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R K Oldham

Publications and source records attributed to R K Oldham.

At least 91 records · Page 5Linked to original sources
PubMed1989

Chemosensitivity testing in a tumor acquisition, propagation, and preservation program.

Chemosensitivity assays were carried out as part of a tumor acquisition, propagation, and preservation program for cancer biotherapy. In addition to biopsy specimens, tumor cells propagated in culture or tumor xenografts grown in nude mice were submitted for chemosensitivity assay when sufficient biopsy material was unavailable. Chemosensitivity was tested utilizing the adhesive tumor cell culture system. A total of 154 specimens was submitted for testing; 96 specimens were assayed. Success rates were 55% for primary cancer biopsies, 67% for metastases, 69% for xenografts, and 70% for cell lines. There were no significant differences evident when the sensitivity to drugs of tumor cells originating from biopsies, xenografts, or tissue culture were compared. Sufficient data were available for 18 patients to compare clinical results of drug treatment with predictive results from the chemo-sensitivity assay. Assay results indicating insensitivity appeared to predict resistance; however, assays indicating sensitivity were not predictive. These results suggest that propagated tumor material, such as xenografts and cultured cell lines, may be useful when biopsy tissue is not available.

Animals↗
PubMed1989

Multiple cycles of constant infusion recombinant interleukin-2 in adoptive cellular therapy of metastatic renal carcinoma.

Twenty patients were treated with metastatic renal cell cancer with 5-day cycles of constant infusion recombinant interleukin-2 (rIL-2) at 3 X 10(6) U/m2/day and with infusion of in vitro activated autologous mononuclear cells. The initial eight patients completed all rIL-2 and cellular therapy in a single 25-day treatment period. The subsequent 12 patients entered a 6-month treatment program involving two separate 15-day cycles of cellular therapy followed by four monthly cycles of maintenance rIL-2. Among eight patients in the 25-day treatment program, there were two with partial response (PR) and one with minor response (MR). None of these responses exceeded 2 months in duration. Among the 12 patients undergoing recycling of therapy, there were two with complete response (CR), two with PR, and one with MR. All four patients with CR or PR in this group demonstrated continuing response with recycling of treatment and none relapsed while receiving maintenance interleukin-2. Three remain in remission at 10, 11, and 12 months. These pilot data confirm that patients can tolerate multiple cycles of adoptive immunotherapy involving constant infusion rIL-2 and suggest that recycling of therapy is necessary to achieve clinically meaningful results.

Adult↗
PubMed1989

Therapeutic murine monoclonal antibodies developed for individual cancer patients.

The purpose of this work was to create antibodies that are highly specific to epitopes on the surface of patient tumor cells that, when added together as a "cocktail," bind to greater than 99% of the patient's tumor cells. We describe the rationale and the methods used to develop new murine hybridomas that secrete monoclonal antibodies reactive with surface markers expressed on breast, lung, colon, kidney, islet cell, and miscellaneous carcinomas and melanoma. A rapid immunofluorescence method (cell concentration fluorescence immunoassay) is also described that has been developed to rapidly screen culture supernatants on viable patient tumor cells, tumor cell lines, or peripheral blood cells. We report the development of one breast, five colon, and three melanoma, three nephroma, and two pancreatic islet cell carcinoma antibodies. The breast antibody binds to 75% of the breast tumors tested thus far and to the same percentage of colon tumors as do the five colon antibodies, 77-85%. The melanoma antibodies described react with 90-100% of the melanoma and prostate cancers tested. The total process of creating the hybridomas and screening the antibodies for potential clinical usefulness has taken from 6 to 9 months to complete, including testing normal tissue reactivity by immunohistochemistry and production of gram quantities of monoclonal antibodies from ascites.

Animals↗
PubMed1989

Tumor-derived activated cells: preliminary laboratory and clinical results.

It is well known that T lymphocytes can mediate significant anti-tumor responses. A limiting factor has always been the ability to expand T cells, whether from the peripheral blood, spleen, or tumor. The recent availability of recombinant interleukin-2 (r-IL2) has demonstrated the feasibility of expanding T cells and the clinical efficacy of these cells as anti-tumor effectors in murine models. Concomitantly, researchers discovered that lymphokine-activated killer cells--peripheral blood cells functionally distinct from T cells--could be cultured, expanded, and re-infused in patients, with significant clinical effects. For many years, the infiltrating lymphocytes have been recognized in tumor biopsies and known to be cytolytically active. Major limiting factors were the ability to culture large numbers of these infiltrating cells and the limited understanding of the tumor antigens involved for T-cell stimulation. Restimulation by antigen (tumor cells) appears to provide the ongoing antigen stimulation needed to maintain selective killing of tumor cells. By defining various factors in the medium that support and enhance T-cell growth and activation, the components are becoming available to develop a broad attack on advanced cancer by using this laboratory-based technology of stimulation and expansion of tumor-derived activated cells.

Antigens, Neoplasm↗
PubMed1988

Enhancement of human lymphokine-activated killer cell cytolysis and a method for increasing lymphokine-activated killer cell yields to cancer patients.

In a continued effort to make interleukin-2/lymphocyte-activated killer (LAK) cell therapy safer and more efficacious for cancer patients, we examined methods of increasing the yields of cells obtained as a final product for reinfusion. Previously, the major cell loss occurred in the Ficoll-Hypaque gradient separation procedure used before cell culture. Therefore, we investigated the necessity of this step. Leukapheresis procedures (n = 105) from 40 different cancer patients showed that the resultant cell product is predominantly mononuclear (lymphocytes and monocytes; greater than 97%) before the gradient purification step. The only cells observed to decrease in percentage as a result of the step were red blood cells (RBC: WBC ratio of 17:1 before purification to 1:3 after purification). Our study showed that the cytolytic potential of unpurified leukapheresis products against the LAK-sensitive line Daudi and the natural killer cell-sensitive line K562 was greater and that the patients received significantly more cells at times of reinfusion if the gradient separation step was eliminated. By additional experiments, we determined that autologous red blood cells enhance the generation of cytolytic LAK cells. This enhancement was greater if the red blood cells were in contact with the mononuclear cells during the time of cell culture. The elimination of the Ficoll-Hypaque purification step not only reduces the time and cost of the cell collection procedures, it also allows us to return to the patients greater numbers of cytolytic LAK cells following the activation period.

Chromium↗
PubMed1988

Characterization of a method using viable human target cells as the solid phase in a cell concentration fluorescence immunoassay (CCFIA) for screening of monoclonal antibodies and hybridoma supernatants.

A new method has been characterized for the use of viable target cells as the solid phase for screening of hybridoma supernatants in a cell concentration fluorescence immunoassay (CCFIA). Briefly, the specific target antigen on the cells is bound by the monoclonal antibodies and revealed by use of a fluoresceinated second antibody. Separation of free from bound antibody is accomplished by filtration in the 0.2 micron filter-bottom wells of specialized assay plates. Processing is automated in a Pandex screen machine, resulting in numerical fluorescence values for each well. This method is rapid (under 1 h per 96-well plate), highly sensitive (down to 0.2 ng/ml) and sparing of target cells (0.3-2.5 X 10(4) cells per assay well). It has been applied to 37 different varieties of human solid tumor cells, as well as to human peripheral blood mononuclear cells. The cells used as targets for the characterization of this method were still capable of attachment and growth when recovered post-assay. This method was compared with a viable cell enzyme-linked immunosorbent assay (ELISA) method, showing similar sensitivity and greatly shortened assay time. Comparison of the results from this method with those obtained from flow cytometric analysis performed on viable cells showed close correlation, whereas a lower correlation was seen with immunohistochemical methods using acetone-fixed cells. Development of this method made it possible to rapidly screen many thousands of hybridoma supernatants and successfully select those which were specific for surface antigens on viable cells.

Adenocarcinoma↗
PubMed1988

Who's paying for new drugs?

Direct payment by patients for treatment with drugs still in development is the subject of controversy. The matter goes deeper than it might first appear.

Biomedical Research↗
PubMed1988

Principles of biotherapy and its application to the treatment of disseminated renal cancer.

Monoclonal antibody technology permits the preparation of tumor-specific immunoglobulin reagents that can be used directly in tumor therapy or that can be coupled to various chemotherapeutic drugs or toxins to aid in their delivery to the tumor site and thus enhance their therapeutic effectiveness. Additionally, recombinant DNA technology has facilitated the economic production of rare lymphokines (e.g., interleukin 2, interferon alpha and interferon gamma) or cytokines (tumor necrosis factor, lymphotoxin) that can either modulate the host immune response or kill tumor cells, respectively. These developments collectively have led to the development of a fourth modality for treatment of human cancers--biotherapy--as an addition to surgery, radiation, and chemotherapy modalities. This paper presents the rationale and emerging practice of the biotherapy of cancer and documents early clinical results, including the treatment of metastatic renal carcinoma at the Biological Therapy Institute.

Animals↗
PubMed1988

Regulatory hierarchies.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Adriamycin custom-tailored immunoconjugates in the treatment of human malignancies.

Twenty-three patients with disseminated refractory malignancies each received a tailored combination of adriamycin-conjugated murine monoclonal antibodies. Tumors were typed using a panel of antibodies. Cocktails of up to six antibodies were selected based on binding greater than 80% of the malignant cells as tested by immunoperoxidase and flow cytometry. These monoclonal antibodies were then conjugated to Adriamycin and administered intravenously. Seventeen of 23 patients had reactions to the administration of immunoconjugates, but these were tolerable in all but two patients. Fever, chills, pruritus, and skin rash were by far the most common transitory reactions. All were well controlled with premedication. In several patients there was limited antigenic drift among various biopsies within the same patient over time. This observation confirms the necessity for the use of a cocktail of antibodies if one wishes to cover all tumor cells. Preliminary serologic evidence suggests that the development of an IgM antibody, which is specific against the mouse monoclonal antibody, has the specificity and sensitivity to predict clinical reactions. Selected patients were re-treated. One patient with chronic lymphocytic leukemia had re-treatment on three occasions and demonstrated regression of peripheral lymph nodes. Two patients with breast carcinoma had definite improvement in ulcerating skin lesions and two patients with tongue carcinoma had shrinkage of their lesions. In the course of the study free Adriamycin released from the monoclonal antibodies was discovered to be a limiting factor in the amount of antibody that could be administered. Up to 1 g of Adriamycin and up to 5 g of monoclonal antibody were administered. The limiting factor appeared to be a variable dissociation of active Adriamycin from the antibody that unpredictably caused hemopoietic depression. This study demonstrates the feasibility and reviews technical considerations in preparing immunoconjugate cocktails for patients with refractory malignancies. The major technical hurdle appears to be the selection of an effective conjugation method that can be used to optimally bind Adriamycin to monoclonal antibodies for targeted cancer therapy.

Animals↗
PubMed1987

An improved method for the generation of human lymphokine activated killer cells.

In an effort to make interleukin-2/lymphokine-activated killer cell (IL-2/LAK) therapy safer for cancer patients, we examined the efficacy of using Fenwal PL732 bags as tissue culture flasks. These bags can be sterilly connected using tubing kits thus reducing the risk of contamination to the cells. Peripheral blood mononuclear cells were obtained from normal donors or cancer patients undergoing IL-2/LAK cell therapy. Following Ficoll-Hypaque purification, these cells were incubated in the presence of IL-2 in either PL732 plastic bags or standard tissue culture flasks. Our results showed that LAK cells could be generated from either normal donors or cancer patients in the bags as well as in the flasks. Comparisons were made of the LAK cell populations obtained from the two sources and showed that each was similar in terms of morphology as determined by Wright stain differentials. The populations of cells were also similar in regard to cell surface phenotype as determined by flow cytometric analysis. In addition, recoveries from either tissue culture vessel as well as cell viability of the LAK cells were comparable. Finally, the LAK cells obtained from both sources were assessed for cytolytic activity against the tumor cell lines K562 and Daudi. These results showed that the cytolytic activity of the LAK cells against these target cells was the same whether the cells were obtained from the flasks or the bags.

Antigens, Surface↗
PubMed1987

Immunotoxins to a human melanoma-associated antigen: comparison of gelonin with ricin and other A chain conjugates.

Gelonin, a ribosome-inactivating protein from the seeds of Gelonium multiflorum, has been conjugated to antibodies. Previous reports have indicated variable potency of such immunotoxins. The lack of toxicity of gelonin, however, makes it attractive for immunoconjugate production. The ribosome-inactivating protein was covalently linked (using N-succinimidyl-3-(2-pyridyldithio)propionate) to monoclonal antibody, 9.2.27, directed to a human melanoma-associated glycoprotein/proteoglycan. The immunoconjugate showed high selectivity with dose-dependent cytotoxic activity to cultured human melanoma cells (50% inhibitory dose; 1-3 X 10(-11) M versus antigen-positive cells; 1-3 X 10(-7) M versus antigen-negative cells). Specificity and immunoreactivity of the conjugate were similar to those of unconjugated antibody. Biodistribution studies with iodine trace-labeled conjugate in nude mice indicated that tumor localization of the gelonin conjugate was decreased compared to unconjugated antibody. However, a significant therapeutic effect of the conjugate was found with multiple but not single dose i.v. treatment in nude mice bearing established palpable melanoma. These in vivo experiments showed that gelonin conjugates are not toxic up to 2 mg total dose/mouse and significantly retarded the growth of established s.c. tumor. Comparison of gelonin conjugates in vitro and in vivo with other A-chain conjugates of 9.2.27 (abrin and ricin) indicated that gelonin had similar potency, better selectivity, better tumor localization, and more significant therapeutic effects.

Abrin↗
PubMed1987

Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer.

Adoptive immunotherapy involving bolus-dose recombinant interleukin-2 (rIL-2) has been reported to induce tumor regression in some patients with cancer, but has been associated with severe fluid retention and cardiopulmonary stress. In an effort to preserve the efficacy but reduce the toxicity of this treatment, we used escalating doses of rIL-2 as a constant infusion rather than as a bolus dose. Forty-eight patients with advanced cancer received rIL-2 as a 24-hour infusion in five-day cycles separated by five-day periods of rest and leukapheresis. Eight patients were removed from the study before receiving cells activated in vitro. In the 40 who could be evaluated for their response, there were 13 partial responses (32.5 percent) and 2 minor responses. Partial responses were observed in Hodgkin's disease (one of one), non-Hodgkin's lymphoma (one of one), lung cancer (one of five), ovarian cancer (one of one), parotid cancer (one of two), renal cancer (three of six), and melanoma (five of ten). Responses were associated with a good performance status, a base-line lymphocyte count above 1400 per cubic millimeter, and an rIL-2-induced lymphocyte count of at least 6000. Optimal lymphocytosis required a priming dose of rIL-2 of 3 X 10(6) U per square meter of body-surface area per day, and 15 of 28 patients receiving this priming dose responded to treatment. A weight gain of more than 10 percent of total body weight (five patients) and dyspnea at rest (six patients) were unusual events restricted to patients with poorer pretreatment performance. We conclude that the administration of rIL-2 as a constant infusion may preserve the antineoplastic activity of adoptive immunotherapy while increasing the safety and comfort of patients.

Adult↗
PubMed1987

Gamma-interferon: physiology and speculation on its role in medicine.

Gamma-interferon appears to be a pivotal molecule in the immune system. Recombinant DNA technology has permitted the cloning and expression of the gene for gamma-interferon (gamma-IFN), leading to an exponential increase in the level of knowledge both in vitro and in vivo. Laboratory evidence suggests a clinical role for gamma-IFN in collagen vascular disease, chronic granulomatous infectious diseases, hematology, and medical oncology. Phase I trials have identified the toxicities; these toxicities are primarily clinical and include fever, fatigue, flu-like symptoms, and hypotension. Antitumor activity has been noted in the early development of the drug.

Animals↗