Immunomodulatory properties and toxicity of interleukin 2 in patients with cancer.

We performed a phase Ia/Ib study of interleukin 2 (IL2) in patients with cancer. Single doses of IL2 from 10(3) units/m2 to 10(7) units/m2 were well tolerated but failed to induce significant immunological changes. Chronic IL2 treatment for 5 days out of 7 for 3 weeks was well tolerated at doses below 10(7) units/m2 and was accompanied by significant immunological changes.

Intraperitoneal lymphokine-activated killer cell/interleukin-2 therapy in patients with intra-abdominal cancer: immunologic considerations.

Lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2) were administered by the ip route to patients with intra-abdominal malignancies. Pharmacokinetic studies of IL-2 revealed 10- to 100-fold higher concentrations of IL-2 in peritoneal fluid versus serum. Ip levels of IL-2 were maintained well above those required to generate and maintain LAK cells in vitro.

Lymphocyte subset distribution and natural killer activity in growth hormone deficiency before and during short-term treatment with growth hormone releasing hormone.

Natural killer (NK) cell activity was assessed in the peripheral blood of 20 patients with growth hormone (GH) deficiency due to a hypothalamic deficit of GH-releasing hormone (GHRH). All patients failed to respond to at least two provocative tests of GH secretion (GH below 7 ng/ml) but responded to a single GHRH iv bolus injection (1 microgram/kg body wt). In 14 of the 20 patients (20 determinations), lymphocyte subsets were also measured; in all patients the distribution of lymphocyte subsets was within the normal range.

Serum soluble IL-2 receptor as a tumor marker in patients with hairy cell leukemia.

Activated T cells synthesize and express a cell membrane-bound receptor for interleukin-2 (IL-2) and have recently been shown to secrete a soluble form of the same receptor. Hairy cell leukemia is a chronic disorder caused by expansion of a clonal population of an unusual mononuclear cell of B cell origin. These cells have previously been shown to express an IL-2 receptor on the cell membrane.

The determination of an immunologically active dose of interferon-gamma in patients with melanoma.

This study was undertaken to determine an immunologically active regimen for the administration of recombinant gamma-interferon (rIFN-gamma). The patient population included patients with completely resected melanoma, stage I (Clark's level IV or V) or stage II. All patients exhibited no evidence of disease (NED) at the time of the study.

Lymphokine-activated killer cells: culture conditions for the generation of maximal in vitro cytotoxicity in cells from normal donors.

The current method for generating lymphokine-activated killer (LAK) cells for use in human clinical trials is both labor intensive and expensive. Therefore, we altered cell culture conditions to determine whether LAK cells with enhanced lytic activity could be generated. Culture of normal human peripheral blood leukocytes for 7 days generated LAK cells with 4-fold more lytic activity than culture for 3 days.

The effect of acute and chronic leukapheresis on the natural killer (NK) cell function of normal human volunteers.

Twenty-two normal volunteers had approximately eight, 2-hr-long leukapheresis procedures over a 2-year period and their natural killer (NK) cell function was prospectively measured. The NK activity of the preprocedure peripheral blood (pre-PB) was found to correlate well with the NK activity of the inital leukocytes removed by leukapheresis (I-Leuk). When the I-Leuk specimens were compared with the leukapheresis specimens removed at the termination of leukapheresis (T-Leuk), T-Leuk showed a consistent 10% increase in NK activity.

Alterations in cytotoxic and helper T cell function after infection of T cell clones with human T cell leukemia virus, type I.

HTLV-I is a transforming human retrovirus that is an etiologic agent of adult T cell leukemia/lymphoma. To investigate the effects of this virus on T cell functions, two OKT3+, OKT4+, OKT8- cytotoxic clones (8.7 and 8.

Relationship of the clinical response and binding of recombinant interferon alpha in patients with lymphoproliferative diseases.

Patients with hairy cell leukemia (HCL) and chronic lymphocytic leukemia (CLL) were treated with recombinant interferon alpha A (rIFN-alpha A). The binding of iodinated recombinant interferon-alpha to baseline samples of peripheral blood mononuclear cells (PBMCs) from the leukemia patients was compared with clinical responsiveness to rIFN-alpha A. HCL patients (8/10) responded to rIFN-alpha A therapy, whereas none (0/10) of the CLL patients studied responded.

Recombinant leukocyte A interferon therapy for advanced hairy cell leukemia. Therapeutic and immunologic results.

Hairy cell leukemia is a lymphoproliferative disorder characterized clinically by cytopenias. Standard therapy following variable periods of disease stability consists of splenectomy that often restores normal hematologic parameters for periods ranging from weeks to years. Fifteen patients (five without prior splenectomy or chemotherapy) were treated with 3 X 10(6) units per day of recombinant leukocyte A interferon and 14 of 15 patients completed eight weeks of therapy and were evaluated for response.

Comparative evaluation of multiple lymphoid and recombinant human interleukin-2 preparations.

Six lymphoid human interleukin-2s (nIL-2s) [four from peripheral blood mononuclear cells (PBMC) and two from JURKAT cells] and six recombinant IL-2s (rIL-2s) were obtained for comparative evaluation. The main issues addressed were possible differences among the preparations in potency in T cell growth assays and other functional assays, and the possible presence of other cytokine activities or contaminants. Each preparation was assigned a standardized IL-2 activity in reference units (RU) by comparing its T cell growth promoting activity against the Biological Response Modifiers Program IL-2 (JURKAT) reference reagent.

Immunological monitoring of clinical trials using biological response modifiers.

Phase I clinical trials of Biological Response Modifiers must be designed to provide information not only regarding toxicities, pharmacokinetics and anti-tumor response, but also on their many immunomodulatory properties. If BRMs are to be used rationally, then detailed standardized data must be obtained in such a way as to enable meaningful conclusions to be drawn from the monitoring assays. Assay selection, timing for monitoring and methods for data interpretation are important considerations in the design of such trials.

Immunomodulatory effects of poly(I,C)-LC in cancer patients.

Poly(I,C)-LC was administered in low (1 mg/m2) and intermediate (4 mg/m2) doses to cancer patients by intramuscular injection or intravenous infusion to evaluate the immunomodulatory effects. Natural killer cell (NK) activity was elevated slightly at the low dose and remained unchanged overall, but some depression was observed at the 4 mg/m2 intravenous dose. Monocyte function was elevated in all groups of patients, as was the interferon-induced enzyme 2'5'-oligo-A synthetase.

Assessment of biological responses: what to measure and when.

During the past several years, increasing attention has been devoted to the use of biological response modifiers (BRMs) for the treatment of cancer. Phase I trials of BRMs must be designed to provide information not only regarding toxic effects, pharmacokinetics, and antitumor activities, but also on the many immunomodulatory effects. Biological monitoring must be carefully planned to enable meaningful conclusions to be drawn as to the optimal dose, schedule, and route of administration.

Hyporesponsiveness to augmentation of murine natural killer cell activity in different anatomical compartments by multiple injections of various immunomodulators including recombinant interferons and interleukin 2.

Augmentation of natural killer (NK) cell activity has been observed after the single administration of a wide variety of biological response modifiers (BRM); however, multiple injections of BRM have resulted in hyporesponsiveness to NK augmentation in both preclinical and clinical studies. In these studies, hyporesponsiveness to augmentation of NK cell activity occurred after multiple injections of interferon (IFN recombinant human IFN-alpha A/D and recombinant IFN-gamma) and interleukin 2 and was found to be systemic (lungs, liver, blood, and spleen). In contrast, hyporesponsiveness to augmentation by multiple injections of maleicanhydride divinyl ether (MVE-2) or Propionibacterium acnes was limited to the spleen and peripheral blood lymphocytes, with continued augmentation of NK cell activity in the peritoneum, lungs, and liver.

Prognostic risk assessment in primary breast cancer by behavioral and immunological parameters.

Although findings from recent animal studies suggest that behavioral factors such as "helplessness" play a role in cancer progression, very few such studies with humans have been carried out. The study investigated the predictive power of an immunologic effector cell, the natural killer (NK) cell, as well as selected psychological and demographic factors, to breast cancer prognostic risk status. It was found that NK activity predicted the status of cancer spread to the axillary lymph nodes.

A phase I trial of recombinant gamma interferon in patients with cancer.

A total of 11 patients were treated on an escalating, single dose trial of recombinant gamma interferon (rIFN-gamma), 6 patients by the i.m. and 5 patients by the i.

A preliminary Phase I trial of partially purified interferon-gamma in patients with cancer.

Thirty-three patients were treated in an escalating single-dose trial of partially purified nonrecombinant interferon-gamma (IFN-gamma). The first seven patients received intramuscular injections of IFN-gamma in doses up to 20 X 10(6) units/m2. When it became clear that these patients had no detectable antiviral activity in their serum, subsequent patients were treated by the intravenous route of administration, generally with 2-h infusions.

Immunomodulation and antitumor effects of MVE-2 in mice.

The biological response modifier maleic anhydride-divinyl ether (MVE-2) can activate natural killer (NK) cells and macrophages and can act as an immunoadjuvant for T and B cells. MVE-2 activates macrophages following intravenous or intraperitoneal injection in a compartmentalized manner, i.e.

Response of warts in epidermodysplasia verruciformis to treatment with systemic and intralesional alpha interferon.

The susceptibility of human papillomavirus infection to polyclonal human leukocyte interferon (IFN-alpha) has been evaluated in patients with epidermodysplasia verruciformis (EV), a disease with extensive chronic papillomavirus-induced warts. In a double-blind, placebo-controlled study with intralesional IFN-alpha, four of five IFN-alpha-treated warts regressed; none of the placebo-treated warts responded (p = 0.024).

A system for obtaining large numbers of cryopreserved human monocytes purified by leukapheresis and counter-current centrifugation elutriation (CCE).

A system has been developed for the isolation of large numbers of unfractionated mononuclear cells from single, well characterized normal individuals and for the separation by elutriation of these cells into populations of greater than 90% pure monocytes and greater than 99% pure lymphocytes. The total number of monocytes obtained from a single donor averaged about 550 million. After cryopreservation and thawing of these cells, the viability remained greater than 90%, 80% of original cells were recovered, and the ability to ingest antibody-coated targets was comparable to that of fresh monocytes.