Hyperbaric Oxygen Boosts PD-1 Antibody Delivery and T Cell Infiltration for Augmented Immune Responses Against Solid Tumors.
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SUBMITTER: Liu X
PROVIDER: S-EPMC8336507 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abstract Background Immune checkpoint inhibitors (ICI) PD-1/PD-L1 antibody are key drugs for the treatment of cancer. Bispecific antibody is one of the strategies aimed to meet the clinical needs for cancer patients who are resistant to or refractory from ICI treatment. TIM-3, one of the next generation of ICI targets, co-expressed on exhausted T cells with PD-1. It is also expressed by innate immune populations, including NK and DC. Dual blocking PD-1 and TIM-3 not only on T cells but also on DC, NK cells may achieve better clinical benefit for patients who are resistant to or refractory from ICI treatment. Method A bivalent TIM-3 and PD-1 bispecific antibody (Bis5) was developed, a series of in vitro and in vivo efficacy, preclinical pharmacokinetic and toxicity studies were conducted. A Phase I, multicenter, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary efficacy of Bis5 in patients with advanced and/or metastatic solid tumors is ongoing in China. Results Bis5 showed affinity of 5-8 nM to both TIM-3 and PD-1, with better cell activity than TIM-3 and PD-1 mAb combination to activated T cell as well as NK and DC, over the other clinical stage reference BsAb. In huPD-1/TIM-3 double knock in mice-CT26 tumor model, Bis5 showed significant tumor inhibition activity and doubled the survival rate, while neither PD-1 mAb, TIM-3 mAb nor PD-1 and TIM-3 antibody combination showed activity. The highest non-severe toxicity dose (HNSTD) was 200mg/kg in monkeys. Nine cohorts (0.001-15 mg/kg) are planned to be enrolled sequentially in the dose escalation part in the Phase I study, as of April 2023, seven cohorts enrollment have completed. No dose limiting toxicity was observed, and the optimal effective dose was not reached. No TRAE higher than grade 2 was observed. The TRAE with ≥10% Incidence was anemia. SD >4 or 2 months were shown in the suboptimal dose levels in NSCLC and CRC (0.3mg/kg, 1mg/kg). The Part 2 dose expansion will further characterize the safety profile and preliminary tumor response in several cohorts including NSCLC, CRC, ESCC etc. Conclusion Bis5 showed good preclinical efficacy and safety profile, its clinical performance is expected. Clinical trial information: NCT05357651.
| S-EPMC10370444 | biostudies-literature
Project description:Background This study evaluated the safety, tolerability, pharmacokinetics, immunogenicity and antitumor activity of single and multiple doses of nivolumab in Japanese patients with malignant solid tumors. Subjects and Methods This was an open-label, dose-escalation study in 17 patients with advanced solid tumors with a life expectancy of ?3 months. Patients were observed for 3 weeks after a single dose of nivolumab at 1, 3, 10 or 20 mg/kg, then received the same dose of nivolumab every 2 weeks until unacceptable toxicity or disease progression occurred. This study included a maximum dose of 20 mg/kg, which is the highest dose of nivolumab evaluated to date. The maximum dose was 10 mg/kg in previous studies. Results The commonest adverse drug reaction was lymphopenia, which occurred in 10 (58.8%) patients, including two (11.8%) with Grade ?3 events. No dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg. The area under the concentration-time curve from time 0 to the last measurable concentration was linear up to 20 mg/kg. The maximum concentration showed dose-dependency up to 10 mg/kg, but not between 10 and 20 mg/kg. One durable complete response and two partial responses were observed. Conclusions Nivolumab at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid tumors.
| S-EPMC5352798 | biostudies-literature
Project description:BackgroundAlthough immune checkpoint inhibitors (ICIs) have influenced the treatment paradigm for multiple solid tumors, increasing evidence suggests that primary and adaptive resistance may limit the long-term efficacy of ICIs. New therapeutic strategies with other drug combinations are hence warranted to enhance the antitumor efficacy of ICIs. As a novel tumor suppressor, histone deacetylase (HDAC) inhibitor tucidinostat has been successfully confirmed to act against hematological malignancies. However, the underlying mechanisms of action for tucidinostat and whether it can manipulate the tumor microenvironment (TME) in solid tumors remain unclear.MethodsThree murine tumor models (4T1, LLC, and CT26) were developed to define the significant role of different doses of tucidinostat in TME. The immunotherapeutic effect of tucidinostat combined with anti-programmed cell death ligand 1 antibody (aPD-L1) was demonstrated. Furthermore, the effect of tucidinostat on phenotypic characteristics of peripheral blood mononuclear cells (PBMCs) from lung cancer patients was investigated.ResultsWith an optimized dose, tucidinostat could alter TME and promote the migration and infiltration of CD8+ T cells into tumors, partially by increasing the activity of C-C motif chemokine ligand 5 (CCL5) via NF-κB signaling. Moreover, tucidinostat significantly promoted M1 polarization of macrophages and increased the in vivo antitumor efficacy of aPD-L1. Tucidinostat also enhanced the expression of the costimulatory molecules on human monocytes, suggesting a novel and improved antigen-presenting function.ConclusionsA combination regimen of tucidinostat and aPD-L1 may work synergistically to reduce tumor burden in patients with cancer by enhancing the immune function and provided a promising treatment strategy to overcome ICI treatment resistance.
| S-EPMC9648046 | biostudies-literature
Project description:Recombinant immunotoxins (RIT) are targeted anticancer agents that are composed of a targeting antibody fragment and a protein toxin fragment. SS1P is a RIT that targets mesothelin on the surface of cancer cells and is being evaluated in patients with mesothelioma. Mesothelin, like many other target antigens, is shed from the cell surface. However, whether antigen shedding positively or negatively affects the delivery of RIT remains unknown. In this study, we used experimental data with SS1P to develop a mathematical model that describes the relationship between tumor volume changes and the dose level of the administered RIT, while accounting for the potential effects of antigen shedding.
| S-EPMC3408876 | biostudies-literature
Project description:The immune composition of the tumor microenvironment influences response and resistance to immunotherapies. While numerous studies have identified somatic correlates of immune infiltration, germline features that associate with immune infiltrates in cancers remain incompletely characterized. We analyze seven million autosomal germline variants in the TCGA cohort and test for association with established immune-related phenotypes that describe the tumor immune microenvironment. We identify one SNP associated with the amount of infiltrating follicular helper T cells; 23 candidate genes, some of which are involved in cytokine-mediated signaling and others containing cancer-risk SNPs; and networks with genes that are part of the DNA repair and transcription elongation pathways. In addition, we find a positive association between polygenic risk for rheumatoid arthritis and amount of infiltrating CD8+ T cells. Overall, we identify multiple germline genetic features associated with tumor-immune phenotypes and develop a framework for probing inherited features that contribute to differences in immune infiltration.
| S-EPMC7082123 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a granulocyte macrophage colony-stimulating factor secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor-bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared with PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8 T lymphocytes and tumor-specific interferon-? production of CD8 T cells in the tumor microenvironment. Immunosuppressive pathways, including regulatory T cells and CTLA-4 expression on T cells were overcome by the addition of vaccine and low-dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment.
| S-EPMC4258151 | biostudies-other
Project description:BackgroundPucotenlimab is a humanized immunoglobulin G4 (IgG4) anti programmed cell death protein 1 (anti-PD-1) monoclonal antibody (mAb) with a S228P hinge mutation and an engineered Fc domain. Preclinical data suggests that pucotenlimab exerts antitumor effects. In this phase I study, which was prospectively registered on www.chinadrugtrials.org.cn (CTR20180125), the safety, maximum tolerated dose, preliminary antitumor activity, pharmacokinetics, and immunogenicity of pucotenlimab were evaluated in patients with advanced solid tumors.MethodsPatients with advanced solid tumors refractory to standard therapies were recruited. In a 3+3 dose escalation study, 13 patients received pucotenlimab intravenously every 3 weeks (Q3W) until disease progression or unacceptable toxicity occurred at doses of 1 mg/kg, 3 mg/kg, 10 mg/kg, and 200 mg. 17 additional patients were assigned in the expansion period.ResultsA total of 30 patients were enrolled. No dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common treatment-related adverse events of any grade were proteinuria (40%), fatigue (36.7%), weight loss (26.7%), fever (26.7%), increased aspartate aminotransferase (26.7%), rash (23.3%), and anorexia (20.0%). Partial responses occurred in five patients, with an objective response rate of 16.7%. Pharmacokinetics analysis showed rapid absorption followed by slow terminal elimination, with a mean half-life of 17.1-23.5 days across all dose groups.ConclusionsPucotenlimab had an acceptable toxicity profile at doses up to 10 mg/kg and the maximum tolerated dose was not reached. Based on the pharmacokinetics, efficacy, and safety profile, 3 mg/kg Q3W or 200 mg Q3W are optimal for further drug development.
| S-EPMC8182631 | biostudies-literature
Project description:While remarkable advances have been made in the treatment of pediatric leukemia over the past decades, new therapies are needed for children with advanced solid tumors and high-grade brain tumors who fail standard chemotherapy regimens. Immunotherapy with immune checkpoint inhibitors acting through the programmed cell death-1 (PD-1) pathway has shown efficacy in some chemotherapy-resistant adult cancers, generating interest that these agents may also be helpful to treat certain refractory pediatric malignancies. In this manuscript we review current strategies for targeting the PD-1 pathway, highlighting putative biomarkers and the rationale for investigation of these drugs to treat common pediatric tumors such as sarcoma, neuroblastoma, and high-grade glioma. We summarize the completed and ongoing clinical trial data available, and suggest potential applications for further study.
| S-EPMC5396947 | biostudies-literature
Project description:BackgroundSeveral programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) antibodies have been approved for cancer treatment worldwide. Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries, but related data in Chinese patients are limited. This study was conducted to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamics of an anti-PD-1 antibody, toripalimab, in Chinese patients.MethodsA single-center phase I study was conducted in Sun Yat-sen University Cancer Center. Eligible patients were adults with histologically confirmed, treatment-refractory, advanced, solitary malignant tumors. Toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg. The study followed standard 3 + 3 design.ResultsBetween 15th March 2016 and 27th September 2016, 25 patients were enrolled, of whom 3 (12.0%), 7 (28.0%), 6 (24.0%), 6 (24.0%), 3 (12.0%) received 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg toripalimab, respectively. After a median follow-up time of 5.0 months (range: 1.5-19.8 months), we observed that the commonest treatment-related adverse events (TRAEs) were fatigue (64.0%) and rash (24.0%). No grade 3 or higher TRAEs were observed. No dose-limiting toxicity, treatment-related serious adverse events (SAEs), or treatment-related death occurred. Objective response rate was 12.5%. The half-life of toripalimab was 150-222 h after a single dose infusion. Most patients, including those from the 0.3 mg/kg group, maintained complete PD-1 receptor occupancy (> 80%) on activated T cells since receiving the first dose of toripalimab.ConclusionsToripalimab is a promising anti-PD-1 antibody, which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors. Further exploration in various tumors and combination therapies is warranted.
| S-EPMC7427305 | biostudies-literature
Project description:ABSTRACT BACKGROUND:Monoclonal antibodies have become attractive clinical anti-cancer drugs in the last 3 decades due to their targeting specificity and suitable pharmacokinetic properties. Mesothelin is a tumor-associated antigen with limited expression in normal tissues. It is frequently over-expressed on the cell membrane of a number of epithelial malignancies (e.g. mesothelioma, pancreatic, ovarian, lung, triple negative breast and gastric cancers). METHODS:Mesothelin is validated as a suitable antibody target for cancer therapy. A number of novel antibody therapeutics targeting mesothelin in development are compared and their mechanisms of action are also discussed. Both basic science and clinical data are provided to give a complete veiw of how an agent is developed from bench to bedside. RESULTS:Novel antibody therapeutics, including unconjugated monoclonal antibodies, recombinant immunotoxins and antibody-drug conjugates, targeting mesothelin exert anti-tumor activities by different mechanisms of action. Based on the convincing preclinical data generated with these molecules, the antibody therapeutics have been brought into early clinical evaluation where initial promising results were obtained. CONCLUSION:These antibody therapeutics directed against mesothelin are expected to have different safety profiles, based on their different mechanism of action. Further clinical development will reveal which of these molecules shows the best efficacy and widest therapeutic window and thus is best suited to bring benefit to the patients.
| S-EPMC5080863 | biostudies-literature