The Experts below are selected from a list of 123 Experts worldwide ranked by ideXlab platform
Volker Schirrmacher - One of the best experts on this subject based on the ideXlab platform.
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Autologous Tumor Cell vaccines for post-operative active-specific immunotherapy of colorectal carcinoma: long-term patient survival and mechanism of function.
Expert review of vaccines, 2014Co-Authors: Volker Schirrmacher, Philippe Fournier, Peter M. SchlagAbstract:Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Surgery remains the primary curative treatment but nearly 50% of patients relapse as consequence of micrometastatic or minimal residual disease (MRD) at the time of surgery. Spontaneous T-Cell-mediated immune responses to CRC Tumor-associated antigens (TAAs) in Tumor-draining lymph nodes and in the bone marrow (BM) lead to infiltration of the Tumors by lymphocytes. Certain types of such Tumor-infiltrating lymphocytes (TILs) have a positive and others a negative impact on the patients' prognosis. This review focuses on advances in CRC active-specific immunotherapy (ASI), in particular on results from randomized controlled clinical studies employing therapeutic Autologous Tumor Cell vaccines. The observed improvement of long-term survival is explained by activation and mobilization of a pre-existing repertoire of Tumor-reactive memory T Cells which, according to recent discoveries, reside in distinct niches of patients' bone marrow in neighborhood with hematopoietic (HSC) and mesenchymal (MSC) stem Cells. Interestingly, memory T Cells also contain a subset of stem memory T Cells (SMTs) in addition to effector (EMTs) and central memory T Cells (CMTs). The mechanism of function of a therapeutic vaccine in a chronic disease is distinct from that of prophylactic vaccines which have to generate de novo protective immune responses. The advantage of Autologous vaccines for mobilization of a broad and highly individual repertoire of memory T Cells will be discussed.
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antiTumor vaccination in patients with head and neck squamous Cell carcinomas with Autologous virus modified Tumor Cells
Cancer Research, 2004Co-Authors: Jochen Karcher, Volker Schirrmacher, Gerhard Dyckhoff, Philipp Beckhove, Christoph Reisser, Michael Brysch, Yvonne Ziouta, Burkhard H Helmke, H Weidauer, Christel HeroldmendeAbstract:Prognosis of patients with advanced head and neck squamous Cell carcinomas (HNSCC) is still poor. Therefore, we analyzed whether antiTumor vaccination with a virus-modified Autologous Tumor Cell vaccine is feasible and safe in HNSCC patients. Furthermore, we determined the influence on disease-free survival and overall survival and the vaccination-induced antiTumor reactivity. In a nonrandomized pilot study, 20 patients were vaccinated postoperatively. Vaccine was prepared from the Tumor Cell cultures of patients by infection of the Cells with Newcastle Disease Virus, followed by γ-irradiation, and vaccine was applied up to five times. AntiTumor immune reactivity was determined in the skin by delayed type hypersensitivity skin reaction and in the blood by enzyme-linked immunospot assay. Establishment of Tumor Cell cultures was successful in about 80% of the cases. After vaccination, we observed no severe side effects. Percentages of survival of vaccinated patients with stage III and stage IV Tumors (n = 18) were 61% at 5 years. Immune monitoring revealed significant increases of antiTumor delayed type hypersensitivity reactivity especially in disease-free patients, and in a significant proportion of vaccinated patients the presence of Tumor-reactive T-Cells in the peripheral blood even 5 to 7 years after the last vaccination. Postoperative vaccination with virus-modified Autologous Tumor Cells seems to be feasible and safe and may improve the prognosis of HNSCC patients with advanced Tumors. This could be supported by antiTumor immune responses that we observed especially in long-term surviving patients.
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Clinical trials of antiTumor vaccination with an Autologous Tumor Cell vaccine modified by virus infection: improvement of patient survival based on improved antiTumor immune memory
Cancer immunology immunotherapy : CII, 2004Co-Authors: Volker SchirrmacherAbstract:For active specific immunotherapy of cancer patients, we designed the Autologous virus–modified Tumor Cell vaccine ATV-NDV. The rationale of this vaccine is to link multiple Tumor-associated antigens (TAAs) from individual patient-derived Tumor Cells with multiple danger signals (DS) derived from virus infection (dsRNA, HN, IFN-α). This allows activation of multiple innate immune responses (monocytes, dendritic Cells, and NK Cells) as well as adaptive immune responses (CD4 and CD8 memory T Cells). Preexisting antiTumor memory T Cells from cancer patients could be activated by antiTumor vaccination with ATV-NDV as seen by augmentation of antiTumor memory delayed-type hypersensitivity (DTH) responses. In a variety of phase II vaccination studies, an optimal formulation of this vaccine could improve long-term survival beyond what is seen in conventional standard therapies. A new concept is presented which proposes that a certain threshold of antiTumor immune memory plays an important role (1) in the control of residual Tumor Cells which remain after most therapies and (2) for long-term survival of treated cancer patients. This immune memory is T-Cell based and most likely maintained by persisting TAAs from residual dormant Tumor Cells. Such immune memory was prominent in the bone marrow in animal Tumor models as well as in cancer patients. Immunization with a Tumor vaccine in which individual TAAs are combined with DS from virus infection appears to have a positive effect on antiTumor immune memory and on patient survival.
H M Pinedo - One of the best experts on this subject based on the ideXlab platform.
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immunotherapy with Autologous Tumor Cell bcg vaccine in patients with colon cancer a prospective study of medical and economic benefits
Vaccine, 2005Co-Authors: C Uylde A Groot, M G Hanna, Jan B Vermorken, Paul Verboom, M T Groot, G J Bonsel, Chris J L M Meijer, H M PinedoAbstract:We have completed a multicenter, randomized controlled phase III clinical trial in Stages II and III colon cancer patients with active specific immunotherapy (ASI) using Autologous Tumor Cells with an immunomodulating adjuvant bacillus Callmette-Gu ´ (BCG) vaccine (OncoVAX ® ) in an adjuvant setting. In this study, patients were randomized to receive either OncoVAX ® therapy or no therapy after surgical resection of the primary Tumor and stratified by stage of disease. Since the biologic essence of the effective Tumor immunotherapy is the presence in the vaccine of a minimum number of viable, metabolically active, Autologous Tumor Cells, the processing of the vaccine product, occurred within 48 h after surgery. Analysis of prognostic benefit in the pivotal phase III trial, with a 5.8 year median follow-up, showed that a beneficial effect of OncoVAX ® is statistically significant for all endpoints including recurrence-free interval, overall survival, and recurrence-free survival in Stage II col on cancer patients. Surgery alone cures approximately 65% of Stage II (Dukes B2 ,B 3) colon cancer patients. In the remaining patients, OncoVAX ® in an adjuvant setting, significantly prolongs recurrence-free interval (57.1% relative risk reduction) and significantly improves 5-year overall survival and recurrence-free survival. No statistically significant prognostic benefits were achieved in Stage III (Duke’s C 1–C3) patients. A health economics assessment was performed on these results in Stage II colon cancer patients using disease-free survival and overall survival (for the entire intent-to-treat population). Cost-effectiveness, cost-utility and sensitivity analysis were applied with, cost of life years, recurrence-free life years and quality adjusted life years (QALYs) as the primary endpoints to this analysis. The perspective of the economic analysis was the current direct medical cost established by the health care providers. The introduction of new technologies often leads to additional costs. This report verified that the use of OncoVAX ® for patients with Stage II colon cancer not only has significant prognostic benefit and positive clinical outcomes, but also showed that OncoVAX ® therapy yields impressive health economics benefits.
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adjuvant active specific immunotherapy of stage ii and stage iii colon cancer with an Autologous Tumor Cell vaccine first randomized phase iii trials show promise
Vaccine, 2001Co-Authors: M G Hanna, Herbert C. Hoover, Jules E Harris, Jan B Vermorken, H M PinedoAbstract:We performed three multi-institutional, prospectively randomized, controlled clinical trials, assessing the therapeutic effect of post-resection adjuvant active specific immunotherapy in patients with stage II and stage III colon cancer. In each study four outcomes were considered: time-to-disease recurrence, overall survival intervals, disease-free survival intervals, and recurrence-free survival intervals using the Kaplan-Meir method for generating curves and the log-rank test used to compare efficacy distributions. In addition, a meta-analysis of the three phase III trials was performed since the trials had proven homogeneity. Two main analyses were performed: (1) the intent-to-treat colon cancer patients from all three studies; and (2) analyzable colon cancer patients in all three studies. The conclusion of these analyses is that adjuvant active specific immunotherapy provided significant clinical benefits in patients with stage II colon cancer and appears to be an important new adjuvant treatment for these patients.
Scott J Antonia - One of the best experts on this subject based on the ideXlab platform.
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a phase i trial using a universal gm csf producing and cd40l expressing bystander Cell line gm cd40l in the formulation of Autologous Tumor Cell based vaccines for cancer patients with stage iv disease
Annals of Surgical Oncology, 2007Co-Authors: Eduardo M Sotomayor, Mary Dunn, David Noyes, Sophie Dessureault, David Haldane Lee, William J Janssen, Alan B Cantor, Jane L Messina, Scott J AntoniaAbstract:Significant antiTumor T-Cell responses are generated in vitro when human lymphocytes are stimulated with Autologous Tumor Cells in the presence of bystander Cells transfected with CD40L and GM-CSF. Our goal was to test this bystander-based vaccine strategy in vivo in cancer patients with stage IV disease. Patients received three intradermal vaccine injections (irradiated Autologous Tumor Cells plus GM.CD40L bystander Cells) at 28-day intervals. Patients with no disease progression received three additional vaccines at 4, 12, and 24 months. Patients were monitored for toxicity, Tumor response, and Tumor-specific immune responses. Twenty-one patients received at least three vaccine injections, with no toxicity attributable to the vaccine. Immunohistochemistry of vaccine injection site biopsies with CD1a and CD86 antibodies confirmed recruitment and activation of dendritic Cells. There was no Tumor regression after vaccination, but many patients had stable disease, including six of ten melanoma patients. Four patients developed Tumor-specific T-Cell responses on ELISPOT testing. One patient, who had stable disease for 24 months, demonstrated an increase in MART-1-specific T-Cells by tetramer analysis after re-immunization; biopsy of the Tumor that progressed 2 years after the onset of vaccination revealed a massive periTumoral and intraTumoral T-Cell infiltrate. Vaccination of cancer patients with Autologous Tumor Cells and GM.CD40L bystander Cells (engineered to express GM-CSF and CD40L) is safe, can recruit and activate dendritic Cells, and can elicit Tumor-specific T-Cell responses. Phase-II trials are underway to evaluate the impact of bystander-based vaccines on melanoma and mantle Cell lymphoma.
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phase i trial of a b7 1 cd80 gene modified Autologous Tumor Cell vaccine in combination with systemic interleukin 2 in patients with metastatic renal Cell carcinoma
The Journal of Urology, 2002Co-Authors: Scott J Antonia, Mary Jane Farmelo, J J Mahany, John D Seigne, Jose I Diaz, Carlos A Murocacho, Martine Extermann, Maria Friberg, Marwan Alsarraj, Julio M PowsangAbstract:Purpose: A reason that the immune system may fail to reject Tumors is that T Cells encounter Tumor antigen derived peptides on the surface of Tumor Cells in a tolerizing rather than activating context since Tumor Cells do not express T Cell co-stimulatory molecules such as B7-1 (CD80). In preclinical models over expression of B7-1 on the surface of Tumor Cells has been shown to activate T Cells which kill Tumor Cells. We conducted a phase I clinical trial testing this approach in patients with metastatic renal Cell carcinoma.Materials and Methods: Resected Tumors from 15 patients were disaggregated and adapted to tissue culture, transduced with the B7-1 gene and injected subcutaneously as a vaccine. The dose of the vaccine was escalated in 3 separate cohorts of patients, and systemic interleukin-2 (IL-2) was administered as an adjuvant designed to enhance the proliferation of the vaccine activated T Cells.Results: Of the 15 patients 9 had measurable disease, 2 had a partial response and 2 had stable disea...
M G Hanna - One of the best experts on this subject based on the ideXlab platform.
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a key to the backdoor into the castle the clinical ramifications of immunoediting driven by antigenic competition
Human Vaccines & Immunotherapeutics, 2017Co-Authors: M G Hanna, Jason D HowardAbstract:ABSTRACTOver the last decade the field of cancer biology has gained considerable data on genomic heterogeneity. This situation creates challenges and possibly opportunities for cancer treatment. The evolution of the Tumor at all stages also requires the growing malignancy to confront and avoid the immune system. What we describe here is the interaction of two immune phenomena that work together to change the characteristics of the Tumor, i.e., antigenic competition and immune editing. These two systems are mutually functional and their interaction is capable of altering the characteristics of the Tumor for protection and survival in an immune competent host as well as restricting the diversity of the Tumor clones. Therefore, the final outcome of these interactions can also become the key to the backdoor into the castle. Through an additional immune manipulation, Autologous Tumor Cell immunization, we can achieve prevention of disease recurrence after surgical resection and by analyzing induced human monoc...
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immunotherapy with Autologous Tumor Cell bcg vaccine in patients with colon cancer a prospective study of medical and economic benefits
Vaccine, 2005Co-Authors: C Uylde A Groot, M G Hanna, Jan B Vermorken, Paul Verboom, M T Groot, G J Bonsel, Chris J L M Meijer, H M PinedoAbstract:We have completed a multicenter, randomized controlled phase III clinical trial in Stages II and III colon cancer patients with active specific immunotherapy (ASI) using Autologous Tumor Cells with an immunomodulating adjuvant bacillus Callmette-Gu ´ (BCG) vaccine (OncoVAX ® ) in an adjuvant setting. In this study, patients were randomized to receive either OncoVAX ® therapy or no therapy after surgical resection of the primary Tumor and stratified by stage of disease. Since the biologic essence of the effective Tumor immunotherapy is the presence in the vaccine of a minimum number of viable, metabolically active, Autologous Tumor Cells, the processing of the vaccine product, occurred within 48 h after surgery. Analysis of prognostic benefit in the pivotal phase III trial, with a 5.8 year median follow-up, showed that a beneficial effect of OncoVAX ® is statistically significant for all endpoints including recurrence-free interval, overall survival, and recurrence-free survival in Stage II col on cancer patients. Surgery alone cures approximately 65% of Stage II (Dukes B2 ,B 3) colon cancer patients. In the remaining patients, OncoVAX ® in an adjuvant setting, significantly prolongs recurrence-free interval (57.1% relative risk reduction) and significantly improves 5-year overall survival and recurrence-free survival. No statistically significant prognostic benefits were achieved in Stage III (Duke’s C 1–C3) patients. A health economics assessment was performed on these results in Stage II colon cancer patients using disease-free survival and overall survival (for the entire intent-to-treat population). Cost-effectiveness, cost-utility and sensitivity analysis were applied with, cost of life years, recurrence-free life years and quality adjusted life years (QALYs) as the primary endpoints to this analysis. The perspective of the economic analysis was the current direct medical cost established by the health care providers. The introduction of new technologies often leads to additional costs. This report verified that the use of OncoVAX ® for patients with Stage II colon cancer not only has significant prognostic benefit and positive clinical outcomes, but also showed that OncoVAX ® therapy yields impressive health economics benefits.
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adjuvant active specific immunotherapy of stage ii and stage iii colon cancer with an Autologous Tumor Cell vaccine first randomized phase iii trials show promise
Vaccine, 2001Co-Authors: M G Hanna, Herbert C. Hoover, Jules E Harris, Jan B Vermorken, H M PinedoAbstract:We performed three multi-institutional, prospectively randomized, controlled clinical trials, assessing the therapeutic effect of post-resection adjuvant active specific immunotherapy in patients with stage II and stage III colon cancer. In each study four outcomes were considered: time-to-disease recurrence, overall survival intervals, disease-free survival intervals, and recurrence-free survival intervals using the Kaplan-Meir method for generating curves and the log-rank test used to compare efficacy distributions. In addition, a meta-analysis of the three phase III trials was performed since the trials had proven homogeneity. Two main analyses were performed: (1) the intent-to-treat colon cancer patients from all three studies; and (2) analyzable colon cancer patients in all three studies. The conclusion of these analyses is that adjuvant active specific immunotherapy provided significant clinical benefits in patients with stage II colon cancer and appears to be an important new adjuvant treatment for these patients.
Jules E Harris - One of the best experts on this subject based on the ideXlab platform.
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adjuvant active specific immunotherapy of stage ii and stage iii colon cancer with an Autologous Tumor Cell vaccine first randomized phase iii trials show promise
Vaccine, 2001Co-Authors: M G Hanna, Herbert C. Hoover, Jules E Harris, Jan B Vermorken, H M PinedoAbstract:We performed three multi-institutional, prospectively randomized, controlled clinical trials, assessing the therapeutic effect of post-resection adjuvant active specific immunotherapy in patients with stage II and stage III colon cancer. In each study four outcomes were considered: time-to-disease recurrence, overall survival intervals, disease-free survival intervals, and recurrence-free survival intervals using the Kaplan-Meir method for generating curves and the log-rank test used to compare efficacy distributions. In addition, a meta-analysis of the three phase III trials was performed since the trials had proven homogeneity. Two main analyses were performed: (1) the intent-to-treat colon cancer patients from all three studies; and (2) analyzable colon cancer patients in all three studies. The conclusion of these analyses is that adjuvant active specific immunotherapy provided significant clinical benefits in patients with stage II colon cancer and appears to be an important new adjuvant treatment for these patients.
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adjuvant active specific immunotherapy for stage ii and iii colon cancer with an Autologous Tumor Cell vaccine eastern cooperative oncology group study e5283
Journal of Clinical Oncology, 2000Co-Authors: Jules E Harris, Herbert C. Hoover, Louise Ryan, Robert K Stuart, Martin M Oken, Al B Benson, Edward G Mansour, Daniel G Haller, Judith Manola, Michael G. HannaAbstract:PURPOSE: A randomized phase III clinical trial of adjuvant active specific immunotherapy (ASI) with an Autologous Tumor Cell–bacillus Calmette-Guerin (BCG) vaccine was conducted to determine whether surgical resection plus ASI was more beneficial than resection alone in stage II and III colon cancer patients. PATIENTS AND METHODS: Patients (n = 412) with colon cancer (297 with stage II disease, 115 with stage III disease) were randomly allocated to an observation arm or to a treatment arm in which they received three weekly intradermal vaccine injections of 107 irradiated Autologous Tumor Cells beginning approximately 4 weeks after surgery. The first two weekly injections also contained 107 BCG organisms. Patients were observed for determination of time to recurrence and disease-free and overall survival. RESULTS: This was a negative study in that after a 7.6-year median follow-up period, there were no statistically significant differences in clinical outcomes between the treatment arms. However, there we...
