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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: Avelumab in Patients With Metastatic Colorectal Cancer.

Redman, Jason M / O'Sullivan Coyne, Geraldine / Reed, Clay T / Madan, Ravi A / Strauss, Julius / Steinberg, Seth J / Marté, Jennifer / Cordes, Lisa / Heery, Christopher / Gulley, James L

The oncologist

2023 Volume 28, Issue 9, Page(s) 823–e804

Abstract: Background: Metastatic colorectal cancer (mCRC) is incurable, and median overall survival is less than 2½ years. Although monoclonal antibodies that block PD-1/PD-L1 interactions are active in microsatellite unstable/mismatch repair deficient tumors, a ... ...

Abstract	Background: Metastatic colorectal cancer (mCRC) is incurable, and median overall survival is less than 2½ years. Although monoclonal antibodies that block PD-1/PD-L1 interactions are active in microsatellite unstable/mismatch repair deficient tumors, a growing dataset shows that most patients with microsatellite stable/mismatch repair proficient tumors will not benefit from the blockade of PD-1/PD-L1 interactions. Here we present results from patients with mCRC (n = 22) treated with the anti-PD-L1 monoclonal antibody avelumab. Methods: Patients received treatment on a phase I, open-label, dose-escalation trial via a consecutive parallel-group expansion in colorectal cancer. Patients aged 18 years and older with mCRC measurable by RECIST v1.1 who had received at least 1 line of systemic therapy for metastatic disease enrolled. Patients with prior immune checkpoint inhibitor treatment were excluded. Patients received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was the objective response rate. Results: Twenty-two participants received treatment from July 2013 to August 2014. There were no objective responses and median progression-free survival was 2.1 months (95% CI: 1.4-5.5 months). There were 5 grade 3 treatment-related adverse events: GGT elevation (n = 2), PRESS (n = 1), lymphopenia (n = 1), and asymptomatic amylase/lipase elevation (n = 1). Conclusion: As demonstrated with other anti-PD-1/PD-L1 monoclonal antibodies, avelumab is not active in unselected patients with mCRC (ClinicalTrials.gov Identifier: NCT01772004).
MeSH term(s)	Humans ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal, Humanized/therapeutic use ; Colonic Neoplasms ; Colorectal Neoplasms/drug therapy ; Rectal Neoplasms ; Response Evaluation Criteria in Solid Tumors
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; avelumab (KXG2PJ551I)
Language	English
Publishing date	2023-06-14
Publishing country	England
Document type	Journal Article ; 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/oyad162
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Article ; Online: Early changes in immune cell subsets with corticosteroids in patients with solid tumors: implications for COVID-19 management.

Marté, Jennifer L / Toney, Nicole J / Cordes, Lisa / Schlom, Jeffrey / Donahue, Renee N / Gulley, James L

Journal for immunotherapy of cancer

2020 Volume 8, Issue 2

Abstract: Background: The risk-benefit calculation for corticosteroid administration in the management of COVID-19 is complex and urgently requires data to inform the decision. The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation ... ...

Abstract	Background: The risk-benefit calculation for corticosteroid administration in the management of COVID-19 is complex and urgently requires data to inform the decision. The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation associated with poor prognosis in both COVID-19 and cancer. Investigating NLR as an inflammatory marker and lymphocyte levels as a critical component of antiviral immunity may inform the dilemma of reducing toxic hyperinflammation while still maintaining effective antiviral responses. Methods: We performed a retrospective analysis of NLR, absolute neutrophil counts (ANCs) and absolute lymphocyte counts (ALCs) in patients with cancer enrolled in immunotherapy trials who received moderate-dose to high-dose corticosteroids. We compared paired presteroid and available poststeroid initiation values daily during week 1 and again on day 14 using the Wilcoxon signed-rank test. Associated immune subsets by flow cytometry were included where available. Results: Patients (n=48) with a variety of solid tumors received prednisone, methylprednisolone, or dexamethasone alone or in combination in doses ranging from 20 to 190 mg/24 hours (prednisone equivalent). The median NLR prior to steroid administration was elevated at 5.0 (range: 0.9-61.2). The corresponding median ANC was 5.1 K/µL (range: 2.03-22.31 K/µL) and ALC was 1.03 K/µL (0.15-2.57 K/µL). One day after steroid administration, there was a significant transient drop in median ALC to 0.54 K/µL (p=0.0243), driving an increase in NLR (median 10.8, p=0.0306). Relative lymphopenia persisted through day 14 but was no longer statistically significant. ANC increased steadily over time, becoming significant at day 4 (median: 7.31 K/µL, p=0.0171) and remaining significantly elevated through day 14. NLR was consistently elevated after steroid initiation, significantly at days 1, 7 (median: 8.2, p=0.0272), and 14 (median: 15.0, p=0.0018). Flow cytometry data from 11 patients showed significant decreases in activated CD4 cells and effector memory CD8 cells. Conclusions: The early drop in ALC with persistent lymphopenia as well as the prolonged ANC elevation seen in response to corticosteroid administration are similar to trends associated with increased mortality in several coronavirus studies to include the current SARS-CoV-2 pandemic. The affected subsets are essential for effective antiviral immunity. This may have implications for glucocorticoid therapy for COVID-19.
MeSH term(s)	Adrenal Cortex Hormones/administration & dosage ; Adult ; Aged ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/virology ; COVID-19/complications ; COVID-19/drug therapy ; COVID-19/pathology ; COVID-19/virology ; Female ; Humans ; Immunotherapy/adverse effects ; Inflammation/drug therapy ; Inflammation/immunology ; Inflammation/pathology ; Inflammation/virology ; Lymphocyte Count ; Lymphocytes/immunology ; Lymphocytes/virology ; Male ; Middle Aged ; Neoplasms/blood ; Neoplasms/complications ; Neoplasms/pathology ; Neoplasms/therapy ; Neutrophils/immunology ; Neutrophils/virology ; Pandemics ; Risk Assessment ; SARS-CoV-2/pathogenicity
Chemical Substances	Adrenal Cortex Hormones
Language	English
Publishing date	2020-11-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2020-001019
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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: A Phase I Single-Arm Study of Biweekly NHS-IL12 in Patients With Metastatic Solid Tumors.

Gatti-Mays, Margaret E / Tschernia, Nicholas P / Strauss, Julius / Madan, Ravi A / Karzai, Fatima H / Bilusic, Marijo / Redman, Jason / Sater, Houssein Abdul / Floudas, Charalampos S / Toney, Nicole J / Donahue, Renee N / Jochems, Caroline / Marté, Jennifer L / Francis, Deneise / McMahon, Sheri / Lamping, Elizabeth / Cordes, Lisa / Schlom, Jeffrey / Gulley, James L

The oncologist

2023 Volume 28, Issue 4, Page(s) 364–e217

Abstract: Background: NHS-IL12 is a first-in-class, recombinant fusion protein composed of the human monoclonal antibody NHS76 (binds exposed DNA/histones at sites of intratumoral necrosis) fused to 2 IL-12 heterodimers. The maximum tolerated dose (MTD) and ... ...

Abstract	Background: NHS-IL12 is a first-in-class, recombinant fusion protein composed of the human monoclonal antibody NHS76 (binds exposed DNA/histones at sites of intratumoral necrosis) fused to 2 IL-12 heterodimers. The maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NHS-IL12 monotherapy given subcutaneously (SC) every 4 weeks was previously reported. The study was expanded to include a high-exposure cohort with NHS-IL12 SC every 2 weeks (q2w). Methods: This single-arm, phase I trial evaluated NHS-IL12 12 µg/kg SC q2w or 16.8µg/kg SC q2w in patients with metastatic solid tumors. The primary endpoint was safety. Results: Using a 3+3 design, 13 patients with advanced cancer were enrolled and 12 were dose-limiting toxicity (DLT) evaluable. There was 1 DLT (Grade 3 aspartate transaminase/alanine transaminase [AST/ALT] elevation). Other grade 3 toxicities included: flu-like symptoms 1/13 (8%), decreased absolute lymphocyte count (ALC) 1/13 (8%), decreased white blood cell count (WBC) 1/13 (8%), but most adverse events reported were low grade and self-limiting grade. Fifty percent of evaluable patients (6/12) experienced stable disease (SD) with 42% (5/12) developing progressive disease (PD) at the first restaging. Conclusion: Biweekly NHS-IL12 was well tolerated in this small phase I study. Additional studies incorporating NHS-IL12 with other immunomodulating agents are underway. (ClinicalTrials.gov Identifier: NCT01417546).
MeSH term(s)	Humans ; State Medicine ; Interleukin-12/therapeutic use ; Neoplasms/drug therapy ; Neoplasms/pathology ; Neoplasms, Second Primary ; Recombinant Fusion Proteins/therapeutic use
Chemical Substances	Interleukin-12 (187348-17-0) ; Recombinant Fusion Proteins
Language	English
Publishing date	2023-01-13
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	1409038-7
ISSN	1549-490X ; 1083-7159
ISSN (online)	1549-490X
ISSN	1083-7159
DOI	10.1093/oncolo/oyac244
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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: Quantitative Analysis of Serial Positron Emission Tomography Imaging in Men with Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide.

Gandhy, Shruti U / Karzai, Fatima H / Bilusic, Marijo / McMahon, Sheri / Cordes, Lisa M / Marte, Jennifer / Weisman, Amy J / Perk, Timothy G / Lindenberg, Liza / Mena, Esther / Turkbey, Baris / Arlen, Philip M / Dahut, William L / Figg, William D / Choyke, Peter / Gulley, James L / Madan, Ravi A

European urology oncology

2023

Abstract: Background: The emergence of positron emission tomography (PET) in prostate cancer is impacting clinical practice, but little is known about PET imaging as a tool to determine treatment failure in metastatic castration-resistant prostate cancer (mCRPC).! ...

Abstract	Background: The emergence of positron emission tomography (PET) in prostate cancer is impacting clinical practice, but little is known about PET imaging as a tool to determine treatment failure in metastatic castration-resistant prostate cancer (mCRPC). Objective: To evaluate PET imaging dynamics in mCRPC patients on enzalutamide with stable computed tomography (CT) and technetium-99m (Tc99) bone scans. Design, setting, and participants: All patients were on treatment with enzalutamide for first-line mCRPC in a clinical trial at the National Cancer Institute (Bethesda, MD, USA). A volunteer sample had serial 18F-sodium fluoride (NaF) PET in parallel with CT and Tc99. Regions of interest (ROIs) on NaF were analyzed quantitatively for response. Intervention: Patients were randomized to enzalutamide with/without a cancer immunotherapy, Prostvac. Outcome measurements and statistical analysis: A post hoc, descriptive analysis was performed comparing the changes seen on CT and Tc99 as per RECIST 1.1 with NaF PET scans including the use of a quantitative analysis. Results and limitations: Eighteen mCRPC patients had 67 NaF scans. A total of 233 ROIs resolved after treatment, 52 (22%) of which eventually retuned while on therapy. In all, 394 new ROIs were seen, but 112(28%) resolved subsequently. Of 18 patients, 14 had new ROIs that ultimately resolved after appearing. Many patients experienced progression in a minority of lesions, and one patient with radiation intervention to oligoprogression had a remarkable response. This study is limited by its small number of patients and post hoc nature. Conclusions: These data highlight the dynamic nature of NaF PET in mCRPC patients treated with enzalutamide, where not all new findings were ultimately related to disease progression. This analysis also provides a potential strategy to identify and intervene in oligoprogression in prostate cancer. Patient summary: In this small analysis of patients with prostate cancer on enzalutamide, changes on 18F-sodium fluoride positron emission tomography (PET) imaging were not always associated with treatment failure. Caution may be indicated when using PET imaging to determine whether new therapy is needed.
Language	English
Publishing date	2023-10-17
Publishing country	Netherlands
Document type	Journal Article
ISSN	2588-9311
ISSN (online)	2588-9311
DOI	10.1016/j.euo.2023.09.010
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Article ; Online: Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-β blockade in HPV-unrelated head and neck cancer.

The Journal of clinical investigation

2023 Volume 133, Issue 11

MeSH term(s)	Humans ; B7-H1 Antigen ; Transforming Growth Factor beta ; Papillomavirus Infections ; Neoadjuvant Therapy ; Head and Neck Neoplasms/drug therapy ; Immunotherapy
Chemical Substances	B7-H1 Antigen ; Transforming Growth Factor beta
Language	English
Publishing date	2023-06-01
Publishing country	United States
Document type	Journal Article ; Published Erratum
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI172059
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Ua VI Zs.184: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

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Article: A Case Report of Sequential Use of a Yeast-CEA Therapeutic Cancer Vaccine and Anti-PD-L1 Inhibitor in Metastatic Medullary Thyroid Cancer.

Del Rivero, Jaydira / Donahue, Renee N / Marté, Jennifer L / Gramza, Ann W / Bilusic, Marijo / Rauckhorst, Myrna / Cordes, Lisa / Merino, Maria J / Dahut, William L / Schlom, Jeffrey / Gulley, James L / Madan, Ravi A

Frontiers in endocrinology

2020 Volume 11, Page(s) 490

Abstract: Medullary thyroid cancer (MTC) accounts for ~4% of all thyroid malignancies. MTC derives from the neural crest and secretes calcitonin (CTN) and carcinoembryonic antigen (CEA). Unlike differentiated thyroid cancer, MTC does not uptake iodine and I-131 ... ...

Abstract	Medullary thyroid cancer (MTC) accounts for ~4% of all thyroid malignancies. MTC derives from the neural crest and secretes calcitonin (CTN) and carcinoembryonic antigen (CEA). Unlike differentiated thyroid cancer, MTC does not uptake iodine and I-131 RAI (radioactive iodine) treatment is ineffective. Patients with metastatic disease are candidates for FDA-approved agents with either vandetanib or cabozantinib; however, adverse effects limit their use. There are ongoing trials exploring the role of less toxic immunotherapies in patients with MTC. We present a 61-year-old male with the diagnosis of MTC and persistent local recurrence despite multiple surgeries. He was started on sunitinib, but ultimately its use was limited by toxicity. He then presented to the National Cancer Institute (NCI) and was enrolled on a clinical trial with heat-killed yeast-CEA vaccine (NCT01856920) and his calcitonin doubling time improved in 3 months. He then came off vaccine for elective surgery. After surgery, his calcitonin was rising and he enrolled on a phase I trial of avelumab, a programmed death-ligand 1 (PD-L1) inhibitor (NCT01772004). Thereafter, his calcitonin decreased > 40% on 5 consecutive evaluations. His tumor was subsequently found to express PD-L1. CEA-specific T cells were increased following vaccination, and a number of potential immune-enhancing changes were noted in the peripheral immunome over the course of sequential immunotherapy treatment. Although calcitonin declines do not always directly correlate with clinical responses, this response is noteworthy and highlights the potential for immunotherapy or sequential immunotherapy in metastatic or unresectable MTC.
MeSH term(s)	Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents, Immunological/therapeutic use ; B7-H1 Antigen/antagonists & inhibitors ; Cancer Vaccines/administration & dosage ; Carcinoembryonic Antigen/administration & dosage ; Carcinoma, Neuroendocrine/drug therapy ; Carcinoma, Neuroendocrine/immunology ; Carcinoma, Neuroendocrine/pathology ; Drug Therapy, Combination ; Humans ; Immune Checkpoint Inhibitors/therapeutic use ; Male ; Middle Aged ; Prognosis ; Saccharomyces cerevisiae/immunology ; Thyroid Neoplasms/drug therapy ; Thyroid Neoplasms/immunology ; Thyroid Neoplasms/pathology ; Vaccines, DNA/administration & dosage
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antineoplastic Agents, Immunological ; B7-H1 Antigen ; CD274 protein, human ; Cancer Vaccines ; Carcinoembryonic Antigen ; Immune Checkpoint Inhibitors ; Vaccines, DNA ; yeast-CEA vaccine ; avelumab (KXG2PJ551I)
Language	English
Publishing date	2020-08-07
Publishing country	Switzerland
Document type	Case Reports ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2020.00490
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Article ; Online: Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia.

Journal for immunotherapy of cancer

2022 Volume 10, Issue 1

Abstract: Background: The powerful 'graft versus leukemia' effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies ...

Abstract	Background: The powerful 'graft versus leukemia' effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable preclinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease. Methods: We report here the results of 17 H-0026 (PD-AML, NCT02996474), an investigator sponsored, single-institution, single-arm open-label 10-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML). Results: In this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using T cell receptor β sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune-related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable antileukemic response during treatment. Conclusion: Addition of pembrolizumab to 10-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.
MeSH term(s)	Antibodies, Monoclonal, Humanized/pharmacology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Cohort Studies ; Decitabine/pharmacology ; Decitabine/therapeutic use ; Female ; Humans ; Immunotherapy/methods ; Leukemia, Myeloid, Acute/drug therapy ; Male ; Pilot Projects ; Recurrence
Chemical Substances	Antibodies, Monoclonal, Humanized ; Decitabine (776B62CQ27) ; pembrolizumab (DPT0O3T46P)
Language	English
Publishing date	2022-01-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; 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-2021-003392
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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
Database	MEDical Literature Analysis and Retrieval System OnLINE

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