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Biomedical subjects

R K Oldham

Publications and source records attributed to R K Oldham.

At least 145 records · Page 8Linked to original sources
PubMed1984

The NCI preclinical screen of biological response modifiers.

The development of successful approaches to immunotherapy is dependent upon proper consideration of the pathobiology of metastasis and the establishment of a better scientific understanding of the principles of biological response modification. The studies we have undertaken are aimed at the rational development of a preclinical data base to help provide this understanding. Ultimately, these studies will be correlated with clinical trials to assess the predictive value of the preclinical screen. We anticipate that the testing of biological response modifiers (BRMs) in a controlled but evolving system will help eliminate arbitrary decisions on the preparations and use of a given BRM and ultimately will contribute to the development of novel approaches for the treatment of disseminated cancer. Immunotherapy alone or in combination with other therapeutic modalities is an area of rapid evolution with tremendous potential as an adjuvant therapy of disseminated cancer.

Adjuvants, Immunologic↗
PubMed1984

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., peritoneal macrophages (i.p. injection) or alveolar macrophages (i.v. injection). It activates NK cells in vivo but not in vitro, a dichotomy that may be secondary to interferon production. Splenic NK cell activity is not prolonged by the multiple injection of MVE-2; instead, it induces a state of NK cell hyporesponsiveness, which may limit its therapeutic efficiency. Therapeutic properties of MVE-2 are largely limited to nonspecific immunoprophylaxis, which may be associated with NK cell activation but which does not necessarily correlate with the level of splenic NK cell activation. Minimal therapeutic efficiency consisting of a slight prolongation in survival is observed in mice with preexistent disease treated with MVE-2. Prolonged survival is observed only in those animals placed on therapy soon after tumor cell challenge (experimental metastasis) and not in mice with established spontaneous metastasis. The need to manipulate the animal model (MVE-2 injection prior to or rapidly following tumor challenge) seems to predict that this agent is unlikely to be clinically useful against preexistent metastatic tumor burden, although some efficiency may be associated with local treatment into the pleural or peritoneal cavity.

Adjuvants, Immunologic↗
PubMed1984

T65 antigen modulation in a phase I monoclonal antibody trial with chronic lymphocytic leukemia patients.

Antigenic modulation of the T65 cell surface antigen was assessed in chronic lymphocytic leukemia patients (CLL) receiving therapy with the murine monoclonal antibody T101 in a phase I clinical trial. A total of 12 patients received 1, 10, or 40 mg doses administered over 2 hr, or 50 or 100 mg doses administered over 50 hr. Decreases in T65 antigen expression (up to 90%) coincided with decreases in the circulating leukemic cell count in those patients who received T101 over a 2-hr period, indicating that clearance of circulating T65 antigen-positive cells could account for most of the observed decreases in T65 antigen expression. In contrast, analysis of bone marrow specimens from these patients indicated that decreases in T65 antigen density in this relatively stationary population resulted not from a cell decrement but rather from antigenic modulation. Pulmonary toxicity prevented administration of doses greater than 40 mg over a 2-hr period; therefore, higher doses (50 and 100 mg) were administered over a 50-hr period. This treatment schedule resulted in greater than 90% reduction in T65 antigen density of both circulating and bone marrow leukemic cells without dramatic drops in circulating leukemic cell counts, indicating that antigenic modulation accounted for most of the observed decreases in T65 antigen density under these conditions. Reexpression of T65 antigen by modulated cells was observed both in vitro and in vivo within 2 to 4 days. Immunoperoxidase staining of in vivo-modulated specimens and in vitro modulation studies with 125I-T101 suggested that T65 antigen-T101 antibody complexes were internalized during modulation. Although antigenic modulation inhibits the potential therapeutic effectiveness of unconjugated T101 antibody in CLL patients, treatment of CLL with T101 drug or toxin immunoconjugates under conditions that bring about rapid and extensive internalization of the T65 antigen may provide an effective means of therapy.

Antibodies, Monoclonal↗
PubMed1984

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. A total of 26 patients received the agent intravenously in single escalating doses ranging from 0.2 to 60 X 10(6) units/m2, on a twice-weekly schedule for 4-6 weeks. The most common toxicities encountered included fever, chills, fatigue, anorexia, and occasional nausea and vomiting. No myelosuppression or hepatic toxicity was observed. A maximum tolerated dose for single-dose intravenous administration was defined as 50 X 10(6) units/m2 on the basis of unacceptable fatigue and prolonged systolic hypotension. Antiviral activity was detected in the serum following doses greater than 2 X 10(6) units/m2 when the IFN-gamma was administered intravenously. No evidence of antitumor activity was seen in this Phase I trial, although the treatment regimen employed did not lead to high or prolonged levels of serum IFN activity in the majority of patients. An accurate assessment of the antitumor activity of this particular IFN-gamma preparation will require Phase II trials employing multiple-treatment regimens.

Drug Evaluation↗
PubMed1984

Selective antitumor effect on L10 hepatocarcinoma cells of a potent immunoconjugate composed of the A chain of abrin and a monoclonal antibody to a hepatoma-associated antigen.

The toxic A chain of abrin was isolated by affinity chromatography and was demonstrated to be a potent inhibitor of protein synthesis in a cell-free rabbit reticulocyte system with a complete inhibitory dose at 1 X 10(-9) M. This A chain was coupled by a disulfide linkage to a purified monoclonal antibody directed against a tumor-associated antigen found on the line 10 hepatocarcinoma tumor in strain two guinea pigs. The immunoconjugate retained the functions of the individual components, i.e., antigen binding to the intact cell in vitro and inhibition of its protein synthesis. This conjugate was a selective antineoplastic agent with a cytocidal dose at 5 X 10(-9) M toward antigen-bearing cells in vitro. Several antigen-negative cells were much less susceptible to its cytotoxic effect. The cytotoxicity of the conjugate appeared to be by antibody-mediated delivery of toxic A chain into the target cell. When cells were pretreated with excess free antibody followed by a brief exposure to conjugate, there was a reversal of the cytotoxicity to antigen-positive cells but not to the antigen-negative cells. The therapeutic efficacy of the conjugate was assayed by injecting a single dose s.c. or i.v. into syngeneic guinea pigs bearing established line 10 tumors. These in vivo studies showed that (a) the conjugate was not toxic at a dosage of 60 to 1120 micrograms/guinea pig, (b) the conjugate decreased or abolished the growth of established solid tumors, (c) the conjugate delayed or inhibited tumor metastases to lymph nodes, and (d) 20 to 40% of the animals in selective groups had a long-term complete regression.

Abrin↗
PubMed1984

Tumor models to investigate the therapeutic efficiency of immunomodulators.

The development of successful approaches to immunotherapy is dependent on the proper consideration of the pathobiology of metastasis and a better understanding of the principles of biological response modification. Immunomodulation as a therapeutic modality has not proven notably effective in animals with preexistent palpable disease, an observation in agreement with the results from clinical protocols. Therefore, rather than developing experimental immunotherapy models of immunoprophylaxis or models with minimal tumor burden, we believe it more appropriate to develop models based on preexistent metastatic disease in a tumor-conditioned host. The most rigorous test of a biological response modifier's efficiency prior to clinical trials will be provided from immunotherapeutic trials of palpable autochthonous tumors.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

Production of large quantities of human immunoglobulin in the ascites of athymic mice: implications for the development of anti-human idiotype monoclonal antibodies.

Human-murine hybridomas, generated by fusion of human CLL cells with non-Ig-secreting murine myeloma NS-1, and secreting the IgM kappa expressed on the CLL cell surface, were grown in the peritoneal cavity of doubly pristane-primed nude mice to produce large quantities of highly concentrated human IgM kappa for the development of anti-idiotype monoclonal antibodies. Although the hybridomas secreted only 0.8 to 1.5 micrograms/ml/10(6) cells in tissue culture, they produced 8 to 12 ml of ascites from two mice containing 1.7 mg/ml of human IgM. Partial purification was then easily accomplished by euglobulin precipitation. Two weekly injections of 100 micrograms of this material into BALB/c mice resulted in the development of both anti-idiotypic and anti-human IgM antibodies. This system overcomes the major hurdle of generating sufficient quantities of the human idiotypic Ig to immunize and screen for specific murine antiidiotypes, and provides the material to produce these therapeutically promising reagents rapidly for clinical trials. This is, to our knowledge, the first report of a human Ig produced in mouse ascites.

Animals↗
PubMed1984

Practical considerations for the establishment of a screening procedure for the assessment of biological response modifiers.

Studies in therapeutic immunopharmacology have identified a large array of natural and synthetic biological response modifiers (BRM) that can be entered into clinical trials. However, it is obvious that a preclinical screen is needed to limit entry of BRM into Phase I trials to those with the greatest clinical potential. In this article we discuss the development of a preclinical screen for BRM and the necessary attributes for such a screen. During the development of our preclinical screen, we noted numerous immunological and biological criteria crucial to the establishment of relevant and reproducible models of immunomodulation and immunotherapy. These or similar considerations are critical to the development of a strong scientific base needed to establish the principles of biological response modification and to allow their translation into a successful program of clinical immunotherapy.

Animals↗
PubMed1983

Utilization of purified human monocytes in the agarose droplet assay for measuring migration inhibitory factors.

Human monocytes, highly purified by counter-current elutriation, are excellent indicator cells for evaluation of human migration inhibitory factors (MIFs). We have adapted the agarose droplet MIF assay initially developed for guinea pig peritoneal exudate cells to utilize human monocytes. The experimental variables have been evaluated and standardized to make this assay a quantitative and sensitive method for measuring MIF activity. The assay can be performed serum-free in RPMI 1640 medium without protein or hormone additives, thereby increasing the sensitivity and eliminating potential masking of MIF effects by serum components. Cryopreserved monocytes also performed well in this assay, migrating approximately the same distance per unit time and showing migration inhibition in response to inhibitory factors. This assay provides a powerful tool in evaluating MIF-like activities of various lymphokines and factors, and could be used to monitor the activity of fractions produced during the physicochemical separation of MIFs from lymphokine-containing supernatants.

Animals↗
PubMed1983

Monoclonal antibodies in the lymphatics: selective delivery to lymph node metastases of a solid tumor.

After subcutaneous injection, monoclonal antibodies directed against a tumor can enter local lymphatic vessels, pass to the draining lymph nodes, and bind to metastases there. Lymphatic delivery of antibody to early metastases is more efficient than intravenous administration, and the lymphatic route can be used to image smaller metastatic deposits. Perhaps more important, the lymphatic route minimizes binding of antibodies to circulating tumor antigens and to cross-reactive antigens present on normal tissues. Antibodies inappropriate for intravenous use because of binding to normal tissues may therefore be useful against lymph node metastases when injected subcutaneously or directly into lymphatic vessels.

Animals↗
PubMed1983

Natural killer cells: artifact to reality: an odyssey in biology.

The biology of the natural killer cell system is being investigated by many different laboratories using multiple approaches. The rationale for these investigations is the experimental evidence that NK cells play some role in inhibiting tumor growth and metastasis, convey some protective immunity and may be operative in control of differentiation from fetal life to adulthood. Thus, a survey of the literature reveals a multiplicity of studies examining many of these potential roles for NK cells. This review will attempt to summarize some of the findings critical to an understanding of the role NK cells play in immunophysiology and in immune reactions to various diseases. Even after ten years of study, the whole system of 'natural' reactivity remains difficult to define. The evidence available would indicate that the NK system while incompletely understood, may be manipulated in favor of the host when threatened by infectious or neoplastic disorders.

Animals↗
PubMed1983

The treatment of cancer patients with human lymphoblastoid interferon. A comparison of two routes of administration.

Highly purified human lymphoblastoid interferon (HLBI) derived from virus-stimulated Namalwa cells was administered by 6-h IV infusion or IM injection to 40 patients with a variety of disseminated malignancies refractory to standard therapy. Each patient received doses escalating from 0.1 to 50 X 10(6) U for up to 5 weeks. Extensive monitoring for clinical effect, toxicity, and pharmacokinetics has revealed higher peak serum interferon levels and somewhat more pronounced systemic toxicity for the IV than for the IM route of administration. Objective evidence of tumor regression was observed in two patients receiving HLBI IV.

B-Lymphocytes↗
PubMed1983

Characterization of a human blood monocyte subset with low peroxidase activity.

Two human monocyte subsets from the peripheral blood of healthy donors have been isolated in greater than 90% purity by countercurrent centrifugal elutration and human serum albumin gradients and their functional capabilities have been assessed. We have demonstrated that one subset ("regular" monocytes, RM) showed intense cytoplasmic peroxidase staining and contained substantial peroxidase activity. In contrast, another subset ("intermediate" monocytes, IM) stained poorly for peroxidase and had low peroxidase activity. By electron microscopic analysis combined with peroxidase localization, it was found that IM had fewer peroxidase-positive granules per cell than did RM. IM coelutriated with some lymphocytes and by cell sizing analysis were shown to be slightly smaller than RM. Functional and cytochemical analysis of these subsets indicated that IM had less activity than RM in assays such as accessory cell function for mitogen-induced T lymphocyte proliferation and antibody-dependent cellular cytotoxicity, and that fewer IM expressed OKM1 antigen and pokeweed mitogen (PWM) receptors on their membranes than did RM. The subset of IM not bearing either the PWM receptor or the OKM1 antigen had very low peroxidase activity. IM also were found to have a greater sensitivity to polyriboinosinic and polyribocytidilic acid (100 micrograms/ml)-induced secretion of interferon. There was no significant difference in the phagocytic capability, the percentage of Fc receptor-positive cells, 5'-nucleotidase activity, DR antigen expression, or the responsiveness to migration inhibitory factor of IM as compared with RM. Furthermore, it was found that the ratio of IM to RM increased after prolonged cytapheresis, which suggests that IM are more mobilizable than RM from the extravascular reservoirs of human monocytes.

Adult↗
PubMed1983

Monoclonal antibodies in cancer therapy.

The need for improved specificity in cancer therapy is apparent. With the advent of monoclonal antibodies, the possibility of specifically targeted therapy is being considered. Early trials of monoclonal antibody in experimental animals and humans have indicated its ability to traffic to specific tumor sites and to localize on or around the tumor cells displaying antigens to which the antibody is directed. This evidence of specific targeting, along with preliminary evidence of therapeutic efficacy for monoclonal antibodies and immunoconjugates with drugs, toxins, and isotopes is encouraging. The current status of clinical trials with monoclonal antibodies is reviewed and an example of the experimental approach for the development of immunoconjugates in animal models is presented.

Animals↗
PubMed1983

Recombinant leukocyte A interferon in advanced breast cancer. Results of a phase II efficacy trial.

Nineteen patients with advanced refractory metastatic breast cancer no longer responsive to chemotherapy were treated in the first phase II efficacy trial of recombinant leukocyte A interferon (IFL-rA), a highly purified single molecular species of alpha interferon prepared by recombinant DNA methods. Patients received a previously determined maximum tolerated dose for this agent (50 X 10(6) U/m2 body surface area) by intramuscular injection three times weekly for up to 3 months. The symptoms of toxicity observed in this trial resemble those previously reported for alpha interferons and include fever, chills, fatigue, anorexia, and leukopenia. All patients required dose reductions, most often for reasons of severe fatigue. Of the 17 patients evaluable for tumor response, one patient had stable disease and 16 had evidence of tumor progression. We conclude that IFL-rA is not an active agent in the treatment of advanced, refractory breast cancer when used at a maximum tolerated dose on this treatment schedule.

Adult↗