Antisense oligonucleotides as inhibitors of genes that regulate AP-1: pharmacology and clinical development.
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Clinical Trials, Phase II as Topic↗
Biomedical subjects
J Holmlund
Publications and source records attributed to J Holmlund.
Antigen-specific agents in development.
Differences in antigen expression between tumor cells and normal cells can be exploited to develop a variety of therapeutic anticancer agents. For example, vaccines containing tumor antigens can be administered to patients to elicit an immune-mediated attack against the tumor. Tumor antigens can also be targeted by passive transfer of monoclonal antibodies (MoAbs), or MoAbs that have been modified to carry toxin molecules. A large number of these antigen-specific agents are currently in clinical or late preclinical development. For the anticancer vaccines, much of the current development is focused on determining optimum immunization approaches. In the case of antibody-based reagents, second- and third-generation constructs are being developed to improve potency, decrease immunogenicity, and increase distribution to tumor.
Animals↗
A phase I randomized study of subcutaneous adjuvant IL-2 in combination with an autologous tumor vaccine in patients with advanced renal cell carcinoma.
We performed a prospective, randomized study to determine whether subcutaneous administration of interleukin-2 (IL-2) in combination with an autologous renal cell vaccine is feasible and can potentiate antitumor immunity. Seventeen patients with metastatic renal cell carcinoma underwent surgical resection with preparation of an autologous tumor cell vaccine. Patients were vaccinated intradermally twice at weakly intervals with 10(7) irradiated tumor cells plus bacillus Calmette-Guérin, and once with 10(7) tumor cells alone. Patients were randomized to one of three groups: no adjuvant IL-2, low-dose IL-2 (1.2 x 10(6) IU/m2), or high-dose IL-2 (1.2 x 10(7) IU/m2). IL-2 was administered subcutaneously on the day of vaccination and the subsequent 4 days. Immune response was monitored by delayed-type hypersensitivity (DTH) response to tumor cells as compared with normal autologous renal cells. Sixteen of 17 patients received vaccine therapy. Four patients developed cellular immunity specific for autologous tumor cells as measured by DTH responses; two had received no IL-2 and two had received high-dose IL-2. There were two partial responses (PR) noted, both in patients who received high-dose IL-2. One responding patient was DTH(+) and one was negative. A third patient who was DTH(+) after vaccination with no IL-2 had a dramatic PR after receiving IL-2 subcutaneously in a subsequent protocol. Prospective testing of response to recall antigens indicated that only 5 of 12 tested patients were positive, including both clinical responders. These data suggest that subcutaneously administered adjuvant IL-2 does not dramatically augment the immunologic response to autologous renal cell vaccines as determined by the development of tumor-specific DTH response.
Adjuvants, Immunologic↗
Phase I study of subcutaneously administered interleukin-2 in combination with interferon alfa-2a in patients with advanced cancer.
PURPOSE: Although high-dose interleukin-2 (IL-2) can produce durable remissions in a subset of responding patients with renal cell carcinoma (RCC), this occurs in the setting of significant toxicity. The purpose of this study is to define the maximum-tolerated dosage (MTD) of IL-2 and interferon alfa-2a (IFN alpha-2a) that can be administered chronically on an outpatient basis. PATIENTS AND METHODS: Fifty-three patients with advanced cancer of variable histology with good prognostic features were treated in six cohorts. Patients in cohorts one through five received IL-2 (1.5 or 3.0 x 10(6) million units (mU)/m2) Monday through Friday and IFN alpha-2a (1.5 or 3 x 10(6) mU/m2) daily for a 4-week cycle. In cohort six, IFN alpha-2a was given three times a week. Immunologic monitoring, including serum levels of soluble IL-2 receptor (sIL-2R) and neopterin, flow cytometry, and natural killer cell (NK) activity, were measured. Patients were evaluated for toxicity, response, and survival. RESULTS: Almost all patients developed grade I/II toxicities commonly associated with cytokine therapy. Symptoms were most severe with the first treatment of each week. Dose-limiting toxicities included grade III fatigue, hypotension, and creatinine elevations. The MTD was 1.5 mU/m2 daily x 5 given subcutaneously repeated weekly for IL-2 and 1.5 mU/m2 daily subcutaneously (dose level 3) for IFN. Six of 25 assessable patients with RCC (24%) achieved a partial response (PR), including four of eight patients who were previously untreated. There were no objective responses in patients with other tumors, including 12 melanoma patients. CONCLUSION: IL-2 and IFN alpha-2a can be given with tolerable toxicities on an outpatient basis and shows significant activity in patients with metastatic RCC.
Adult↗
Treatment of cancer patients with ex vivo anti-CD3-activated killer cells and interleukin-2.
PURPOSE: This study describes the physiologic and biologic effects resulting from the adoptive transfer of ex vivo anti-CD3-stimulated T-killer cells (T-AK) to patients with advanced cancer in combination with interleukin-2 (IL-2). METHODS: Autologous peripheral-blood mononuclear cells were obtained by leukapheresis and stimulated ex vivo with anti-CD3. The stimulated cells were reinfused at one of three dose levels on the next day (5 x 10(9), 7.5 x 10(9), and 1 x 10(10)). Cell administration was followed by IL-2 given by bolus and continuous infusion (1.5 x 10(6) U/m2 and 3.0 x 10(6) U/m2, respectively) for 7 days, or continuous infusion alone (3.0 x 10(6) U/m2) for 14 days. RESULTS: Pronounced leukocytosis and atypical lymphocytosis were observed with individual values as high as 80,000 and 50,000 cells/microL, respectively. The other major clinical sequelae included a marked lactic acidosis with bicarbonate levels as low as 4.0 mmol/L in some patients, and prolongation of the prothrombin time (PT) and partial thromboplastin time (PTT) due to decreases in clotting factors VII, IX, and X. Antithrombin III levels were also reduced. Hypotension associated with increased serum nitrate and neopterin levels was observed. These toxicities were accompanied by increases in hepatocellular enzymes and creatinine previously described with IL-2. These events occurred at a time when the number of circulating T-AK cells reached their peak. The amount of bolus IL-2 correlated with increases in WBC count (P = .0311), atypical lymphocytes (P = .0241), PT (P = .0006), and PTT (P = .0122). CONCLUSION: Substantial in vivo expansion of activated T lymphocytes was induced by a protocol combining ex vivo activation of peripheral-blood cells with anti-CD3 antibody followed by adoptive transfer and IL-2 administration. The synchronous expansion of these T cells superimposed on diminished liver and kidney function from IL-2 can cause profound but reversible metabolic changes.
Acidosis↗
Low-dose multidrug chemotherapy plus Pneumocystis carinii pneumonia prophylaxis for HIV-related Kaposi's sarcoma.
Treatment of advanced HIV-related Kaposi's sarcoma (KS) with combination chemotherapy yields a high tumor regression rate but also a high incidence of opportunistic infections (OIs), most notably Pneumocystis carinii pneumonia (PCP). We attempted to maintain a high response rate and minimize the likelihood for developing PCP by designing a flexible low-dose weekly multidrug chemotherapy regimen that alternates two myelotoxic with one to two nonmyelotoxic drugs, concurrently with prophylactic aerosolized pentamidine. Eighteen homosexual men were treated, all of whom had had prior OIs or exhibited advanced mucocutaneous or visceral disease and/or systemic symptoms. In 17 evaluable patients, 16 partial responses but no complete responses were observed (objective response rate = 94%). Median time to response and response duration were 2 and 8 months, respectively. Toxicity was limited to a reversible sensory neuropathy in three patients, and five required blood transfusions. With a median follow-up time of 17 months, two cases of PCP and six other OIs occurred. Overall median survival was 12 months, with most of the deaths (8 of 14) secondary to recurrent KS. Weekly low-dose multidrug chemotherapy + PCP prophylaxis yields a high response rate but high relapse rate, a low incidence of PCP, and comparable or better survival to other regimens not employing PCP prophylaxis. Our results suggest that the optimal combined modality approach for patients with advanced HIV-KS should include a more intensive multidrug chemotherapy regimen in combination with a vigorous, broad-scoped prophylactic regimen for PCP and other potential OIs.
Administration, Inhalation↗