Abstract:Background
In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab demonstrated a high objective response rate, including complete responses in patients with advanced melanoma.
Methods
In this double-blind study, 142 treatment-naïve patients with metastatic melanoma were randomized 2:1 to receive ipilimumab 3 mg/kg combined with either nivolumab 1 mg/kg or placebo every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg or placebo every 2 weeks until … Show more
“…Peptides #42, #36 and #78 were the most frequently immunogenic sequences amongst highly conserved peptides, with specific T-cell responses detected for each peptide in 5 macaques (31%). These data illustrate the ability of the Ad-MAGEA3:MG1-MAGEA3 vaccination to induce populations of auto-reactive T-cells in primates.10.1080/2162402X.2018.1512329-F0006Figure 6.Ad-MAGEA3:MG1-MAGEA3 induces auto-reactive T-cells.5x10 5 PBMCs were seeded and re-stimulated for 24 hours with one of the 87 overlapping peptides that cover the complete sequence of the hMAGE-A3 antigen. Reactivity against each peptide was detected by ELISpot.…”
Section: Resultsmentioning
confidence: 81%
“…5x10 5 PBMCs were seeded and re-stimulated for 24 hours with one of the 87 overlapping peptides that cover the complete sequence of the hMAGE-A3 antigen. Reactivity against each peptide was detected by ELISpot.…”
Multiple immunotherapeutics have been approved for cancer patients, however advanced solid tumors are frequently refractory to treatment. We evaluated the safety and immunogenicity of a vaccination approach with multimodal oncolytic potential in non-human primates (NHP) (Macaca fascicularis). Primates received a replication-deficient adenoviral prime, boosted by the oncolytic Maraba MG1 rhabdovirus. Both vectors expressed the human MAGE-A3. No severe adverse events were observed. Boosting with MG1-MAGEA3 induced an expansion of hMAGE-A3-specific CD4+ and CD8+ T-cells with the latter peaking at remarkable levels and persisting for several months. T-cells reacting against epitopes fully conserved between simian and human MAGE-A3 were identified. Humoral immunity was demonstrated by the detection of circulating MAGE-A3 antibodies. These preclinical data establish the capacity for the Ad:MG1 vaccination to engage multiple effector immune cell populations without causing significant toxicity in outbred NHPs. Clinical investigations utilizing this program for the treatment of MAGE-A3-positive solid malignancies are underway (NCT02285816, NCT02879760).
“…Peptides #42, #36 and #78 were the most frequently immunogenic sequences amongst highly conserved peptides, with specific T-cell responses detected for each peptide in 5 macaques (31%). These data illustrate the ability of the Ad-MAGEA3:MG1-MAGEA3 vaccination to induce populations of auto-reactive T-cells in primates.10.1080/2162402X.2018.1512329-F0006Figure 6.Ad-MAGEA3:MG1-MAGEA3 induces auto-reactive T-cells.5x10 5 PBMCs were seeded and re-stimulated for 24 hours with one of the 87 overlapping peptides that cover the complete sequence of the hMAGE-A3 antigen. Reactivity against each peptide was detected by ELISpot.…”
Section: Resultsmentioning
confidence: 81%
“…5x10 5 PBMCs were seeded and re-stimulated for 24 hours with one of the 87 overlapping peptides that cover the complete sequence of the hMAGE-A3 antigen. Reactivity against each peptide was detected by ELISpot.…”
Multiple immunotherapeutics have been approved for cancer patients, however advanced solid tumors are frequently refractory to treatment. We evaluated the safety and immunogenicity of a vaccination approach with multimodal oncolytic potential in non-human primates (NHP) (Macaca fascicularis). Primates received a replication-deficient adenoviral prime, boosted by the oncolytic Maraba MG1 rhabdovirus. Both vectors expressed the human MAGE-A3. No severe adverse events were observed. Boosting with MG1-MAGEA3 induced an expansion of hMAGE-A3-specific CD4+ and CD8+ T-cells with the latter peaking at remarkable levels and persisting for several months. T-cells reacting against epitopes fully conserved between simian and human MAGE-A3 were identified. Humoral immunity was demonstrated by the detection of circulating MAGE-A3 antibodies. These preclinical data establish the capacity for the Ad:MG1 vaccination to engage multiple effector immune cell populations without causing significant toxicity in outbred NHPs. Clinical investigations utilizing this program for the treatment of MAGE-A3-positive solid malignancies are underway (NCT02285816, NCT02879760).
“…Despite the success of immune checkpoint blockade, disease progression remains unabated in a significant proportion of treated patients 196 . Relieving neutrophil-induced immunosuppression may be one way to improve immunotherapy.…”
Section: Combining Neutrophil Targeting With Other Anti-cancer Therapiesmentioning
SummaryNeutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view.The traditionally held belief that neutrophils are inert bystanders is being challenged by recent literature. Emerging evidence indicates that tumors manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumor behavior. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets.
2The name neutrophil -given to polymorphonuclear, granulocytic cells by Paul Ehrlich in the late 19th century -is based on the inability of these cells to retain acidic or basic dyes and for their preferential uptake of pH neutral dyes 1 . Although their neutral staining led to the identification of these cells, neutrophils in the cancer setting are anything but neutral.Neutrophils in tumor-bearing hosts can oppose or potentiate cancer progression. These two types of behavior are controlled by signals emanating from cancer cells or stromal cells within the tumor microenvironment, which educate neutrophils to execute the demise of the tumor or facilitate support networks that lead to its expansive spread. These functions can occur locally in or around the tumor microenvironment, as well as systemically in distant organs.Until the past few years, other immune cells such as macrophages have overshadowed the role of neutrophils in cancer. But recent studies and the development of new genetic tools have provided the cancer community with new insights into the profound influence of these dynamic cells by uncovering distinct capabilities for neutrophils throughout each step of carcinogenesis: from tumor initiation to primary tumor growth to metastasis.During these processes, neutrophils take on different phenotypes and sometimes opposing functions. Emerging evidence also indicates that these cells are highly influential, and are able to change the behavior of other tumor-associated cell types -primarily other immune cells. In this Review, we focus on how tumors manipulate the generation and release of neutrophils from the bone marrow. We discuss the mechanisms identified in animal models by which neutrophils participate in tumor initiation, growth and metastasis. Finally, we highlight the potential of these cells as clinical biomarkers and therapeutic targets. In humans, neutrophils are the most abundant immune cell population, representing 50-70% of all leukocytes. Over 10 11 neutrophils may be produced per day 2 , and tumors can increase this number by even more. Indeed, patients with various cancer types, including but not limited to breast, lung and colorectal cancer, often exhibit increased numbers of circulating neutrophils 3,4 . Recent studies have identified key pathways that tumors exploit to disrupt normal neutrophil homeostasis and these are discuss...
“…The PD-1/PD-L1 and CTLA-4 blockers target different pathways involved in immune regulation, and the combination of these agents enhances tumor response compared with monotherapy [141]. The initial approval of ipilimumab/nivolumab combination therapy for first-line treatment of melanoma was based on the high ORR reported with this combination versus single-agent ipilimumab in the CheckMate 069 study (Table 3) [35], and was further supported by the phase 3 CheckMate 067 study, which showed significant improvements in median PFS [12,24]. The accelerated approval of pembrolizumab plus chemotherapy (pemetrexed/carboplatin) for first-line treatment of non-squamous NSCLC was based on the high ORR reported with this combination versus pemetrexed/carboplatin alone in the KEYNOTE-021 trial (Table 3) [52].…”
Immune checkpoint blockers have revolutionized cancer treatment in recent years. These agents are now approved for the treatment of several malignancies, including melanoma, squamous and non-squamous non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck squamous cell carcinoma. Studies have demonstrated the significant impact of immunotherapy versus standard of care on patient outcomes, including durable response and extended survival. The use of immunotherapy-based combination therapy has been shown to further extend duration of response and survival. Immunotherapies function through modulation of the immune system, which can lead to immune-mediated adverse events (imAEs). These include a range of dermatologic, gastrointestinal, endocrine, and hepatic toxicities, as well as other less common inflammatory events. ImAEs are typically low grade and manageable when identified early and treated with appropriate measures. Identifying the right patient for the right therapy will become more important as new immunotherapies and immunotherapy-based combinations are approved and costs of cancer care continue to rise.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
