Gold standard or wrong standard?
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Antineoplastic Agents↗
Biomedical subjects
Robert Dillman
Publications and source records attributed to Robert Dillman.
A theoretical approach for T-lymphocyte monitoring of autologous cancer vaccine therapy using autologous HLA-class I and HLA-class II constructs.
It is desirable to have in vitro surrogate endpoints that reflect changes in cellular immunity in patients who are undergoing treatment with anticancer, autologous, tumor-cell vaccines. The tetramer assay appears to be useful for monitoring T-lymphocyte responses to a single, specific, known tumor peptide antigen, but cell-based vaccines may express multiple tumor-associated antigens that are important in a host immune response to their own cancer. We describe a hypothetical alternative to the standard artificial tetramer assay, that has the potential to detect CD4+ and CD8+ T-lymphocytes that react with any peptides expressed in the context of HLA-class I or HLA-class II. Such an assay should enable monitoring for specific T-lymphocyte antitumor activity in patients being treated with patient specific, autologous, tumor-cell vaccines.
Cancer Vaccines↗
Autologous tumor cell line-derived vaccine for patient-specific treatment of advanced renal cell carcinoma.
AIM: We previously reported the laboratory methodology for producing patient-specific irradiated autologous tumor-cell products derived from short-term cultured tumor cells from resected renal cell carcinoma, and described preliminary clinical results. In this study, we report the final clinical results and efforts to define vaccine potency on the basis of clinical outcome for these 25 patients with advanced renal cell carcinoma. MATERIALS AND METHODS: Approximately 10(8) cells from successful short-term cell lines were irradiated, frozen in aliquots of 10(7) cells, then thawed and administered subcutaneously (s.c.) once a week for 3 weeks, then once a month for 5 months. Patients included 19 men and 6 women, who were 43-82 years of age. Six (6) patients had a large primary lesion, 2 patients had regionally advanced disease, 3 patients had been rendered disease-free by surgical resection of distant metastases, and 14 patients had measurable distant metastatic disease. RESULTS: The vaccines were well tolerated, and no delayed autoimmune effects were documented. Delayed-type hypersensitivity (DTH) tests of irradiated tumor cells were positive in only 1 of 25 patients at week 0, but converted to positive in 6 of 18 patients of DTH-negative patients who were retested at week 4. Objective response rate in patients who had measurable metastatic disease was 0 of 14 patients. With a median follow-up of greater than 7 years from the date of the first DTH test, median survival is 33.4 months, 5-year survival is 43%, and 10 patients are alive 3-12 years later. The 7 DTH+ patients survived a median of 2.5 years, and 3 patients are alive after 3, 4, and 7 years. There was no correlation between the number of irradiated cells or viable irradiated cells injected and tumor DTH reactivity or survival. CONCLUSION: This approach is feasible and the therapy is well tolerated, but clinical benefit was not established in this trial. Any further exploration of this product should be limited to the adjuvant setting in a randomized trial.
Adult↗
Phase I/II trial of autologous tumor cell line-derived vaccines for recurrent or metastatic sarcomas.
AIM: We previously reported the laboratory methodology for producing patient-specific irradiated autologous tumor-cell products derived from short-term cultured tumor cells. We attempted to determine the feasibility, safety, and clinical effects of autologous tumor vaccine-derived sarcomas. PATIENTS AND METHODS: Efforts were made to establish tumor cell lines in tissue culture with expansion to 100 million cells for patients who were candidates for therapy. Cells were irradiated and cryopreserved in aliquots of 10 million cells for subcutaneous (s.c.) injections, once a week for 3 weeks, then once a month for 5 months. RESULTS: Efforts were made to establish short-term tumor cell lines from 86 fresh sarcoma specimens (10 primary, 14 recurrent, and 62 metastatic). Initial growth was successful for 48 patients (56%), and cultures were expanded for 36 patients, with 25 patients treated. There were 23 evaluable patients, including 12 women and 11 men, with a median age of 52 years and a range from 16-79 years. Vaccine therapy was well tolerated. Delayed-type hypersensitivity (DTH) tests to irradiated tumor cells were positive in 0 of 20 patients tested at baseline, but converted to positive after 3 weekly vaccinations in 8 of 16 patients who were retested. Median survival for the 8 DTH converters was 16.6 months versus 8.2 months for the 8 responders whose tumor DTH test remained negative, and 6.0 months for the 7 patients who were not tested. No objective responses were recorded among 12 evaluable patients with measurable disease; 10 patients have survived more than 1 year. CONCLUSIONS: This approach is feasible, well tolerated, and the resulting DTH conversion rate is of interest. Patients with minimal tumor burden would be preferred for further future testing.
Adolescent↗
Phase I/II trial of melanoma patient-specific vaccine of proliferating autologous tumor cells, dendritic cells, and GM-CSF: planned interim analysis.
AIM: The aim of this study was to investigate the feasibility, safety, and clinical efficacy of patient-specific dendritic cell vaccines in patients with metastatic melanoma. A planned interim analysis was conducted on the first 20 patients. METHODS: Tumor cell lines were established from metastatic tumor, expanded to 200 million cells, and then incubated with interferon-gamma for patients who were candidates for therapy. Cells were irradiated and cryopreserved. Patients underwent leukapheresis to obtain mononuclear cells that were cultured in the presence of IL-4 and GM-CSF to produce dendritic cells, which were incubated with cryopreserved, irradiated tumor cells, and then stored in aliquots of about 20 million cells for subcutaneous (s.c.) injections with GM-CSF once a week for 3 weeks, then once a month for 5 months. RESULTS: The first 20 eligible patients included 10 men and 10 women, with a median age of 48 years (range, 16-79 years). Three (3) patients had brain metastases, and 13 patients had experienced disease progression after biochemotherapy. At the time of vaccine treatment, 6 patients had evaluable metastatic disease, while 14 patients lacked measurable disease. Vaccine therapy was well tolerated, except for what appeared to be GM-CSF-related allergic reactions in 2 patients. Delayed-type hypersensitivity (DTH) tests to irradiated tumor cells were positive in 0 of 20 patients tested at baseline, but converted to positive in 8 patients (40%). At a median follow-up of 13.8 months, there is a 95% overall survival and a 48% progression-free survival. Four (4) patients have already survived more than 3.0 years since starting the vaccine. CONCLUSION: Based on tolerability, rate of tumor DTH conversion, and encouraging survival, the trial will continue accrual to at least 19 patients with measurable disease and 40 patients who lack measurable disease at the time of treatment.
Adolescent↗
Tumor-infiltrating lymphocytes and interleukin-2: dose and schedules of administration in the treatment of metastatic cancer.
PURPOSE: The potential for therapeutic use of tumor-infiltrating lymphocytes (TIL), as adoptive cellular therapy has been touted for many years with some encouraging reports in patients with metastatic melanoma. MATERIALS AND METHODS: We previously described methodologies for TIL production and phenotypic characterization of TIL generated in our laboratory between 1991 and 1995 in semipermeable bags and between 1996 and 2000 in bioreactors. Patients treated in the earlier era were to have received a hybrid bolus and a 12-hour continuous infusion of interleukin (IL)-2 (total, 48 MIU), while in the latter era 4 days of interferon- alpha preceded the TIL and IL-2; which was given by a hybrid schedule that included bolus and 72- hour continuous IL-2 (total, 96 MIU). There were 55 patients, including 23 patients with melanoma, 9 patients with renal cell carcinoma, and 8 patients with colorectal cancer. There was only 1 objective tumor response, which was noted in a patient with renal cell carcinoma. The 55 patients who received these products were grouped in cohorts by treatment era, quantity of TIL received, amount of IL-2 intended, and different combinations of TIL and IL-2. RESULTS: There was no difference in survival by production method (treatment era), or amount of IL-2 given with TIL, but 33 patients who received an intermediate or higher dose of TIL (mean = 54.4 x 10(9)) had a median survival of 11.8 months, compared to 6.4 months for 22 patients who received 1 low-dose TIL (mean = 6.48 x 10(9)) (p = 0.059, log rank test). The objective response rate in this heterogeneous group of patients was not encouraging. The data suggest there may be a dose/benefit relationship between the total number of TIL infused and survival.
Adolescent↗
PITUITARY TUMOR, QT PROLONGATION AND VENTRICULAR ARRHYTHMIA.
Various types of nervous system diseases have been associated with QT prolongation and ventricular arrhythmias. This report describes a young woman with a pituitary tumor, who had QT prolongation and recurrent syncope secondary to ventricular fibrillation. Effective therapy with digoxin and propranolol are described, and pathophysiology of the syndrome is discussed.
Journal Article↗