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-γ), 6 patients by the i.m. and 5 patients by the i.v. route of administration. Dose ranges within each individual were from 0.05 mg/m 2 of IFN (1 mg≥10×10 6 units of IFN) escalating to 10 mg/m 2 . All dosages were delivered twice weekly and the i.v. dose was infused over 5 min. The most common toxicities encountered included fever, chils, fatigue, anorexia, and granulocytopenia. The influenzalike symptoms were very similar to those encountered with IFN-α but were generally less severe. The granulocytopenia was dose-related and transient with recovery generally seen within 48–72 h following administration of rIFN-γ. Absolute granulocyte counts only rarely dropped below 1000 mm 3 . Hepatotoxicity was not observed. IFN levels were determined by both a bioassay and an enzyme-linked immunosorbent assay. By the i.v. route, the peak level of IFN activity could usually be seen at completion of the infusion with a serum half-life of 30 min. By the i.m. route, the peak level of serum activity was generally detected between 4–8 h with a serum half-life of 4.5 h after the initial elimination phase. Peak IFN levels appeared to correlate with maximum toxicity. One patient with melanoma had a 25% reduction in a cutaneous lesion, but there were no other minimal, partial, or complete responses.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46852/1/262_2004_Article_BF00205575.pd

Role of Interferons in the Thearpy of Melanoma

A range of potent immunoregulatory molecules termed cytokines has become available for the therapy of human melanoma. Among the cytokines, the interferons (IFN) have been examined in great depth for the therapy of melanoma. IFN are able to modulate host effector cell function, including the tumor cytolytic function of lymphocytes and monocytes. IFN also have the capacity to regulate the distribution of circulating immunoregulatory (T) lymphocytes and the expression of tumor cell surface antigens, as well as class I and II products of the major histocompatibility locus. These activities of the IFN have led to their early application for treatment of human melanoma. The empirical evidence that IFN alpha exerts clinically significant anti-tumor effects against melanoma is reviewed, and evolving status of adjuvant trials of IFN alpha and gamma is noted. New indirect host-mediated anti-tumor activities that may potentially be manifest by IFN have yet to be fully harnessed. The opportunity to obtain meaningful anti-tumor activity in advanced disease or adjuvant settings, at dose ranges below those which are toxic (conventional maximal tolerable), are at hand. The U.S. cooperative groups [Eastern Cooperative Oncology Group (ECOG), Cancer and Leukemia Group B (CALGB), and South West Oncology Group (SWOG)] are studying IFN gamma in pursuit of this goal in advanced and adjuvant settings for melanoma and other tumors. The determination of the clinical role of IFN as biologic response modifiers demands equal commitment to the clinical assessment of immunobiologic mechanisms and anti-tumor effects. The immunologic assessment of IFN and a number of other cytokines cytokines such as interleukin-2 (IL-2) may be the most appropriate and is a major focus of the Pittsburgh Cancer Institute.Regional delivery of least toxic approach, given their half-life. Regional therapy by the intralesional route has yielded enhanced activity for a range of biologics, including bacillus Calmette-Guerin (BCG), IL-2, and tumor necrosis factor (TNF). Intralymphatic therapy with methanol extraction residue of BCG (MER-BCG) has been tested, and trials are now in progress with IL-2 to assess the optimal dosage by this route.It is likely that the optimal role of IFN and other cytokines will be found in combination with one another, and with different biologic modalities such as monoclonal antibodies and vaccines, to allow expansion and heightened activity of the desired effector cell populations in the host. Enhanced host toxicities, as well as anti-tumor effects, may require that special attention be devoted to optimal sequence of administration to enhance the therapeutic index

Alpha interferon in the treatment of hematologic malignancies

The interferons are an important first member of a family of biologic response-modifiers used in treating human malignancies. Activities associated with the interferons include inhibition of viral replication, influence on cellular protein production, direct antiproliferative effects, and a variety of modulatory effects on the immune response. These regulatory functions of interferon underlie the interest in its use as an anticancer agent. Alpha interferon is the most extensively studied interferon species. Although antitumor activity has been seen both in vitro and in vivo in some solid malignancies, the most impressive responses have occurrred in the hematologic malignancies. More than 90 percent of patients with hairy cell leukemia have a sustained recovery of their peripheral blood cell counts with alpha interferon therapy. Approximately 50 percent of patients with low-grade non-Hodgkin's lymphoma and cutaneous T cell lymphoma demonstrate a response to alpha interferon. More than 80 percent of patients with chronic myelogenous leukemia have a response to alpha interferon, and in one study, nearly half of the patients with response had complete suppression of the Philadelphia chromosome clone on at least one examination. Ongoing clinical trials are addressing such issues as optimal dosage, duration of alpha interferon therapy, and combinations of alpha interferon with other biologic agents, chemotherapy drugs, and radiation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26440/1/0000528.pd

Experiences with Leukocyte Adherence Inhibition in Human Cancer

The original hemocytometer leukocyte adherence inhibition technique has been used to study immunological reactivity of patients with a variety of tumors. Cellular activity was closely correlated with exposure to tumor of the appropriate type. Specificity and sensitivity in terms of having few false positives and false negatives were of the order of 90% or greater, and repeated testing of the same patients showed a high degree of reproducibility. Patients with tumors showed specific leukocyte reactivity at all stages of tumor growth, and there was no “eclipse” phase even in very advanced disease

Cell-mediated immunity and specific serum factors in human cancer: The leukocyte adherence inhibition test

Blood leukocytes from patients with cancer (malignant melanoma; adenocarcinoma of colon, rectum, and breast) reacted with aqueous extracts of tumors of the corresponding type, with the result that adherence of the leu kocytes to glass was diminished. Leukocytes from normal individuals did not react. The leukocyte adherence inhibition (LAI) test could be completed in a few hours. Sera from tumor-bearing patients blocked the LAI reaction of their own leukocytes or leukocytes from other patients with the same type of tumor. Serum blocking activity was lost soon after surgical removal of the tumor; the patient’s serum then became unblocking. The LAI technique gave consistent results in a series of patients, analogous to those reported with the lymphocyte cytotoxicity test, and was easier and quicker

Quantitation of anti-tumor cell-mediated immunity by a lymphokine-Dependent reaction using small volumes of blood

A two-stage modification of the leucocyte adherence inhibition (LAI) test is described, which quantitates cell-mediated immunity (CMI) in vitro with 0.5-ml samples of blood from mice exposed to methylcholanthrene-induced tumors. The total blood cells are washed and incubated for 30 min with tumor antigen, then centrifuged, and the supernatant assayed in the LAI test with normal peritoneal cells. The first stage of the reaction depends on the rapid formation of a soluble mediator which appears to be a lymphokine. By this method, the daily changes in specific CMI were followed in individual mice after syngeneic tumor transplantation