The Experts below are selected from a list of 297 Experts worldwide ranked by ideXlab platform
David Edward Gilham - One of the best experts on this subject based on the ideXlab platform.
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the optimal Antigen Response of chimeric Antigen receptors harboring the cd3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous tcr cd3 complex
Journal of Immunology, 2010Co-Authors: John S Bridgeman, Robert E Hawkins, Steven Bagley, Mark Holland, Morgan Blaylock, David Edward GilhamAbstract:Chimeric Ag receptors (CARs) expressed in T cells permit the redirected lysis of tumor cells in an MHC-unrestricted manner. In the Jurkat T cell model system, expression of a carcinoembryonic Ag-specific CD3ζ CAR (MFEζ) resulted in an increased sensitivity of the transduced Jurkat cell to generate cytokines when stimulated through the endogenous TCR complex. This effect was driven through two key characteristics of the MFEζ CAR: 1) receptor dimerization and 2) the interaction of the CAR with the endogenous TCR complex. Mutations of the CAR transmembrane domain that abrogated these interactions resulted in a reduced functional capacity of the MFEζ CAR to respond to carcinoembryonic Ag protein Ag. Taken together, these results indicate that CARs containing the CD3ζ transmembrane domain can form a complex with the endogenous TCR that may be beneficial for optimal T cell activation. This observation has potential implications for the future design of CARs for cancer therapy.
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the optimal Antigen Response of chimeric Antigen receptors harboring the cd3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous tcr cd3 complex
Journal of Immunology, 2010Co-Authors: John S Bridgeman, Robert E Hawkins, Steven Bagley, Mark Holland, Morgan Blaylock, David Edward GilhamAbstract:Chimeric Ag receptors (CARs) expressed in T cells permit the redirected lysis of tumor cells in an MHC-unrestricted manner. In the Jurkat T cell model system, expression of a carcinoembryonic Ag-specific CD3zeta CAR (MFEzeta) resulted in an increased sensitivity of the transduced Jurkat cell to generate cytokines when stimulated through the endogenous TCR complex. This effect was driven through two key characteristics of the MFEzeta CAR: 1) receptor dimerization and 2) the interaction of the CAR with the endogenous TCR complex. Mutations of the CAR transmembrane domain that abrogated these interactions resulted in a reduced functional capacity of the MFEzeta CAR to respond to carcinoembryonic Ag protein Ag. Taken together, these results indicate that CARs containing the CD3zeta transmembrane domain can form a complex with the endogenous TCR that may be beneficial for optimal T cell activation. This observation has potential implications for the future design of CARs for cancer therapy.
Tomasz M Beer - One of the best experts on this subject based on the ideXlab platform.
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complete biochemical prostate specific Antigen Response to sipuleucel t with enzalutamide in castration resistant prostate cancer a case report with implications for future research
Urology, 2013Co-Authors: Julie N Graff, Charles G Drake, Tomasz M BeerAbstract:Objective To describe the case of a patient with castration-resistant, metastatic prostate cancer who achieved a complete and durable biochemical Response after treatment with sipuleucel-T while continuing with enzalutamide and to explore the immunologic basis for such a Response. Materials and Methods We obtained serial prostate-specific Antigen (PSA) measurements and bone scans to assess the patient's Response to enzalutamide followed by the addition of sipuleucel-T. Using preclinical and clinical data, we describe his Response through known immunobiologic mechanisms. Results This patient's PSA level became undetectable during treatment with enzalutamide and began to increase again after 14 months. He opted for treatment with sipuleucel-T, while continuing with the enzalutamide. This resulted in another complete PSA Response 6 months after exposure to sipuleucel-T. Conclusion Sipuleucel-T typically does not produce significant PSA reductions, and, to the best of our knowledge, only 1 previous report of a durable complete PSA Response in a patient with metastatic disease has been published. The timing of this Response supports an immune mechanism. The biologic rationale for the combination, coupled with the clinical result observed in our patient, provides a basis for studies of the combination of sipuleucel-T and enzalutamide.
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Phase II Study of Androgen Synthesis Inhibition with Ketoconazole, Hydrocortisone, and Dutasteride in Asymptomatic Castration-Resistant Prostate Cancer
Clinical Cancer Research, 2009Co-Authors: Mary-ellen Taplin, Meredith M. Regan, Glenn J. Bubley, Stephen Duggan, Lillian Werner, Tomasz M. Beer, Christopher W. Ryan, Tomasz M Beer, Paul MathewAbstract:Purpose: Increasing evidence indicates that enhanced intratumoral androgen synthesis contributes to prostate cancer progression after androgen deprivation therapy. This phase II study was designed to assess Responses to blocking multiple steps in androgen synthesis with inhibitors of CYP17A1 (ketoconazole) and type I and II 5α-reductases (dutasteride) in patients with castration-resistant prostate cancer (CRPC). Experimental Design: Fifty-seven men with CRPC were continued on gonadal suppression and treated with ketoconazole (400 mg thrice daily), hydrocortisone (30 mg/AM, 10 mg/PM), and dutasteride (0.5 mg/d). Results: Prostate-specific Antigen Response rate (≥50% decline) was 56% (32 of 57; 95% confidence interval, 42.4-69.3%); the median duration of Response was 20 months. In patients with measurable disease, 6 of 20 (30%) responded by the Response Evaluation Criteria in Solid Tumors. Median duration of treatment was 8 months; 9 patients remained on therapy with treatment durations censored at 18 to 32 months. Median time to progression was 14.5 months. Grade 3 toxicities occurred in 32% with only one reported grade 4 (thrombosis) toxicity. Dehydroepiandrosterone sulfate declined by 89%, androstenedione by 56%, and testosterone by 66%, and dihydrotestosterone declined to below detectable levels compared with baseline levels with testicular suppression alone. Median baseline levels and declines in dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were not statistically different in the responders versus nonresponders, and hormone levels were not significantly increased from nadir levels at relapse. Conclusion: The Response proportion to ketoconazole, hydrocortisone, and dutasteride was at least comparable with previous studies of ketoconazole alone, whereas time to progression was substantially longer. Combination therapies targeting multiple steps in androgen synthesis warrant further investigation. (Clin Cancer Res 2009;15(22):7099–105)
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Imatinib mesylate and zoledronic acid in androgen-independent prostate cancer.
Urology, 2004Co-Authors: Natasha M. Tiffany, Emily M. Wersinger, Mark Garzotto, Tomasz M BeerAbstract:Objectives. To determine the safety and efficacy of zoledronic acid (Zometa) combined with imatinib mesylate (Gleevec) in patients with bone pain due to androgen-independent prostate cancer. Methods. Fifteen patients were treated with zoledronic acid 4 mg intravenously every 28 days and imatinib mesylate 400 mg/day. The pain Response, defined as a 2-point reduction in the Present Pain Intensity Scale or normalization if the initial score was 1, was the primary endpoint. Secondary endpoints included palliative Response, prostate-specific Antigen Response, measurable disease Response, time to progression, impact on quality of life, decrease in markers of bone turnover, and tolerability of the drug combination. Results. The study was stopped early because of a lack of activity. No palliative or clinical activity was detected for the combination, and no prostate-specific Antigen Responses were observed. The median time to progression was 4 weeks (95% confidence interval 3 to 5), and the median duration of treatment was 8 weeks (range 1.6 to 16.7). The median overall survival was 54 weeks (95% confidence interval 18 to 90). Therapy was associated with a reduction in urine N-telopeptides and a trend toward a reduction in serum osteocalcin, but no change occurred in bone-specific alkaline phosphatase. Conclusions. In this patient population, imatinib mesylate and zoledronic acid produced no prostatespecific Antigen Responses and had no palliative or clinical activity. UROLOGY 63: 934‐939, 2004. © 2004 Elsevier Inc.
John S Bridgeman - One of the best experts on this subject based on the ideXlab platform.
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the optimal Antigen Response of chimeric Antigen receptors harboring the cd3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous tcr cd3 complex
Journal of Immunology, 2010Co-Authors: John S Bridgeman, Robert E Hawkins, Steven Bagley, Mark Holland, Morgan Blaylock, David Edward GilhamAbstract:Chimeric Ag receptors (CARs) expressed in T cells permit the redirected lysis of tumor cells in an MHC-unrestricted manner. In the Jurkat T cell model system, expression of a carcinoembryonic Ag-specific CD3ζ CAR (MFEζ) resulted in an increased sensitivity of the transduced Jurkat cell to generate cytokines when stimulated through the endogenous TCR complex. This effect was driven through two key characteristics of the MFEζ CAR: 1) receptor dimerization and 2) the interaction of the CAR with the endogenous TCR complex. Mutations of the CAR transmembrane domain that abrogated these interactions resulted in a reduced functional capacity of the MFEζ CAR to respond to carcinoembryonic Ag protein Ag. Taken together, these results indicate that CARs containing the CD3ζ transmembrane domain can form a complex with the endogenous TCR that may be beneficial for optimal T cell activation. This observation has potential implications for the future design of CARs for cancer therapy.
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the optimal Antigen Response of chimeric Antigen receptors harboring the cd3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous tcr cd3 complex
Journal of Immunology, 2010Co-Authors: John S Bridgeman, Robert E Hawkins, Steven Bagley, Mark Holland, Morgan Blaylock, David Edward GilhamAbstract:Chimeric Ag receptors (CARs) expressed in T cells permit the redirected lysis of tumor cells in an MHC-unrestricted manner. In the Jurkat T cell model system, expression of a carcinoembryonic Ag-specific CD3zeta CAR (MFEzeta) resulted in an increased sensitivity of the transduced Jurkat cell to generate cytokines when stimulated through the endogenous TCR complex. This effect was driven through two key characteristics of the MFEzeta CAR: 1) receptor dimerization and 2) the interaction of the CAR with the endogenous TCR complex. Mutations of the CAR transmembrane domain that abrogated these interactions resulted in a reduced functional capacity of the MFEzeta CAR to respond to carcinoembryonic Ag protein Ag. Taken together, these results indicate that CARs containing the CD3zeta transmembrane domain can form a complex with the endogenous TCR that may be beneficial for optimal T cell activation. This observation has potential implications for the future design of CARs for cancer therapy.
Oliver Sartor - One of the best experts on this subject based on the ideXlab platform.
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Early prostate-specific Antigen Response post-abiraterone as predictor of overall survival in metastatic castrate-resistant prostate cancer
BMC cancer, 2019Co-Authors: Joshua Schiff, Patrick Cotogno, Allison H. Feibus, Peter Steinwald, Elisa Ledet, Brian E. Lewis, Oliver SartorAbstract:Abiraterone is an important agent in the treatment of advanced prostate cancer. Early changes in prostate-specific Antigen while on abiraterone in patients with metastatic castrate-resistant prostate cancer potentially have financial and health implications for patients. Limited data is available on early prostate-specific Antigen change and subsequent survival given phase III trials did not measure prostate-specific Antigen changes before 12 weeks. A single-center retrospective study was performed. Metastatic castrate-resistant prostate cancer patients treated with abiraterone (without prior enzalutamide) at Tulane Cancer Center were reviewed with a focus on early prostate-specific Antigen decline and relationship to overall survival. A total of 110 patients were analyzed for prostate-specific Antigen Response of ≥ 30 and > 50% at 4, 8, and 12 weeks. A prostate-specific Antigen Response of either > 30% or > 50% at 4, 8, or 12 weeks was associated with improved overall survival at all time points except > 50% decline at 8 weeks. Multivariate analysis indicated, for all time points, that early prostate-specific Antigen declines were predictive of overall survival. The neutrophil to lymphocyte ratio and docetaxel pretreatment also were predictive in many, but not all, of the multivariate analyses. A > 30% or > 50% prostate-specific Antigen decline at 4, 8, or 12 weeks provides important information regarding subsequent overall survival for patients with metastatic castrate-resistant prostate cancer. While these data require validation with a large, multi-institutional trial, they can provide physicians with information regarding prognosis and the timing of expected outcomes. These data affirms the notion that prostate-specific Antigen Responses as early as 4 weeks after abiraterone initiation can be used to inform both patients and physicians about metastatic castrate-resistant prostate cancer outcomes after initiating treatment with this important but costly therapeutic choice.
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Extreme Prostate-Specific Antigen Response to Infusional 5-Flourouracil in Castrate-Resistant Prostate Cancer.
The oncologist, 2017Co-Authors: Charlotte Manogue, Elisa Ledet, Brian E. Lewis, A. Kumar Guddati, Oliver SartorAbstract:Prostate cancer that has progressed after androgen deprivation, abiraterone, and taxane therapy is challenging to treat successfully. Herein we report a dramatic Response to continuous-infusion 5-fluorouracil (5-FU) at a dose of 200 mg/m2 in a patient with rapidly progressive, heavily pretreated, metastatic castrate-resistant prostate cancer. Baseline prostate-specific Antigen values declined from 1,890 ng/mL to
Michael G. Miller - One of the best experts on this subject based on the ideXlab platform.
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factors influencing prostate specific Antigen Response among men treated with testosterone therapy for 6 months
The Journal of Sexual Medicine, 2014Co-Authors: Abraham Morgentaler, Janet Benesh, Bela S. Denes, Diala Harb, Natalia Kandobrosky, Michael G. MillerAbstract:Abstract Introduction Factors influencing prostate‐specific Antigen (PSA) changes in men undergoing testosterone (T) therapy have not been well studied. Aim The aim of this study was to assess the influence of selected variables on PSA changes in hypogonadal men administered with 1.62% testosterone gel (T‐gel) for 6 months. Methods A double‐blind, placebo‐controlled study of 274 (234 T‐gel, 40 placebo) hypogonadal men >18 years of age, with baseline T concentrations Main Outcome Measures Changes in mean serum PSA, percentage of free PSA (%fPSA), and T from baseline to 6 months (182 days). Results Mean age was 53.5 years and baseline mean values were total T 247 ng/dL, PSA 0.9 ng/mL, and %fPSA 24.6%. Among men treated with T‐gel, T increased to 499 ng/dL and PSA increased by 0.1 ng/mL ( P = 0.0012). PSA increased ≥0.3 ng/mL in 26.3%, P = 0.0006). Mean PSA did not change in men with baseline serum T >250 ng/dL, whereas it increased by 0.2 ng/mL in men with T ≤250 ng/dL ( P = 0.0031). PSA increased 0.3 ng/mL in men with baseline %fPSA Conclusions Overall, T‐gel treatment was associated with a minor increase in PSA, of questionable clinical significance. Factors predicting greater PSA increases included age ≥60 years, baseline T ≤250 ng/dL, and %fPSA 250 ng/dL and age Morgentaler A, Benesh JA, Denes BS, Kan‐Dobrosky N, Harb D, and Miller MG. Factors influencing prostate‐specific Antigen Response among men treated with testosterone therapy for 6 months. J Sex Med 2014;11:2818–2825.
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Factors Influencing Prostate‐Specific Antigen Response among Men Treated with Testosterone Therapy for 6 Months
The journal of sexual medicine, 2014Co-Authors: Abraham Morgentaler, Janet Benesh, Bela S. Denes, Natalia Kan-dobrosky, Diala Harb, Michael G. MillerAbstract:Abstract Introduction Factors influencing prostate‐specific Antigen (PSA) changes in men undergoing testosterone (T) therapy have not been well studied. Aim The aim of this study was to assess the influence of selected variables on PSA changes in hypogonadal men administered with 1.62% testosterone gel (T‐gel) for 6 months. Methods A double‐blind, placebo‐controlled study of 274 (234 T‐gel, 40 placebo) hypogonadal men >18 years of age, with baseline T concentrations Main Outcome Measures Changes in mean serum PSA, percentage of free PSA (%fPSA), and T from baseline to 6 months (182 days). Results Mean age was 53.5 years and baseline mean values were total T 247 ng/dL, PSA 0.9 ng/mL, and %fPSA 24.6%. Among men treated with T‐gel, T increased to 499 ng/dL and PSA increased by 0.1 ng/mL ( P = 0.0012). PSA increased ≥0.3 ng/mL in 26.3%, P = 0.0006). Mean PSA did not change in men with baseline serum T >250 ng/dL, whereas it increased by 0.2 ng/mL in men with T ≤250 ng/dL ( P = 0.0031). PSA increased 0.3 ng/mL in men with baseline %fPSA Conclusions Overall, T‐gel treatment was associated with a minor increase in PSA, of questionable clinical significance. Factors predicting greater PSA increases included age ≥60 years, baseline T ≤250 ng/dL, and %fPSA 250 ng/dL and age Morgentaler A, Benesh JA, Denes BS, Kan‐Dobrosky N, Harb D, and Miller MG. Factors influencing prostate‐specific Antigen Response among men treated with testosterone therapy for 6 months. J Sex Med 2014;11:2818–2825.