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Biomedical subjects

R O Dillman

Publications and source records attributed to R O Dillman.

At least 19 recordsLinked to original sources
PubMed2006

Radioimmunotherapy of B-cell lymphoma with radiolabelled anti-CD20 monoclonal antibodies.

CD20 has proven to be an excellent target for the treatment of B-cell lymphoma, first for the chimeric monoclonal antibody rituximab (Rituxan), and more recently for the radiolabelled antibodies Y-90 ibritumomab tiuxetan (Zevalin) and I-131 tositumomab (Bexxar). Radiation therapy effects are due to beta emissions with path lengths of 1-5 mm; gamma radiation emitted by I-131 is the only radiation safety issue for either product. Dose-limiting toxicity for both radiolabelled antibodies is reversible bone marrow suppression. They produce response rates of 70%-90% in low-grade and follicular lymphoma and 40%-50% in transformed low-grade or intermediate-grade lymphomas. Both products produce higher response rates than related unlabelled antibodies, and both are highly active in patients who are relatively resistant to rituximab-based therapy. Median duration of response to a single course of treatment is about 1 year with complete remission rates that last 2 years or longer in about 25% of patients. Clinical trials suggest that anti- CD20 radioimmunotherapy is superior to total body irradiation in patients undergoing stem cell supported therapy for B-cell lymphoma, and that it is a safe and efficacious modality when used as consolidation therapy following chemotherapy. Among cytotoxic treatment options, current evidence suggests that one course of anti-CD20 radioimmunotherapy is as efficacious as six to eight cycles of combination chemotherapy. A major question that persists is how effective these agents are in the setting of rituximab- refractory lymphoma. These products have been underutilised because of the complexity of treatment coordination and concerns regarding reimbursement.

Antibodies, Monoclonal↗
PubMed2004

Combined modality trials of the Cancer and Leukemia Group B in stage III non-small-cell lung cancer: analysis of factors influencing survival and toxicity.

BACKGROUND: Combined modality therapy (CMT) is the standard of care for patients with unresectable stage III non-small-cell lung cancer (NSCLC); however, insufficient data are available regarding prognostic factors in this disease setting. PATIENTS AND METHODS: Six hundred and ninety-four patients included in five trials conducted by the Cancer and Leukemia Group B evaluating CMT in stage III NSCLC were included in this analysis. The primary objective was to identify factors that were predictors of survival and selected radiation-related toxicities using Cox regression models and logistic regression analysis. RESULTS: The Cox model shows that performance status (PS) 1 [hazard ratio (HR) 1.24; 95% confidence interval (CI) 1.06-1.45; P=0.009] and thoracic radiation therapy (TRT) only (HR 1.58; 95% CI 1.22-2.05; P=0.001) predicted for poorer survival, while baseline hemoglobin >/=12 g/dl predicted for improved survival (HR 0.67; 95% CI 0.55-0.81; P </=0.0001). Multivariate logistic regression showed an increase of grade 3 + esophagitis among patients with PS 0 [odds ratio (OR) 1.7; 95% CI 1.1-2.7; P=0.029), >5% weight loss (OR 2.9; 95% CI 1.3-6.6; P=0.008) and patients receiving concurrent chemoradiation (OR 7.3; 95% CI 3.4-15.6; P=0.0001). CONCLUSIONS: Baseline hemoglobin and PS, as well as the use of CMT, have the greatest effect on survival in unresectable stage III NSCLC. The use of concurrent chemoradiation increases the risk of esophagitis, which remains the primary radiation-related toxicity.

Adult↗
PubMed2001

Monoclonal antibodies in the treatment of malignancy: basic concepts and recent developments.

Antibodies have long been considered to be potential anticancer agents because of their specificity for cell-membrane antigens. Applications of hybridoma and recombinant DNA technology have led to the production of unlimited quantities of clinical-grade murine, chimeric, and humanized monoclonal antibodies for clinical use. Whole antibodies may produce anticancer effects in conjunction with the immune system by interaction with complement proteins and/or effector cells via the Fc portion of the antibody molecule. Antibodies may also neutralize circulating ligands or block cell membrane receptors and thus interrupt ligand/receptor interactions and signal transduction that are associated with proliferative or anti-apoptotic effects. The anti-idiotype network cascade provides a rationale for antibodies as vaccine therapy. Antibodies may also serve as the guiding or targeting system for other cytotoxic pharmaceutical products such as (i) radiolabeled antibodies for radioimmunodetection and radioimmunotherapy; (ii) immunotoxins; (iii) chemotherapy/antibody conjugates; (iv) cytokine/antibody conjugates; and (v) immune cell/antibody conjugates. After years of anticipation, as of late 1999 there were four monoclonal antibodies that had been approved by the U.S. Food and Drug Administration based on activity against human malignancy, all of which are in widespread clinical use. Several other products are in various stages of clinical trial testing. Monoclonal antibodies have joined interferon-alpha, interleukin-2 (IL-2), and various hematopoietic growth factors as well-established components of biological therapy, the fourth modality of cancer treatment.

Antibodies, Monoclonal↗
PubMed2001

Short-term tumor cell lines from breast cancer for use as autologous tumor cell vaccines in the treatment of breast cancer.

OBJECTIVE: We tried to establish short-term cultures of autologous tumors from patients with breast carcinoma for potential use as active specific immunotherapy (i.e., autologous vaccine) after resection of primary breast cancer, and/or for the treatment of metastases. METHODS: Between 10/90 and 12/99 the cell biology laboratory of the Hoag Cancer Center attempted to establish short-term tumor cell lines from 115 breast cancer specimens from 56 primary breast lesions, 17 axillary nodes, 14 other lymph node/soft tissue sites, 10 chest wall recurrences, and 6 thoracentesis of malignant pleural effusions. Success was defined by growth of 5 x 10(7) viable cells whose malignant nature and breast cancer origin was confirmed by histology of the submitted tissue, cell morphology and antigenic phenotyping. Variables associated with successful growth of short-term cell lines were examined. RESULTS: Expansion to 5 x 10(7) cells was achieved for only 8/115 samples [7%] including two from chest wall recurrences, and one each from a supraclavicular node, an umbilical node, liver, omentum, and pleural fluid. Two of the successful cell lines were established from tissue that originally had been cryopreserved; the others were initiated from fresh tumor. The success rate was better from regional/distant metastases 7/55 (13%) compared to primary tumors 1/56 (1.8%) (p = 0.063). The success rate for tumors harvested at Hoag Hospital was 4/97 (4%) compared to 4/14 from (31%) distant sites, but all but one of the tumors from a distant geographic site was a metastatic lesion. Tumor cell lines were successfully established from metastatic lesions ranging in size from < 1.0 g to 19 g. Four patients were treated with their autologous vaccine in the setting of chemotherapy-refractory metastatic disease without any significant toxicity. CONCLUSIONS: We were unable to establish short-term cell lines for most patients with primary or metastatic breast cancer using this methodology. However, two long-term cell lines have been established and characterized. Treatment with the autologous irradiated cell product was not associated with acute toxicity.

Autoantigens↗
PubMed2001

Treatment of kidney cancer with autologous tumor cell vaccines of short-term cell lines derived from renal cell carcinoma.

BACKGROUND: We established short-term cultures of autologous tumors from patients with renal carcinoma for use as active specific immunotherapy (i.e., autologous vaccine). METHODS: Between 9/91 and 9/99 the cell biology laboratory of the Hoag Cancer Center received 69 kidney tumor samples that had been surgically excised, including 43 primary tumors and 26 metastatic lesions. Efforts were made to establish short-term tumor cell cultures to use as autologous tumor cell vaccines. Prior to treatment, patients underwent a baseline skin test for delayed tumor hypersensitivity (DTH) and then received s.c. injections of 10 million irradiated tumor cells that were given with various adjuvants weekly x3 and then monthly x5. RESULTS: Cell lines were established for 55/69 patients (80%) including 36/43 (84%) from primary tumors and 19/26 (73%) from distant metastases. Vaccines were prepared for 41 patients; 27 were treated. At the time of this analysis, follow up data was available for 26 patients with a median follow up > 5 years. Treatment was well-tolerated. Of 10 patients who had no evident disease at the time of treatment, nine were alive 1-8 years later; 5/8 had conversion of their DTH test from negative to positive. For 16 patients with measurable metastatic disease at the time of treatment, there were no objective tumor responses; their median survival was 5.0 months. Among these 16 patients, only 1/8 DTH tests converted, but three had a positive baseline DTH test; one was previously treated with interleukin-2 and tumor infiltrating lymphocytes and two others were previously treated with autolymphocyte therapy. CONCLUSIONS: Vaccine therapy with short-term cultures of autologous tumor cells is feasible, well-tolerated and associated with conversion of DTH and long-term survival in patients who are free of disease at the time treatment is initiated. However, significant anti-tumor responses were not seen in patients with measurable disease at the time vaccine treatment was initiated.

Adult↗
PubMed2001

Characterization of human tumor-infiltrating lymphocytes expanded in hollow-fiber bioreactors for immunotherapy of cancer.

We attempted to grow tumor-infiltrating lymphocytes (TIL) from 34 fresh tumors of eight different histologies using flasks for the initiation phase and hollow fiber bioreactors to expand TIL to therapeutic numbers. Overall success rate was 76% (26/34) including melanoma (9/14, 64%) and renal cell carcinoma (11/11, 100%). The mean number of days required to reach successful initiation (1 x 10(9) TIL) for all tumor types was 29 +/- 16 days (mean +/- S.D.). Therapeutic doses of TIL required an average of 88 +/- 23 days (initiation plus expansion) with an average TIL number of 3.2 x 10(10) +/- 2.8 x 10(10). TIL phenotype was predominantly CD4+ in 53% (16/30) and CD8+ in 47% (14/30), renal cell carcinoma samples accounted for 12/14 of the predominantly CD8+ TIL. Cells bearing the natural killer (NK) phenotype represented only 0-7% of TIL while LAK phenotype represented 0-68% (mean 11 +/- 15%); LAK was the predominant phenotype in one patient with kidney cancer. Cytotoxicity tests showed consistent NK and LAK activity in addition to cytolysis of autologous tumor. Autologous tumor cell restricted cytolysis was noted for three TIL cultures. The overall success rate and characteristics of TIL were similar to our results with TIL expanded in semi-permeable plastic bags. This work confirms that hollow-fiber bioreactors are a suitable alternative to semi-permeable bags and roller bottle systems for the expansion of human TIL for therapeutic use in cancer patients.

Bioreactors↗
PubMed2001

Interferon-alpha2a and 13-cis-retinoic acid with radiation treatment for high-grade glioma.

Interferon-alpha (IFN-alpha) has been safely given concurrently with radiation therapy (RT) in treating gliomas. As single agents, both IFN-alpha and cis-retinoic acid (CRA) have produced objective tumor regressions in patients with recurrent gliomas. In vitro, IFN-alpha2a and CRA enhance radiation therapy effects on glioblastoma cells more than either agent alone. This trial was conducted to determine the clinical effects of IFN-alpha2a and CRA when given concurrently with radiation therapy to patients with high-grade glioma. Newly diagnosed patients with high-grade glioma received IFN-alpha2a at a dosage of 3 to 6 million IU s.c. 4 times a day for 3 days per week and 1 mg/kg CRA by mouth 4 times a day for 5 days per week during the delivery of partial brain radiation therapy at 180 cGy x 33 fractions for 5 days per week for a total of 59.4 Gy during the 7-week period. Use of the antiepileptic phenytoin was prohibited after observing that the combination of IFN-alpha2a, CRA, and phenytoin was associated with a high rate of dermatologic toxicity not seen in a previous study with concurrent IFN-alpha2a and radiation therapy. Forty patients (26 men and 14 women) with a median age of 60 (range, 19 to 81 years) were enrolled between August 1996 and October 1998. Histopathologic diagnoses were glioblastoma multiforme or grade 4 anaplastic astrocytoma in 36 patients, and grade 3 anaplastic astrocytoma in 4 patients. Only 4 patients (10%) underwent a gross total resection of tumor prior to this therapy; 50% were asymptomatic when treatment was initiated. The planned 7-week course of concurrent therapy was completed by 75% of patients; 30% completed the 16-week course of IFN-alpha and CRA alone. At a median follow-up of 36 months, there were 37 deaths, with a median overall survival of 9.3 months and a 1-year survival rate of 42%. There was no improvement in survival compared with a similar group of 19 patients treated with concurrent IFN-alpha2a and radiation therapy in a previous trial. In the high-risk group of patients in the present study, concurrent treatment with IFN-alpha2a, CRA, and RT was feasible, but was not associated with a better outcome compared with a similar patient population treated with radiation therapy and IFN-alpha2a, or compared with radiation therapy alone in other trials.

Adult↗
PubMed2001

15th Annual Scientific Meeting of the Society for Biological Therapy. 26-29 October 2000, Seattle, Washington, USA.

The 15th Annual Scientific Meeting of the Society for Biological Therapy (SBT) was held at the Four Seasons Olympic Hotel in Seattle, USA. The meeting was organised on behalf of the society by John A Thompson from the University of Washington (Seattle, USA), Michael B Widmer of Immunex Corp. (Seattle, USA) and Bernard A Fox from the Earle A Chiles Research Institute (Portland, Oregon, USA). The purpose of the organisation, which was founded in 1984 and currently has 300 members, is to bring together those diverse individuals actively investigating biologicals and biological response modifiers in the diagnosis and treatment of cancer, including clinicians and basic scientists from industry, government and academia.

Animals↗
PubMed2001

The history and rationale for monoclonal antibodies in the treatment of hematologic malignancy.

The potential of antibodies as "magic bullets" for cancer therapy has been appreciated for nearly a century. During the past 25 years, various scientific developments have made possible the production of unlimited quantities of clinical-grade murine, chimeric, and humanized monoclonal antibodies (MoAbs). Intact, unconjugated MoAbs may: [1] produce anticancer effects through the immune system on the basis of interactions between the Fc portion of antibody and complement proteins and/or effector cells; [2] induce regulatory effects by neutralizing circulating ligands or blocking cell membrane receptors, thereby interfering with ligand/receptor interactions and signal transduction; [3] serve as immunogens for anti-cancer vaccines through the anti-idiotype-network cascade. Conjugated MoAbs can serve as carriers of other agents such as radioisotopes, natural toxins, chemotherapy drugs, cytokines, and immune cells. Important aspects of the antigenic target are the degree to which it is tumor-specific or tumor-associated, whether it internalizes or not, whether it is shed, the density of expression, and the physiologic significance of the antigen to the target cell. The clinical foundation for antibody-mediated therapy was laid in the 1980s when investigators established the safety of antibody administration, defined certain predictable antibody-mediated toxicities, and confirmed that antibodies could reach tumor targets and produce antitumor effects. A major limitation of these early mouse monoclonal antibodies was overcome with the production of antibodies with varying degrees of humanization. In 1997 rituximab (Rituxan), a mouse-human chimeric anti-CD20, became the first MoAb approved by regulatory agencies for the treatment of a human malignancy.

Animals↗
PubMed2000

Sequential re-analysis of a phase-III clinical trial in non-small cell lung cancer.

This paper presents a reanalysis of a randomized clinical trial conducted by the Cancer and Leukemia Group B (CALGB, Bethesda, MD, USA). This trial found a significant benefit of combination chemotherapy followed by irradiation (CTRT) in comparison to radiotherapy alone (RT) for the treatment of nonsmall cell lung cancer. The validity of the results obtained and the decision to terminate taken by the CALGB, were assessed using sequential methods. The reliability and efficiency of sequential methods were also assessed for this study. Two sequential designs were used: the triangular and the restricted procedure. Initial analyses were conducted with the data from patients actually recruited, adjusting for important prognostic variables at any interim analysis. As a confirmatory technique, a continuation of the trial was simulated, sampling extra patients under the assumption of no treatment difference, preserving the effect of the prognostic variables. Using the results from the 155 patients recruited by the CALGB (88 deaths at termination and 136 after follow-up), the sample path stayed within the continuation region of both sequential designs considered. An underpowered sequential analysis showed significant superiority of CTRT over RT (95% confidence interval (95% CI) 0.50-0.96, p=0.03 for the triangular; 95% CI 0.37-0.88, p=0.01 for the restricted procedure). Conventional analysis of the follow-up data also showed significant superiority of CTRT. The trial extended with simulated data ended at 60 months with 251 patients (178 deaths), showing significant superiority of CTRT under both designs (95% CI for hazard ratio 0.55-0.97). The two sequential procedures would have led to the same conclusion as that reached by the Cancer and Leukemia Group B, still achieving considerable savings in patients recruited and time over the conventional design. The data simulated under the rather conservative null hypothesis did not reverse the positive result claimed by the Cancer and Leukemia Group B.

Carcinoma, Non-Small-Cell Lung↗
PubMed2000

Short-term tumor cell lines from renal cell carcinoma for use as autologous tumor cell vaccines in the treatment of kidney cancer.

OBJECTIVE: We have tried to establish short-term cultures of autologous tumors from patients with renal cell carcinoma that could be used as active specific immunotherapy (i.e., autologous vaccine) in such patients after resection of primary kidney cancer, and/or for the treatment of metastatic cancer. METHODS: Between 10/90 and 9/99 the cell biology laboratory of the Hoag Cancer Center received 69 kidney tumor samples that had been surgically excised, including 43 primary tumors and 26 metastatic lesions. Efforts were made to establish short-term tumor cell cultures, as defined by the growth of 10(8) cells; malignant nature and renal cell origin were confirmed by morphology and antigenic phenotyping. Variables associated with successful growth of short-term cell lines were examined. RESULTS: Short-term cell lines were successfully established from 55/69 samples [80%] including 36/43 (84%) from primary tumors and 19/26 (73%) from metastatic lesions. The success rate for tumors harvested at Hoag Hospital was 40/50 (80%); the success rate for tumors obtained from other geographic areas was 15/19 (79%). Tumor cell lines were successfully established from metastatic lesions ranging in size from a 0.5 g vertebral lesion to a 22 g rib/lung chest wall metastasis, and from primary renal cell lesions ranging in size from 1.5 g to 39.7 g. CONCLUSIONS: Short-term cell lines can be established for most patients with primary or metastatic renal cell carcinoma making a pure autologous tumor-cell vaccine approach feasible. Vaccines have been prepared for 41 patients and a vaccine therapy trial is in progress.

Bone Neoplasms↗
PubMed2000

Phase II trial of subcutaneous interleukin-2, subcutaneous interferon-alpha, intravenous combination chemotherapy, and oral tamoxifen in the treatment of metastatic melanoma: final results of cancer biotherapy research group 94-11.

BACKGROUND: The treatment of metastatic melanoma remains unsatisfactory despite encouraging results with biotherapy and combination chemotherapy. Combining these two modalities may improve outcomes for such patients. METHODS: Eligible patients had metastatic melanoma, were in good medical condition, and had not been treated previously for metastatic disease. A 42-day treatment cycle consisted of: tamoxifen 10 mg p.o. b.i.d. days 1-42, carmustine 150 mg/m2 i.v. on day three, dacarbazine 220 mg/m2 and cisplatin 25 mg/m2 i.v. q.d. days 3-5, and 24-26, interferon-alpha 2b 6.0 MU/m2 s.c. days 8-12 and 29-33, and interleukin-2 11 MU/m2 s.c. days 8, 10, 12 and 29, 31, 33. In the absence of tumor progression, patients could receive up to six cycles of alternating treatment. Toxicity and tumor response was assessed following each treatment cycle; survival was determined from the first date of treatment. RESULTS: The 28 melanoma patients included 21 men and 7 women, with a median age of 55 years with a range of 26-77. Fifty-four percent were asymptomatic when treatment was initiated. Eighty percent had soft tissue metastases, 32% lung, 28% liver, and 8% bone. There were nine patients with significant tumor responses (three complete, six partial) for a response rate of 32% (18-57% 95% CI) based on intent-to-treat analysis, and 38% (18-57%, 95% CI) for the 24 patients who were evaluable for response. The months of duration of survival for responders were 38.9+, 27.2+, 22.8+, 16.3, 13.2, 9.4, 7.5, 6.5+, and 5.8. At a median follow-up of 31 months, the median duration of event-free survival was 4.6 months; median survival was 9.4 months. The survival rate one year from initiating treatment was 42%; 2-year survival was 14%. The most frequent toxicities were 96% nausea/vomiting, 80% fatigue, 73% thrombocytopenia, 60% neutropenia, and 44% fever. Two patients experienced early death that may have been treatment related; one died of cardiovascular complications and the other of a central nervous system event. CONCLUSION: This outpatient regimen was associated with significant toxicity including a 7% rate of possible treatment-related death. Tumor regression rates and survival were similar to results reported for chemotherapy alone, or inpatient IL-2-based therapy, but did not suggest an improvement in outcome.

Administration, Oral↗
PubMed2000

Characterization of cancer cell lines established from two human metastatic breast cancers.

Cell lines are valuable resources for the study of the malignancy and potential therapy of human breast cancer. A major problem with adapting fresh breast tumor specimens to grow in vitro is contamination by fibroblasts. Previously, we have reported a technique to overcome this problem (Nayak, S. K; Dillman, R. O. Clin. Biotechnol. 3:237-242; 1991). We have recently established two new breast cancer cell lines, HH315 and HH375, that were derived from abdominal and supraclavicular lymph node metastases from two patients. They were characterized by (1) growth kinetics; (2) staining with monoclonal antibodies (MoAbs) to cytokeratin-19, epithelial membrane antigen (EMA), anticarcinoembryonic antigen (CEA), breast cancer antigen 1 (BRST-1), breast cancer antigen 2 (BRST-2), Her2/neu, and p53; (3) expression of domains of urinary plasminogen activator (uPA), neural cell adhesion molecule (NCAM), and haptoglobin (Hp) (Harvey et al., 1997); and (4) karyotypic analysis. Growth kinetic studies showed that doubling times for both lines ranged from 48 to 96 h. These two cell lines were found to have characteristics of the metastatic breast cancer cells. Both lines stained positive with MoAbs to cytokeratin-19 and EMA, thus confirming their epithelial origin. They also strongly reacted with the pan-breast carcinoma MoAbs BRST-1 and BRST-2, and carcinoembryonic CEA MoAb. Both cell lines overexpressed the oncogene proteins Her2/neu and p53. The tumor cells were negative for estrogen and progesterone receptors. HH315 cells were poorly differentiated, whereas the HH375 cells exhibited adenocarcinoma morphology. Both cell lines showed intense cell surface and some cytoplasmic staining for uPA, NCAM, and Hp domains, which is a characteristic of malignant neoplasms (Harvey et al., 1997). The HH375 cell line showed two cell types, of which 60% were hyperdiploids with 60-70 chromosomes and 5-10 marker chromosomes. The remaining cells were polyploid with more than 200 chromosomes. Cell line HH315 consisted of only a polyploid population. These cell lines may be useful in breast cancer research.

Breast Neoplasms↗
PubMed2000

Optimizing the use of rituximab for treatment of B-cell non-Hodgkin's lymphoma: a benefit-risk update.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA), the first monoclonal antibody approved in the United States for the treatment of cancer, is indicated for the treatment of patients with relapsed or refractory CD20+ low-grade non-Hodgkin's lymphoma. From November 1997 through May 1999, approximately 36,000 patients have been treated with rituximab. Serious cardiopulmonary infusion reactions culminating in death have been reported to occur in approximately 0.04% to 0.07% of patients. Post-approval tumor lysis syndrome has been reported within 12 to 24 hours after the first antibody infusion and is estimated to occur in 0.04% to 0.05% of patients. The risk of tumor lysis appears to be higher in patients with high numbers of circulating malignant cells. Serious infusion-related adverse drug reactions, most often consisting of cardiopulmonary reactions associated with the rapid lysis of large numbers of circulating malignant cells, have been fatal in approximately 0.5 per 1,000 treated patients. Major risk factors include high numbers of circulating malignant lymphoma cells, pulmonary infiltrates or lymphoma involvement, and prior cardiovascular disease. This report updates the safety experience of rituximab therapy with data from clinical trials and postmarketing safety experience, and examines how this information can be used to optimize therapy.

Antibodies, Monoclonal↗
PubMed1999

Infusion reactions associated with the therapeutic use of monoclonal antibodies in the treatment of malignancy.

With the FDA approval of Rituximab in 1998 for the treatment of lymphoma, and Trastuzumab in 1999 for the treatment of breast cancer, monoclonal antibodies were officially added to the therapeutic armamentarium against malignancy. Most of the side effects associated with these agents are due to antigen-antibody interactions on specific cells and tissues. One of the most predictable side effects of these products is a constellation of various systemic effects including flu-like symptoms such as headache, fever, sweats, skin rash, shortness of breath, hypotension, nausea, and asthenia that occurs with the first infusion of such products. Rarely severe hypotension, bronchospasm, and hypoxia and even death have occurred. The pathophysiology of these reactions appears to be secondary to the release of cytokines as the antibodies bind do circulating antigen-expressing cells that are then removed in the reticuloendothelial system of the lungs, spleen and liver. In patients with large numbers of antigen-dense cells that have a high mitotic index, such as prolymphocytic leukemia, mantle cell lymphoma, or lymphosarcoma cell leukemia, there is a risk of true tumor lysis syndrome. One should be particularly cautious when treating patients with high numbers of circulating antigen-expressing cells in the setting of underlying cardiovascular or respiratory disease.

Antibodies, Monoclonal↗
PubMed1999

Modulation of renal carcinoma cells in vitro: comparison after transduction with retroviral vector containing a human IFN-gamma gene versus incubation with soluble IFN-gamma.

Transduction of renal cell carcinoma (RCC) cells in vitro with a gene for human interferon-gamma (IFN-gamma) results in enhanced expression of key molecules needed for immune recognition. In this study, we investigated the ability of soluble IFN-gamma protein to enhance expression of these key molecules. RCC cells were incubated with and without IFN-gamma, then analyzed by flow cytometry for the percent positive and mean intensity fluorescence (MIF), a measurement of mean antigen density, of HLA-I, HLA-II, ICAM-1, and tumor antigens (URO-2, URO-3, and URO-4). Results were compared to those seen for RCC cells transduced by IFN-gamma. The ability of cytotoxic T lymphocytes (CTL) to lyse RCC targets was measured using a standard [51Cr]lytic assay. Control cells were 99% (MIF 751) and 98% (MIF 315) positive for HLA-I and ICAM-1, respectively, with 2% (MIF 8) positive for HLA-II. Incubation with IFN-gamma protein resulted in 98% positive HLA-I (MIF 2288), 98% positive ICAM-1 (MIF 1132), and 95% positive HLA-II (MIF 287). The results for the cells incubated with IFN-gamma protein were similar to those for the transduced line. Importantly, the enhanced expression was maintained for several days after irradiation and cryopreservation. Expression of the URO tumor markers was not affected. Protein-treated RCC targets showed superior CTL lysis compared with untreated cells. Our results show that IFN-gamma protein incubation in vitro enhances expression of important immune recognition molecules to levels expressed by transduced cells. Increased expression may enhance tumor recognition by the host's immune system, as in the case of tumor cell vaccines. There may be no advantage to IFN-gamma transduction over in vitro incubation with IFN-gamma protein.

Adjuvants, Immunologic↗