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Article ; Online: Blood-based biomarkers in patients with non-small cell lung cancer treated with immune checkpoint blockade.

Tsai, Yo-Ting / Schlom, Jeffrey / Donahue, Renee N

Journal of experimental & clinical cancer research : CR

2024 Volume 43, Issue 1, Page(s) 82

Abstract: The paradigm of non-small cell lung cancer (NSCLC) treatment has been profoundly influenced by the development of immune checkpoint inhibitors (ICI), but the range of clinical responses observed among patients poses significant challenges. To date, ... ...

Abstract	The paradigm of non-small cell lung cancer (NSCLC) treatment has been profoundly influenced by the development of immune checkpoint inhibitors (ICI), but the range of clinical responses observed among patients poses significant challenges. To date, analyses of tumor biopsies are the only parameter used to guide prognosis to ICI therapy. Tumor biopsies, however, are often difficult to obtain and tissue-based biomarkers are limited by intratumoral heterogeneity and temporal variability. In response, there has been a growing emphasis on the development of "liquid biopsy"‒ derived biomarkers, which offer a minimally invasive means to dynamically monitor the immune status of NSCLC patients either before and/or during the course of treatment. Here we review studies in which multiple blood-based biomarkers encompassing circulating soluble analytes, immune cell subsets, circulating tumor DNA, blood-based tumor mutational burden, and circulating tumor cells have shown promising associations with the clinical response of NSCLC patients to ICI therapy. These investigations have unveiled compelling correlations between the peripheral immune status of patients both before and during ICI therapy and patient outcomes, which include response rates, progression-free survival, and overall survival. There is need for rigorous validation and standardization of these blood-based assays for broader clinical application. Integration of multiple blood-based biomarkers into comprehensive panels or algorithms also has the potential to enhance predictive accuracy. Further research aimed at longitudinal monitoring of circulating biomarkers is also crucial to comprehend immune dynamics and resistance mechanisms and should be used alongside tissue-based methods that interrogate the tumor microenvironment to guide treatment decisions and may inform on the development of novel therapeutic strategies. The data reviewed here reinforce the opportunity to refine patient stratification, optimize treatments, and improve outcomes not only in NSCLC but also in the wider spectrum of solid tumors undergoing immunotherapy.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/pathology ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Lung Neoplasms/genetics ; Biomarkers, Tumor/genetics ; Prognosis ; Tumor Microenvironment
Chemical Substances	Immune Checkpoint Inhibitors ; Biomarkers, Tumor
Language	English
Publishing date	2024-03-16
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-024-02969-1
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Article ; Online: Immune correlates of clinical parameters in patients with HPV-associated malignancies treated with bintrafusp alfa.

Tsai, Yo-Ting / Strauss, Julius / Toney, Nicole J / Jochems, Caroline / Venzon, David J / Gulley, James L / Schlom, Jeffrey / Donahue, Renee N

Journal for immunotherapy of cancer

2022 Volume 10, Issue 4

Abstract: Purpose: Bintrafusp alfa is a bifunctional agent consisting of an anti-human PD-L1 antibody linked to two TGFβRII. It is designed to act both as a checkpoint inhibitor and to 'trap' TGFβ in the tumor microenvironment. Phase I and II clinical studies ... ...

Abstract	Purpose: Bintrafusp alfa is a bifunctional agent consisting of an anti-human PD-L1 antibody linked to two TGFβRII. It is designed to act both as a checkpoint inhibitor and to 'trap' TGFβ in the tumor microenvironment. Phase I and II clinical studies demonstrated clinical activity in patients with a range of human papillomavirus (HPV)-associated cancers. The purpose of the studies reported here was the interrogation of various aspects of the peripheral immunome in patients with HPV-associated cancers, both prior to and early in the treatment regimen of bintrafusp alfa to better understand the mode of action of the agent and to help define which patients are more likely to benefit from bintrafusp alfa treatment. Patients and methods: The peripheral immunome of patients (n=65) with HPV Results: Interrogation of the peripheral immunome prior to bintrafusp alfa treatment revealed several factors that associated with clinical response, including (1) higher levels of sCD27:sCD40L ratios, (2) lower levels of TGFβ1 and 12 additional factors associated with tumor mesenchymalization, and (3) higher CD8 Conclusions: These studies add insight into the mechanism of action of bintrafusp alfa and provide evidence that the interrogation of both cellular and soluble components of the peripheral immunome of patients with HPV-associated malignancies, either prior to or early in the therapeutic regimen, can provide information as to which patients are more likely to benefit with bintrafusp alfa therapy.
MeSH term(s)	Alphapapillomavirus ; CD8-Positive T-Lymphocytes/pathology ; Humans ; Immunologic Factors/therapeutic use ; Neoplasms/drug therapy ; Papillomaviridae ; Papillomavirus Infections/complications ; Papillomavirus Infections/drug therapy ; Papillomavirus Infections/pathology ; Tumor Microenvironment
Chemical Substances	Immunologic Factors
Language	English
Publishing date	2022-04-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-004601
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Article ; Online: Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with advanced non-small cell lung cancer.

Rajan, Arun / Abdul Sater, Houssein / Rahma, Osama / Agajanian, Richy / Lassoued, Wiem / Marté, Jennifer L / Tsai, Yo-Ting / Donahue, Renee N / Lamping, Elizabeth / Bailey, Shania / Weisman, Andrew / Walter-Rodriguez, Beatriz / Ito, Rena / Vugmeyster, Yulia / Sato, Masashi / Machl, Andreas / Schlom, Jeffrey / Gulley, James L

Journal for immunotherapy of cancer

2024 Volume 12, Issue 3

Abstract: Background: Bintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-β (TGF-β) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell ... ...

Abstract	Background: Bintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-β (TGF-β) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell lung cancer (NSCLC) in a dose expansion cohort of the phase 1, open-label clinical trial (NCT02517398). Here, we report the safety, efficacy, and biomarker analysis of bintrafusp alfa in a second expansion cohort of the same trial (biomarker cohort). Methods: Patients with stage IIIb/IV NSCLC who were either immune checkpoint inhibitor (ICI)-naïve (n=18) or ICI-experienced (n=23) were enrolled. The primary endpoint was the best overall response. Paired biopsies (n=9/41) and peripheral blood (n=14/41) pretreatment and on-treatment were studied to determine the immunological effects of treatment and for associations with clinical activity. Results: Per independent review committee assessment, objective responses were observed in the ICI-naïve group (overall response rate, 27.8%). No new or unexpected safety signals were identified. Circulating TGF-β levels were reduced (>97%; p<0.001) 2 weeks after initiation of treatment with bintrafusp alfa and remained reduced up to 12 weeks. Increases in lymphocytes and tumor-associated macrophages (TAMs) were observed in on-treatment biospies, with an increase in the M2 (tumor trophic TAMs)/M1 (inflammatory TAMs) ratio associated with poor outcomes. Specific peripheral immune analytes at baseline and early changes after treatment were associated with clinical response. Conclusions: Bintrafusp alfa was observed to have modest clinical activity and manageable safety, and was associated with notable immunologic changes involving modulation of the tumor immune microenvironment in patients with advanced NSCLC.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/pathology ; Lung Neoplasms/pathology ; B7-H1 Antigen ; Immunologic Factors/therapeutic use ; Immunotherapy ; Tumor Microenvironment
Chemical Substances	B7-H1 Antigen ; Immunologic Factors
Language	English
Publishing date	2024-03-13
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-008480
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Article ; Online: Interrogation of the cellular immunome of cancer patients with regard to the COVID-19 pandemic.

Donahue, Renee N / Marté, Jennifer L / Goswami, Meghali / Toney, Nicole J / Tsai, Yo-Ting / Gulley, James L / Schlom, Jeffrey

Journal for immunotherapy of cancer

2021 Volume 9, Issue 3

Abstract: While vaccines directed against the SARS-CoV-2 spike protein will have varying degrees of effectiveness in preventing SARS-CoV-2 infections, the severity of infection will be determined by multiple host factors including the ability of immune cells to ... ...

Abstract	While vaccines directed against the SARS-CoV-2 spike protein will have varying degrees of effectiveness in preventing SARS-CoV-2 infections, the severity of infection will be determined by multiple host factors including the ability of immune cells to lyse virus-infected cells. This review will discuss the complexity of both adaptive and innate immunomes and how a flow-based assay can detect up to 158 distinct cell subsets in the periphery. This assay has been employed to show the effect of age on differences in specific immune cell subsets, and the differences in the immunome between healthy donors and age-matched cancer patients. Also reviewed are the numerous soluble factors, in addition to cytokines, that may vary in the pathogenesis of SARS-CoV-2 infections and may also be employed to help define the effectiveness of a given vaccine or other antiviral agents. Various steroids have been employed in the management of autoimmune adverse events in cancer patients receiving immunotherapeutics and may be employed in the management of SARS-CoV-2 infections. The influence of steroids on multiple immune cells subsets will also be discussed.
MeSH term(s)	Adaptive Immunity/immunology ; Age Factors ; B-Lymphocytes/immunology ; B7-H1 Antigen/immunology ; CD40 Ligand/immunology ; COVID-19/immunology ; COVID-19/prevention & control ; COVID-19 Vaccines/therapeutic use ; Cytokines/immunology ; Dendritic Cells/immunology ; Disease Susceptibility ; Glucocorticoids/therapeutic use ; Granzymes/immunology ; Humans ; Immune Checkpoint Inhibitors/therapeutic use ; Immunity, Innate/immunology ; Immunosenescence/immunology ; Killer Cells, Natural/immunology ; Myeloid-Derived Suppressor Cells/immunology ; Neoplasms/drug therapy ; Neoplasms/immunology ; Programmed Cell Death 1 Receptor/immunology ; Proteome ; SARS-CoV-2 ; Severity of Illness Index ; T-Lymphocyte Subsets/immunology ; T-Lymphocytes/immunology ; Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology
Chemical Substances	B7-H1 Antigen ; COVID-19 Vaccines ; Cytokines ; Glucocorticoids ; Immune Checkpoint Inhibitors ; Programmed Cell Death 1 Receptor ; Proteome ; Tumor Necrosis Factor Receptor Superfamily, Member 7 ; CD40 Ligand (147205-72-9) ; Granzymes (EC 3.4.21.-)
Language	English
Publishing date	2021-03-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2020-002087
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Article ; Online: First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma.

Strauss, Julius / Deville, Jean-Laurent / Sznol, Mario / Ravaud, Alain / Maruzzo, Marco / Pachynski, Russell K / Gourdin, Theodore S / Maio, Michele / Dirix, Luc / Schlom, Jeffrey / Donahue, Renee N / Tsai, Yo-Ting / Wang, XiaoZhe / Vugmeyster, Yulia / Beier, Frank / Seebeck, Joerg / Schroeder, Andreas / Chennoufi, Sarah / Gulley, James L

Journal for immunotherapy of cancer

2023 Volume 11, Issue 5

Abstract: Background: In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose- ... ...

Abstract	Background: In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab. Methods: In the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy. Patients received M9241 at 4, 8, 12, or 16.8 µg/kg every 4 weeks (Q4W) plus avelumab 10 mg/kg every 2 weeks (Q2W, dose levels (DLs) 1-4) or M9241 16.8 µg/kg Q4W plus avelumab 800 mg once a week for 12 weeks followed by Q2W (DL5/dose expansion). Primary endpoints for the dose-escalation part were adverse events (AEs) and dose-limiting toxicities (DLTs), and those for the dose-expansion part were confirmed best overall response (BOR) per investigator (Response Evaluation Criteria in Solid Tumors V.1.1) and safety. The dose-expansion part followed a two-stage design; 16 patients were enrolled and treated in stage 1 (single-arm part). A futility analysis based on BOR was planned to determine whether stage 2 (randomized controlled part) would be initiated. Results: At data cut-off, 36 patients had received M9241 plus avelumab in the dose-escalation part. All DLs were well tolerated; one DLT occurred at DL3 (grade 3 autoimmune hepatitis). The maximum-tolerated dose was not reached, and DL5 was declared the recommended phase II dose, considering an observed drug-drug interaction at DL4. Two patients with advanced bladder cancer (DL2 and DL4) had prolonged complete responses. In the dose-expansion part, no objective responses were recorded in the 16 patients with advanced UC; the study failed to meet the criterion (≥3 confirmed objective responses) to initiate stage 2. Any-grade treatment-related AEs occurred in 15 patients (93.8%), including grade ≥3 in 8 (50.0%); no treatment-related deaths occurred. Exposures for avelumab and M9241 concentrations were within expected ranges. Conclusions: M9241 plus avelumab was well tolerated at all DLs, including the dose-expansion part, with no new safety signals. However, the dose-expansion part did not meet the predefined efficacy criterion to proceed to stage 2.
MeSH term(s)	Humans ; Carcinoma, Transitional Cell/drug therapy ; Antibodies, Monoclonal/adverse effects ; State Medicine ; Urinary Bladder Neoplasms/drug therapy ; Interleukin-12
Chemical Substances	avelumab (KXG2PJ551I) ; Antibodies, Monoclonal ; Interleukin-12 (187348-17-0)
Language	English
Publishing date	2023-05-24
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-005813
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Article ; Online: Joint-Predominant Rheumatic Complications of Immune Checkpoint Inhibitor Therapy in Patients with Thymic Epithelial Tumors.

Mullenix, Cristina / Ballman, Madison / Chen, Haobin / Swift, Shannon / McAdams, Meredith J / Tsai, Yo-Ting / Donahue, Renee N / Poretta, Trina / Gupta, Sarthak / Loehrer, Patrick J / Schlom, Jeffrey / Gulley, James L / Rajan, Arun

The oncologist

2022 Volume 27, Issue 4, Page(s) e353–e356

Abstract: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. However, activation of the immune system can occasionally cause life-threatening toxicity involving critical organs. Induction of immune-mediated toxicity is a ... ...

Abstract	Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. However, activation of the immune system can occasionally cause life-threatening toxicity involving critical organs. Induction of immune-mediated toxicity is a significant concern for patients with thymic epithelial tumors (TETs) due to defects in immune tolerance. An increased risk of skeletal and cardiac muscle inflammation following treatment with ICIs is well recognized in patients with advanced TETs. However, uncommon musculoskeletal and rheumatic complications can also occur. The cases presented in this report highlight the spectrum of presentation of immune-mediated, joint-predominant musculoskeletal adverse events in patients with advanced TETs treated with ICIs, including polymyalgia rheumatica-like illness and inflammatory arthritis.
MeSH term(s)	Humans ; Immune Checkpoint Inhibitors ; Immunotherapy/adverse effects ; Myositis/chemically induced ; Neoplasms/drug therapy ; Neoplasms, Glandular and Epithelial/drug therapy ; Polymyalgia Rheumatica/drug therapy ; Polymyalgia Rheumatica/etiology ; Thymus Neoplasms/drug therapy
Chemical Substances	Immune Checkpoint Inhibitors
Language	English
Publishing date	2022-04-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1409038-7
ISSN	1549-490X ; 1083-7159
ISSN (online)	1549-490X
ISSN	1083-7159
DOI	10.1093/oncolo/oyac026
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Zs.A 4845: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A T cell receptor β chain-directed antibody fusion molecule activates and expands subsets of T cells to promote antitumor activity.

Science translational medicine

2023 Volume 15, Issue 724, Page(s) eadi0258

Abstract: Despite the success of programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) inhibitors in treating solid tumors, only a proportion of patients respond. Here, we describe a first-in-class bifunctional therapeutic molecule, STAR0602, that comprises an ... ...

Abstract	Despite the success of programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) inhibitors in treating solid tumors, only a proportion of patients respond. Here, we describe a first-in-class bifunctional therapeutic molecule, STAR0602, that comprises an antibody targeting germline Vβ6 and Vβ10 T cell receptors (TCRs) fused to human interleukin-2 (IL-2) and simultaneously engages a nonclonal mode of TCR activation with costimulation to promote activation and expansion of αβ T cell subsets expressing distinct variable β (Vβ) TCR chains. In solution, STAR0602 binds IL-2 receptors in cis with Vβ6/Vβ10 TCRs on the same T cell, promoting expansion of human Vβ6 and Vβ10 CD4
MeSH term(s)	Humans ; Animals ; Mice ; Receptors, Antigen, T-Cell, alpha-beta/metabolism ; CD8-Positive T-Lymphocytes ; Programmed Cell Death 1 Receptor/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Antibodies/pharmacology
Chemical Substances	Receptors, Antigen, T-Cell, alpha-beta ; Programmed Cell Death 1 Receptor ; Receptors, Antigen, T-Cell ; Antibodies
Language	English
Publishing date	2023-11-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.adi0258
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Zs.A 6941: Show issues

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Article ; Online: Phase I study of a multitargeted recombinant Ad5 PSA/MUC-1/brachyury-based immunotherapy vaccine in patients with metastatic castration-resistant prostate cancer (mCRPC).

Bilusic, Marijo / McMahon, Sheri / Madan, Ravi A / Karzai, Fatima / Tsai, Yo-Ting / Donahue, Renee N / Palena, Claudia / Jochems, Caroline / Marté, Jennifer L / Floudas, Charalampos / Strauss, Julius / Redman, Jason / Abdul Sater, Houssein / Rabizadeh, Shahrooz / Soon-Shiong, Patrick / Schlom, Jeffrey / Gulley, James L

Journal for immunotherapy of cancer

2021 Volume 9, Issue 3

Abstract: Background: Antitumor vaccines targeting tumor-associated antigens (TAAs) can generate antitumor immune response. A novel vaccine platform using adenovirus 5 (Ad5) vectors [E1-, E2b-] targeting three TAAs-prostate-specific antigen (PSA), brachyury, and ... ...

Abstract	Background: Antitumor vaccines targeting tumor-associated antigens (TAAs) can generate antitumor immune response. A novel vaccine platform using adenovirus 5 (Ad5) vectors [E1-, E2b-] targeting three TAAs-prostate-specific antigen (PSA), brachyury, and MUC-1-has been developed. Both brachyury and the C-terminus of MUC-1 are overexpressed in metastatic castration-resistant prostate cancer (mCRPC) and have been shown to play an important role in resistance to chemotherapy, epithelial-mesenchymal transition, and metastasis. The transgenes for PSA, brachyury, and MUC-1 all contain epitope modifications for the expression of CD8+ T-cell enhancer agonist epitopes. We report here the first-in-human trial of this vaccine platform. Methods: Patients with mCRPC were given concurrently three vaccines targeting PSA, brachyury, and MUC-1 at 5×10 Results: Eighteen patients with mCRPC were enrolled between July 2018 and September 2019 and received at least one vaccination. Median PSA was 25.58 ng/mL (range, 0.65-1006 ng/mL). The vaccine was tolerable and safe, and no grade >3 treatment-related adverse events or dose-limiting toxicities (DLTs) were observed. One patient had a partial response, while five patients had confirmed PSA decline and five had stable disease for >6 months. Median progression-free survival was 22 weeks (95% CI: 19.1 to 34). Seventeen (100%) of 17 patients mounted T-cell responses to at least one TAA, whereras 8 (47%) of 17 patients mounted immune responses to all three TAAs. Multifunctional T-cell responses to PSA, MUC-1, and brachyury were also detected after vaccination in the majority of the patients. Conclusions: Ad5 PSA/MUC-1/brachyury vaccine is well tolerated. The primary end points were met and there were no DLTs. The recommended phase II dose is 5×10 Trial registration number: NCT03481816.
MeSH term(s)	Adenoviridae/genetics ; Adenoviridae/immunology ; Aged ; Aged, 80 and over ; Cancer Vaccines/adverse effects ; Cancer Vaccines/genetics ; Cancer Vaccines/immunology ; Cancer Vaccines/therapeutic use ; Fetal Proteins/genetics ; Fetal Proteins/immunology ; Genetic Vectors ; Humans ; Kallikreins/genetics ; Kallikreins/immunology ; Male ; Middle Aged ; Mucin-1/genetics ; Mucin-1/immunology ; Progression-Free Survival ; Prostate-Specific Antigen/genetics ; Prostate-Specific Antigen/immunology ; Prostatic Neoplasms, Castration-Resistant/genetics ; Prostatic Neoplasms, Castration-Resistant/immunology ; Prostatic Neoplasms, Castration-Resistant/therapy ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/immunology ; Time Factors ; Vaccination ; Vaccine Efficacy ; Vaccines, Combined/adverse effects ; Vaccines, Combined/genetics ; Vaccines, Combined/immunology ; Vaccines, Combined/therapeutic use ; Viral Vaccines
Chemical Substances	Cancer Vaccines ; Fetal Proteins ; MUC1 protein, human ; Mucin-1 ; T-Box Domain Proteins ; Vaccines, Combined ; Viral Vaccines ; KLK3 protein, human (EC 3.4.21.-) ; Kallikreins (EC 3.4.21.-) ; Prostate-Specific Antigen (EC 3.4.21.77) ; Brachyury protein (EQ43SC3GDB)
Language	English
Publishing date	2021-03-24
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2021-002374
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Article ; Online: A Randomized Phase II Trial of mFOLFOX6 + Bevacizumab Alone or with AdCEA Vaccine + Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer.

Redman, Jason M / Tsai, Yo-Ting / Weinberg, Benjamin A / Donahue, Renee N / Gandhy, Shruti / Gatti-Mays, Margaret E / Abdul Sater, Houssein / Bilusic, Marijo / Cordes, Lisa M / Steinberg, Seth M / Marte, Jennifer L / Jochems, Caroline / Kim, Sunnie S / Marshall, John L / McMahon, Sheri / Redmond, Erica / Schlom, Jeffrey / Gulley, James L / Strauss, Julius

The oncologist

2022 Volume 27, Issue 3, Page(s) 198–209

Abstract: Background: FOLFOX plus bevacizumab is a standard of care (SOC) for first-line treatment of microsatellite-stable metastatic colorectal cancer (MSS mCRC). This study randomized patients to SOC or SOC plus avelumab (anti-PD-L1) plus CEA-targeted vaccine.! ...

Abstract	Background: FOLFOX plus bevacizumab is a standard of care (SOC) for first-line treatment of microsatellite-stable metastatic colorectal cancer (MSS mCRC). This study randomized patients to SOC or SOC plus avelumab (anti-PD-L1) plus CEA-targeted vaccine. Methods: Patients with untreated MSS mCRC enrolled to a lead-in arm assessing safety of SOC + immuno-oncology agents (IO). Next, patients were randomized to SOC or SOC + IO. The primary endpoint was progression-free survival (PFS). Multiple immune parameters were analyzed. Results: Six patients enrolled to safety lead-in, 10 randomized to SOC, and 10 to SOC + IO. There was no difference in median PFS comparing SOC versus SOC + IO (8.8 months (95% CI: 3.3-17.0 months) versus 10.1 months (95% CI: 3.6-16.1 months), respectively; hazard ratio 1.061 [P = .91; 95% CI: 0.380-2.966]). The objective response rate was 50% in both arms. Of patients analyzed, most (8/11) who received SOC + IO developed multifunctional CD4+/CD8+ T-cell responses to cascade antigens MUC1 and/or brachyury, compared to 1/8 who received SOC alone (P = .020). We detected post-treatment changes in immune parameters that were distinct to the SOC and SOC + IO treatment arms. Accrual closed after an unplanned analysis predicted a low likelihood of meeting the primary endpoint. Conclusions: SOC + IO generated multifunctional MUC1- and brachyury-specific CD4+/CD8+ T cells despite concurrent chemotherapy. Although a tumor-directed immune response is necessary for T-cell-mediated antitumor activity, it was not sufficient to improve PFS. Adding agents that increase the number and function of effector cells may be required for clinical benefit.
MeSH term(s)	Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Bevacizumab/therapeutic use ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/pathology ; Humans ; Immunotherapy ; Vaccines/therapeutic use
Chemical Substances	Antibodies, Monoclonal, Humanized ; Vaccines ; Bevacizumab (2S9ZZM9Q9V) ; avelumab (KXG2PJ551I)
Language	English
Publishing date	2022-03-11
Publishing country	England
Document type	Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1409038-7
ISSN	1549-490X ; 1083-7159
ISSN (online)	1549-490X
ISSN	1083-7159
DOI	10.1093/oncolo/oyab046
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Zs.A 4845: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Phase I Trial of a Modified Vaccinia Ankara Priming Vaccine Followed by a Fowlpox Virus Boosting Vaccine Modified to Express Brachyury and Costimulatory Molecules in Advanced Solid Tumors.

Collins, Julie M / Donahue, Renee N / Tsai, Yo-Ting / Manu, Michell / Palena, Claudia / Gatti-Mays, Margaret E / Marté, Jennifer L / Madan, Ravi A / Karzai, Fatima / Heery, Christopher R / Strauss, Julius / Abdul-Sater, Houssein / Cordes, Lisa / Schlom, Jeffrey / Gulley, James L / Bilusic, Marijo

The oncologist

2019 Volume 25, Issue 7, Page(s) 560–e1006

Abstract: Lessons learned: Modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury followed by fowlpox virus-BN-Brachyury was well tolerated upon administration to patients with advanced cancer. Sixty-three percent of patients developed CD4+ and/or CD8+ T- ... ...

Abstract	Lessons learned: Modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury followed by fowlpox virus-BN-Brachyury was well tolerated upon administration to patients with advanced cancer. Sixty-three percent of patients developed CD4+ and/or CD8+ T-cell responses to brachyury after vaccination. BN-Brachyury vaccine also induced T-cell responses against CEA and MUC1, which are cascade antigens, that is, antigens not encoded in the vaccines. Background: Brachyury, a transcription factor, plays an integral role in the epithelial-mesenchymal transition, metastasis, and tumor resistance to chemotherapy. It is expressed in many tumor types, and rarely in normal tissues, making it an ideal immunologic target. Bavarian Nordic (BN)-Brachyury consists of vaccination with modified vaccinia Ankara (MVA) priming followed by fowlpox virus (FPV) boosting, each encoding transgenes for brachyury and costimulatory molecules. Methods: Patients with metastatic solid tumors were treated with two monthly doses of MVA-brachyury s.c., 8 × 10 Results: Eleven patients were enrolled from March 2018 to July 2018 (one patient was nonevaluable). No dose-limiting toxicities were observed. The most common treatment-related adverse event was grade 1/2 injection-site reaction observed in all patients. Best overall response was stable disease in six patients, and the 6-month progression-free survival rate was 50%. T cells against brachyury and cascade antigens CEA and MUC1 were detected in the majority of patients. Conclusion: BN-Brachyury vaccine is well tolerated and induces immune responses to brachyury and cascade antigens and demonstrates some evidence of clinical benefit.
MeSH term(s)	Animals ; Fetal Proteins ; Fowlpox virus ; Humans ; Neoplasms/therapy ; T-Box Domain Proteins/genetics ; Vaccinia ; Vaccinia virus/genetics
Chemical Substances	Fetal Proteins ; T-Box Domain Proteins ; Brachyury protein (EQ43SC3GDB)
Language	English
Publishing date	2019-12-26
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article
ZDB-ID	1409038-7
ISSN	1549-490X ; 1083-7159
ISSN (online)	1549-490X
ISSN	1083-7159
DOI	10.1634/theoncologist.2019-0932
Database	MEDical Literature Analysis and Retrieval System OnLINE

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