A5084052125- Cancer Immunotherapy and Biomarkers
- Cancer Research and Treatments
- Ferroptosis and cancer prognosis
- Cancer Genomics and Diagnostics
- Advanced Breast Cancer Therapies
- Immunotherapy and Immune Responses
- interferon and immune responses
- CAR-T cell therapy research
- PARP inhibition in cancer therapy
- TGF-β signaling in diseases
- bioluminescence and chemiluminescence research
- Lung Cancer Treatments and Mutations
- Glycosylation and Glycoproteins Research
- Cancer Mechanisms and Therapy
- Neuroscience and Neural Engineering
- Retinal Development and Disorders
- Hepatocellular Carcinoma Treatment and Prognosis
- Cancer, Hypoxia, and Metabolism
- Cancer Cells and Metastasis
- Adenosine and Purinergic Signaling
- Genetic factors in colorectal cancer
- Nanoplatforms for cancer theranostics
- Cancer-related Molecular Pathways
- Alzheimer's disease research and treatments
- Prostate Cancer Treatment and Research
Ono Pharmaceutical (United States)
2013-2024
Research & Development Institute
2018-2022
Merck (Germany)
2016-2021
Merck Serono (Italy)
2013-2019
Brigham and Women's Hospital
2000-2001
Harvard University
2000
Blockade of PD-L1 and TGF-β pathways with M7824 activates effective innate adaptive antitumor immune responses.
Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation programmed cell death-ligand 1 (PD-L1) transforming growth factor β (TGF-β). We report a bifunctional fusion protein simultaneously inhibits TGF-β PD-L1, bintrafusp alfa (BA), effectively synergizes with radiotherapy, leading to superior survival multiple therapy-resistant murine tumor models poor...
Purpose: To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies.Experimental Design: BALB/c mice bearing orthotopic EMT-6 mammary tumors μMt- subcutaneous MC38 were treated NHS-muIL12, avelumab, or therapy; tumor growth survival assessed. Tumor recurrence following remission rechallenge was evaluated tumor-bearing mice. Immune cell populations...
Abstract Radiotherapy is the most widely used cancer treatment and improvements in its efficacy safety are highly sought-after. Peposertib (also known as M3814), a potent selective DNA-dependent protein kinase (DNA-PK) inhibitor, effectively suppresses repair of radiation-induced DNA double-strand breaks (DSB) regresses human xenograft tumors preclinical models. Irradiated cells devoid p53 activity especially sensitive to DNA-PK they lose key cell-cycle checkpoint circuit enter mitosis with...
Bintrafusp alfa (BA) is a bifunctional fusion protein designed for colocalized, simultaneous inhibition of two immunosuppressive pathways, transforming growth factor-β (TGF-β) and programmed death-ligand 1 (PD-L1), within the tumor microenvironment (TME). We hypothesized that targeting PD-L1 to by BA colocalizes TGF-β trap (TGF-βRII) TME, enabling it sequester in more effectively than systemic blockade, thereby enhancing antitumor activity.Multiple technologies were used characterize binding...
Generation of a floxed Presenilin-1 (PS1) allele involved two recombination events in the embryonic stem (ES) cells. First, targeting vector containing loxP site intron 1 and CMV-HYG/TK double selection cassette 3 was integrated into PS1 locus by homologous recombination. The use negative cassette, PGK-DTA, dramatically increased efficiency within targeted (75-fold). Second, an expression encoding Cre recombinase introduced to excise via site-specific However, all five ES cell clones testing...
Combinatorial immunotherapy approaches are emerging as viable cancer therapeutic strategies for improving patient responses and outcomes. This study investigated whether two such immunotherapies, with complementary mechanisms of action, could enhance antitumor activity in murine tumor models. The immunocytokine NHS-IL12, surrogate NHS-muIL12, designed to deliver IL-12 muIL-12, respectively, the microenvironment (TME) activate NK cells CD8+ T increase their cytotoxic functions. Bintrafusp...
6027 Background: Xevinapant is a first-in-class, oral IAP (inhibitor of apoptosis protein) inhibitor designed to restore cancer cell sensitivity apoptosis, induced by RT and chemotherapy, enhance antitumor immunity. In randomized phase 2 study patients with unresected locally advanced squamous carcinoma the head neck, xevinapant + chemoradiotherapy (CRT) significantly improved 18-month locoregional control 3-year progression-free survival 5-year overall vs placebo CRT. A 3 confirmatory...
Abstract Background: Xevinapant is a first-in-class, oral IAP (inhibitor of apoptosis protein) inhibitor designed to restore cancer cell sensitivity induced by radiotherapy (RT) and chemotherapy. In randomized phase 2 study patients with unresected locally advanced squamous carcinoma the head neck, xevinapant + chemoradiotherapy (CRT) significantly improved locoregional control at 18 months, 3-year progression-free survival nearly doubled 5-year overall vs. placebo CRT (53% 28%). Two 3...
<div>Abstract<p>Radiotherapy is the most widely used cancer treatment and improvements in its efficacy safety are highly sought-after. Peposertib (also known as M3814), a potent selective DNA-dependent protein kinase (DNA-PK) inhibitor, effectively suppresses repair of radiation-induced DNA double-strand breaks (DSB) regresses human xenograft tumors preclinical models. Irradiated cells devoid p53 activity especially sensitive to DNA-PK they lose key cell-cycle checkpoint circuit...
Abstract Background. L-BLP25 is an investigational antigen-specific cancer immunotherapeutic agent targeting human mucin 1 (MUC1). A single low dose of cyclophosphamide (CPA) known to be immunostimulatory and may enhance the anti-tumor effects when given 3 days before treatment initiation. Here we report immune efficacy with CPA pretreatment in subcutaneous (s.c.) orthotopic models murine pancreatic cancer. These allow for reproduction clinical scenario, where 8 weekly doses are...
Meeting abstracts Tecemotide is a MUC1 antigen-specific therapeutic cancer vaccine. In phase III clinical studies, delivery of tecemotide preceded by single low dose cyclophosphamide (CPA) to inhibit regulatory T cells (Tregs) and enhance the response tumor-associated antigen. Here,
<div>Abstract<p><b>Purpose:</b> To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies.</p><p><b>Experimental Design:</b> BALB/c mice bearing orthotopic EMT-6 mammary tumors μMt<sup>−</sup> subcutaneous MC38 were treated NHS-muIL12, avelumab, or therapy; tumor growth survival assessed....
<p>Heatmap of selected genes from a Nanostring gene expression panel.</p>
<p>NHS-muIL12 and avelumab combination treatment changed the immunophenotypic signature in spleen tumor.</p>
<p>PD-L1 is expressed on TILs, but not tumor cells, in EMT-6 tumors.</p>
<div>Abstract<p><b>Purpose:</b> To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies.</p><p><b>Experimental Design:</b> BALB/c mice bearing orthotopic EMT-6 mammary tumors μMt<sup>−</sup> subcutaneous MC38 were treated NHS-muIL12, avelumab, or therapy; tumor growth survival assessed....
<p>Supplementary Materials and Methods</p>
<p>NHS-muIL12 and avelumab combination treatment enhanced antitumor efficacy even in well-established tumors.</p>
<p>Supplementary Materials and Methods</p>
<p>Metacore pathway analysis of Nanostring gene expression data.</p>
<p>NHS-muIL12 and avelumab combination treatment increased p15E-reactive cells in an ELISpot assay.</p>