Biomedical subjects
R K Oldham
Publications and source records attributed to R K Oldham.
Combination biotherapy utilizing interleukin-2 and alpha interferon in patients with advanced cancer: a National Biotherapy Study Group Trial.
The National Biotherapy Study Group (NBSG) conducted a broad phase II trial using interleukin-2 (IL-2) by continuous infusion and alpha interferon (IFN) subcutaneously in 267 patients with a variety of advanced cancers, including 29 with breast cancer, 89 with renal cancer, and 69 with melanoma. IL-2 [18 million international units (MIU)/m2] was given by continuous infusion for 108 hours with 3 mu/m2 subcutaneous IFN every other day during the IL-2 infusion. The patients were treated for 1 week followed by a 2-week rest. After two cycles of treatment, patients were evaluated for response. Of the 237 patients evaluable for response, 20 (8%) had a complete or partial response and 128 (54%) were stable. Therefore, 62% of the evaluable patients were nonprogressive during the first 90 days of IL-2/IFN therapy. The objective response rate was 11% in melanoma, 7% in renal cancer, 14% in breast cancer, and 3% in patients with a variety of malignancies for an overall response rate of 7% in these patients with advanced cancer. The patients were treated on a general medical ward and tolerated treatment well with fatigue and fever being nearly universal. Dyspnea, pruritus, chills, and elevated creatinines were frequent but less common. This combination biotherapy regimen has minimal activity in a variety of advanced cancers and must be compared with the best existing chemotherapy for each cancer type in randomized, prospective trials.
Continuous interleukin-2 and tumor-infiltrating lymphocytes as treatment of advanced melanoma. A national biotherapy study group trial.
Melanoma metastases were harvested from 82 patients for the purpose of growing and expanding tumor-infiltrating lymphocytes (TIL). Tumor tissue cell suspensions were incubated with interleukin-2 (IL-2), followed by repeated exposure to tumor antigen with or without OKT3 monoclonal antibody (MoAb). Initial growth success was achieved in 56 of 82 cultures (72%). Efforts were made to expand 26 of these 56 cultures for therapeutic TIL; 23 of 26 early cultures (88%) were successfully expanded for in vivo therapy. It took a mean of 78.5 +/- 25.4 days to grow sufficient TIL for treatment. Therapy included cyclophosphamide (1 g/m2) on day 1, followed by a 96-hour continuous infusion of IL-2 (18 x 10(6) IU/m2/d) on days 2 to 5, and approximately 10(11) (mean 1.49 +/- 0.93 x 10(11)) TIL on day 2. Patients who responded received monthly IL-2 as a 96-hour infusion. Median patient age was 45 years of age. Sixty-seven percent of the patients were men. Performance status was 0 to 1 in 77% of patients. Thirty-four percent of the patients had liver metastases. The usual IL-2 toxicities were seen. Response rate for 21 patients was 24% (95% confidence interval, 10% to 49%). One complete response was achieved with cells 98% CD4+; four partial responses were achieved with cells 80%, 94%, 98%, and 98% CD8+, respectively. Four of eight patients who received TIL, which had never been stimulated with OKT3, had tumor response. The authors conclude that a treatment plan for IL-2/TIL is technically difficult, costly, and effective for only a minority of patients. Overall, clinical results are not clearly superior to those obtained with other IL-2 regimens.
Practice-based research.
Explore the source record for details and available documents.
Continuous interleukin-2 and lymphokine-activated killer cells for advanced cancer: a National Biotherapy Study Group trial.
We conducted a multicenter, phase II trial of continuous-infusion recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells. Patients had advanced cancer, measurable disease, and a good performance level. Treatment included a 5-day continuous infusion of 18 x 10(6) IU/m2/d of rIL-2 followed by 1 day of rest, 4 days of leukapheresis to collect cells for in vitro augmentation of cellular cytotoxicity, and 5 more days of rIL-2 infusion with reinfusion of LAK cells for 3 successive days. Therapy was repeated after 2 weeks. There were 117 patients enrolled: 63% were males, with a median age of 51 years. Eighty-two percent were managed in oncology units, and 18% were in intensive care units. Six patients died within 1 month of initiating therapy. In renal cell carcinoma, the response rate was one of 31 patients (3%), with a median survival of 10.7 months. In melanoma, the response rate was four of 33 patients (12%), with a median survival of 6.1 months. For all other histologies, response rate was three of 53 patients (5%), with a median survival of 7.4 months. All responders were asymptomatic when therapy was initiated. This trial confirms the feasibility of administering continuous rIL-2 and LAK cells outside the intensive care unit environment. Antitumor activity in melanoma was similar to that seen in multicenter trials of bolus rIL-2 and LAK cells. Activity in renal cell cancer was disappointing.
Billing for physicians in training: educational subsidy or fraud?
Explore the source record for details and available documents.
Cancer research: a public trust.
Explore the source record for details and available documents.
Custom-tailored drug immunoconjugates in cancer therapy.
Forty-three patients with disseminated refractory malignancies each received an individually specified combination of either Adriamycin (n = 24) or mitomycin-C (n = 19) conjugated to a cocktail of murine monoclonal antibodies (mAb). Cancers were typed with both immunohistochemistry and flow cytometry using a panel of antibodies. Cocktails of up to six antibodies were selected based on total binding of greater than 80% of the malignant cells in the biopsy specimen. These mAb cocktails were then drug conjugated, safety tested, and administered intravenously. The Adriamycin immunoconjugates were well tolerated in 22/24 patients, with 17/24 having significant side effects. Fever, chills, pruritus, and skin rash were by far the most common transitory reactions. All were well controlled with premedication. A total of up to 1 g Adriamycin and 5 g mAb were administered to each patient. The limiting factor appeared to be a variable dissociation of active Adriamycin from the antibody that unpredictably caused hemopoietic depression. Similar findings were noted among 19 patients treated with mitomycin-C conjugates. Thrombocytopenia at a 60-mg dose of mitomycin-C in this schedule was dose limiting. Serological evidence suggested that the development of an immunoglobulin M antibody specific against the mouse mAb had the specificity and sensitivity to predict clinical reactions. These antibodies were quantitatively less in mitomycin-C-treated patients. Selected patients were retreated. One patient with chronic lymphocytic leukemia was treated on three occasions with 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. No responses were seen with mitomycin-C conjugates but binding was noted to tumors. Drug-induced colitis was seen at higher doses with some binding of these conjugates to normal colon epithelium. This study demonstrated the feasibility of preparing individually specified drug immunoconjugate cocktails for patients with refractory malignancies. Cocktail formulation and antibody delivery to the tumor in vivo was accomplished. There was limited antigenic drift among various biopsies within the same patient over time. The major technical hurdle continues to be the selection of effective drug conjugation methods to optimally bind drugs to mAbs for targeted cancer therapy.
Whose rights come first?
Explore the source record for details and available documents.
Continuous infusion interleukin-2 and tumor-derived activated cells as treatment of advanced solid tumors: a National Biotherapy Study Group Trial.
Metastases from patients with solid tumors were harvested from 196 patients for the purpose of growing tumor-derived activated cells (TDAC). Cells were prepared from autologous tumor cultures by incubation with Interleukin-2 (IL-2) followed by repeated exposure to tumor antigen and/or anti-CD3 monoclonal antibody. Initial growth success was achieved in 66%; 45/56 (80%) of these early cultures were subsequently expanded for in vivo therapy. It took a mean of 69.4 +/- 24.0 days to grow TDAC for treatment. Thirty-eight patients were treated with cyclophosphamide (1 g/m2) on day one followed by a 96-hour continuous infusion of IL-2 (18 x 10(6) IU/m2/day) on days 2-5 and approximately 10(11) TDAC on day 2. Patients subsequently received monthly IL-2 as a 96-hour constant infusion if their cancers were stable or regressing. Median age was 51 yrs; 58% were male. Performance status was 0-1 in 64%, 29% had lung metastases; 34% had liver metastases. The usual IL-2 toxicities were seen. Responses were seen only in 1/38 patients (3%); a partial response in a patient with lymphoma. Forty-two percent were stable 90 days post-treatment, the rest were progressive or inevaluable. We conclude that a treatment plan for IL-2/TDAC is technically difficult, costly, and not practical under these conditions. Clinical results to date are not clearly different than those obtained with other IL-2 regimens.
Continuous infusion of interleukin-2 and cyclophosphamide as treatment of advanced cancers: a National Biotherapy Study Group Trial.
We have evaluated the effect of Interleukin-2 [IL-2] after Cyclophosphamide (C) chemotherapy in 41 patients with metastatic cancer. IL-2 was given as a continuous infusion priming cycle 36 hours after C at 1 gm/m2 intravenously. In 39 evaluable patients, there were no complete remissions [CR], 2 partial remissions [PR], and 1 had a minor response [MR]. Stable disease for 30 days was seen in 16 patients whereas 20 progressed. The durations of partial and minor responses were brief, ranging from 1-6 months. Grade 3-4 neutropenia was seen in 41%. This was more severe than seen with IL-2 alone or IL-2 combined with lower doses of C. The marrow suppression was due to the chemotherapy. This combination of IL-2 and C appears to be reasonably well tolerated by patients, but toxicity is greater and the response rate is no better than results achieved by IL-2 alone. Responses of 26 patients with renal cancer appear to be inferior to our historical data using IL-2/LAK cells without C. Immune monitoring demonstrated changes expected with C chemotherapy (i.e., a non-selective decline in immune function). C induced no further differences in IL-2 induced changes in immune function.
Reimbursement for clinical investigation.
Explore the source record for details and available documents.
Evaluation and clinical relevance of patient immune responses to intravenous therapy with murine monoclonal antibodies conjugated to adriamycin.
A retrospective study was performed in order to examine the clinical relevance of human anti-murine antibodies (HAMA) to concurrent clinical events in 21 patients receiving intravenous therapy with cocktails of murine monoclonal antibodies conjugated to Adriamycin. In vivo tumor localization of the murine antibodies was also evaluated. Serum levels of HAMA, human-murine immune complexes (HMIC), and murine antibodies were measured using an automated fluorescence immunoassay. Immunohistochemical staining was performed on frozen sections of tumor biopsies from eight of the patients to examine the in vivo binding of the murine antibodies. The patients were divided into low, intermediate, and high antibody dose groups. The incidence of allergic symptoms (80%) and HAMA correlation (75%) were highest in the low dose group. Specific IgM HAMA was the most highly correlated with allergic reactions, being present in 61.5% of the allergic patients. Thirteen of the 21 patients studied (61.9%) developed allergic symptoms after one or more doses of the murine monoclonal antibody conjugates. The percentages of total antibody doses in the patients' sera at varying intervals post-infusion varied widely from patient to patient for any given time point and dose, suggesting complex factors in the distribution and clearance of the murine antibodies. All eight of the patients biopsied during or post-therapy exhibited tumor localization of the murine monoclonal antibodies. Six of the eight had concurrent HAMA in their sera. Thus, the presence of HAMA did not prevent in vivo localization of the murine antibodies in the target tumors.(ABSTRACT TRUNCATED AT 250 WORDS)
Is informed consent a function of who pays?
Explore the source record for details and available documents.
Recombinant interleukin-2 and adoptive immunotherapy alternated with dacarbazine therapy in melanoma: a National Biotherapy Study Group trial.
We evaluated adoptive cellular therapy with recombinant interleukin-2 (rIL-2) plus lymphokine-activated killer (LAK) cells alternating with sequential dacarbazine chemotherapy in 27 patients with metastatic melanoma. rIL-2 was given to the patients as a 5-day continuous-infusion priming cycle followed by 1 day of rest, 4 days of leukapheresis for in vitro LAK cell expansion, and then 4 1/2 days of continuous rIL-2 infusion in conjunction with reinfusion of LAK cells during the first 3 days of the continuous infusion. Two weeks later, patients received dacarbazine (1,200 mg/m2) chemotherapy. Two patients achieved complete remission, and five achieved a partial remission for a response rate of 26% (95% confidence interval = 12%-47%). Three patients had mixed responses. The partial and mixed responses were brief, ranging from 1 month to 6 months, whereas the two complete responses have been sustained for 13+ and 24+ months. There were no additive toxic effects except for thrombocytopenia, which delayed treatment in two patients. Alternating adoptive immunotherapy and dacarbazine chemotherapy appear to be reasonably tolerated by patients, but the response rate is not clearly better than that achieved with other rIL-2 regimens or with chemotherapy alone.
Use of anti-CD3 monoclonal antibody in the generation of effector cells from human solid tumors for use in cancer biotherapy.
Activated lymphocytes derived from tumor biopsies are very important as a source of biotherapy for cancer. The growth of lymphocytes requires periodic stimulation with specific antigen. In the case of tumor-derived lymphocytes, tumor cells in the biopsy can serve this function. This stimulation provides proliferative potential as well as functional specificity. Often, however, required numbers of viable tumor cells are not available for antigen dosing. In the present study, anti-CD3 antibody was used as a substitute for specific antigen in the generation of effector cells for biotherapy. Periodic stimulation of tumor-derived activated cells (TDAC) using anti-CD3 antibody immobilized on plastic tissue culture plates or PL-732 plastic bags resulted in continued proliferation of the TDAC. In addition, maintenance of cytotoxic activity was observed. In this study, we expanded lymphocytes from 15 tumor biopsies (five different tumor types) to therapeutic doses (greater than 5.0 X 10(10) TDAC). The average time for expansion was 70 days. Our studies showed upregulation of CD25 expression by 18 h. Proliferation of the TDAC occurred when cultures were supplemented with interleukin-2 (IL-2). The characteristics of anti-CD3 antibody-stimulated TDAC were similar to those reported before by our group using tumor biopsy for stimulation. This study provides evidence for the practical usefulness of anti-CD3 antibody stimulation of lymphocytes used in the biotherapy of cancer.
PVB chemotherapy: cost-benefit analysis.
Explore the source record for details and available documents.