) has been reported to induce remissions in patients with ATL. The purpose of this study was to evaluate the clinical response and toxicity following administration of a combination of IFNα-2b and AZT in patients with human T-cell lymphotropic virus type I (HTLV-I)-associated ATL. Eighteen patients with ATL (chronic, crisis, acute or lymphoma type) were treated with the combination of AZT (50–200 mg orally 5 times a day) and IFNα-2b (2.5–10 million units subcutaneously daily). Three patients had objective responses lasting more than one month. One patient had a clinical complete remission, lasting 21.6 months and two patients had partial remissions lasting 3.7 and 26.5 months. Six patients were not considered evaluable for response due to short and/or interrupted periods of treatment. Seventeen patients have died with a median survival time after initiation of therapy of 6 months. Neutropenia and thrombocytopenia were the dose limiting toxicities. In conclusion, the response rate in this study was lower than noted in the two previous published series. This may be due to the amount and type of prior treatment our patients had received.

UNLABELLED Monoclonal antibodies (MoAb) labeled with 90Y are being used for radioimmunotherapy. Because 90Y is a beta emitter, quantitative information from imaging is suboptimal. With the concept of a "matched pair" of isotopes, 111In is used as a surrogate markerfor90Y. We evaluated the differences in biodistribution between 111In- and 90Y-labeled murine antiTac MoAb directed against the IL-2Ralpha receptor. METHODS The antiTac was conjugated to the 2-(4-isothiocyanatobenzyl)-6-methyl-diethylenetriamine pentaacetic acid (1B4M-DTPA, also known as MX-DTPA). Nine patients with adult T-cell leukemia were treated. Patients received approximately 185 MBq (5 mCi) 111In-labeled antiTac for imaging and 185-555 MBq (5-15 mCi) 90Y-labeled antiTac for therapy. The immunoreactivity of 111In-labeled antiTac was 90%+/-6%, whereas for 90Y-labeled antiTac, it was 74%+/-12%. RESULTS The differences in blood and plasma kinetics of the two isotopes were small. The area undemeath the blood radioactivity curve was 1.91 percentage+/-0.58 percentage injected dose (%ID) x h/mL for 111In and 1.86%+/-0.64 %ID x h/mL for 90Y. Urinary excretion of 90Y was significantly greater than that of 111In in the first 24 h (P = 0.001), but later, the excretion of 111In was significantly greater (P = 0.001 to P = 0.04). Core biopsies of bone marrow showed a mean of 0.0029+/-0.0012 %ID/g for 111In, whereas the 90Y concentration was 0.0049+/-0.0021 %ID/g. Analyses of activity bound to circulating cells showed concentrations of 500-30,000 molecules of antiTac per cell. When cell-bound activity was corrected for immunoreactive fraction, the ratio of 111In to 90Y in circulating cells was 1.11+/-0.17. Three biopsies of tumor-involved skin showed ratios of 111In to 90Y of 0.7, 0.9 and 1.1. CONCLUSION This study shows that differences typically ranging from 10% to 15% exist in the biodistribution between 111In- and 90Y-labeled antiTac. Thus, it appears that 111In can be used as a surrogate marker for 90Y when labeling antiTac with the 1 B4M chelate, although underestimates of the bone marrow radiation dose should be anticipated.

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disease that results from an interaction of retroviral infection and immune activation. In this study, five doses (1 mg/kg) of humanized anti-Tac antibody were administered to 9 HAM/TSP patients at weeks 0, 2, 6, 10, and 14. Preliminary immunological studies on HAM/TSP patients treated with humanized anti-Tac indicate that there is a selective down-regulation of activated T cells and a decrease in the HTLV-I viral load in peripheral blood lymphocytes, most likely through the selective removal of HTLV-I-infected, activated CD4(+) lymphocytes.

Adult T-cell leukemia (ATL) is a malignancy of mature lymphocytes caused by the retrovirus human T-cell lymphotropic virus-I. It is an aggressive leukemia with a median survival time of 9 months; no chemotherapy regimen appears successful in inducing long-term disease-free survival. The scientific basis of the present study is that ATL cells express high-affinity interleukin-2 receptors identified by the anti-Tac monoclonal antibody, whereas normal resting cells do not. To exploit this difference, we administered anti-Tac armed with Yttrium-90 (90Y) to 18 patients with ATL initially (first 9 patients) in a phase I dose-escalation trial and subsequently (second group of 9 patients) in a phase II trial involving a uniform 10-mCi dose of 90Y-labeled anti-Tac. Patients undergoing a remission were permitted to receive up to eight additional doses. At the 5- to 15-mCi doses used, 9 of 16 evaluable patients responded to 90Y anti-Tac with a partial (7 patients) or complete (2 patients) remission. The responses observed represent improved efficacy in terms of length of remission when compared with previous results with unmodified anti-Tac. Clinically meaningful (> or = grade 3) toxicity was largely limited to the hematopoietic system. In conclusion, radioimmunotherapy with 90Y anti-Tac directed toward the IL-2R expressed on ATL cells may provide a useful approach for treatment of this aggressive malignancy.

Background. Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T-cells occurring in patients infected with the human T-cell lymphotropic virus-I. These patients frequently develop a variety of infections throughout their disease course.Methods. Charts and autopsy reports were reviewed for 41 patients with ATL with follow-up varying from 2 to 120 months. Infectious episodes were identified and documented. Analyses of humoral and cell-mediated immunity were performed. Cell-mediated immunity was assessed in vivo with the Merieux multitest skin test panel. Humoral immunity was assessed by quantitative immunoglobulin levels, by determining human antimouse antibody after murine monoclonal antibody infusion acid by an in vitro immunoglobulin biosynthesis coculture system.Results. A total of 112 infectious episodes were documented. Fifty-seven serious infections were identified. The incidence of total infections was 1.40/patient-year and for serious infections was 0.71/patient-year. The mean serum IgG and IgA levels were within normal range, the mean IgM level was at the lower limit of normal. Peripheral blood mononuclear cells from all patients studied failed to make meaningful amounts of IgG, M, or A when activated. Peripheral blood mononuclear cells of all of the 13 patients studied suppressed production of immunoglobulin by cocultured normal PBMC. Twenty-three of the 27 patients tested were anergic.Conclusions. ATL is a profoundly immunosuppressing malignancy. This is manifested by an extremely high incidence of infectious episodes/patient-year. The incidence of infection appears to be greater than for mycosis fungoides, Hodgkin's lymphoma and non-Hodgkin's lymphoma.