Single Agent
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2021 ◽  
Vol 33 (5) ◽  
pp. 987-1003
Hiroto Saito ◽  
Arata Horie ◽  
Azumi Maekawa ◽  
Seito Matsubara ◽  
Sohei Wakisaka ◽  

Recent advances in human-computer integration (HInt) have focused on the development of human-machine systems, where both human and machine autonomously act upon each other. However, a key challenge in designing such systems is augmenting the user’s physical abilities while maintaining their sense of self-attribution. This challenge is particularly prevalent when both human and machine are capable of acting upon each other, thereby creating a human-machine mutual action (HMMA) system. To address this challenge, we present a design framework that is based on the concept of transparency. We define transparency in HInt as the degree to which users can self-attribute an experience when machines intervene in the users’ action. Using this framework, we form a set of design guidelines and an approach for designing HMMA systems. By using transparency as our focus, we aim to provide a design approach for not only achieving human-machine fusion into a single agent, but also controlling the degrees of fusion at will. This study also highlights the effectiveness of our design approach through an analysis of existing studies that developed HMMA systems. Further development of our design approach is discussed, and future prospects for HInt and HMMA system designs are presented.

2021 ◽  
Vol 12 (1) ◽  
Britton Boras ◽  
Rhys M. Jones ◽  
Brandon J. Anson ◽  
Dan Arenson ◽  
Lisa Aschenbrenner ◽  

AbstractCOVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.

2021 ◽  
Qi Zhang ◽  
Peter Radvak ◽  
Juhyung Lee ◽  
Yue Xu ◽  
Vivian Cao-Dao ◽  

Spike-mediated entry of SARS-CoV-2 into human airway epithelial cells is an attractive therapeutic target for COVID-19. In addition to protein receptors, the SARS-CoV-2 spike (S) protein also interacts with heparan sulfate, a negatively charged glycosaminoglycan (GAG) attached to certain membrane proteins on the cell surface. This interaction facilitates the engagement of spike with a downstream receptor to promote viral entry. Here, we show that Mitoxantrone, an FDA-approved topoisomerase inhibitor, targets a spike-GAG complex to compromise the fusogenic function of spike in viral entry. As a single agent, Mitoxantrone inhibits the infection of an authentic SARS-CoV-2 strain in a cell-based model and in human lung EpiAirway 3D tissues. Gene expression profiling supports the plasma membrane as a major target of Mitoxantrone but also underscores an undesired activity targeting nucleosome dynamics. We propose that Mitoxantrone analogs bearing similar GAG-binding activities but with reduced affinity for DNA topoisomerase may offer an alternative therapy to overcome breakthrough infections in the post-vaccine era.

2021 ◽  
Vol 11 ◽  
Edmund K. Bartlett ◽  
Sandra P. D’Angelo ◽  
Ciara M. Kelly ◽  
Robert H. Siegelbaum ◽  
Charles Fisher ◽  

Treatment options for patients with advanced sarcoma remain limited. Promising responses to checkpoint inhibition have been observed, but responses to single-agent PD-1 inhibition are rare. We report on two patients with multiply recurrent myxofibrosarcoma treated with the combination of regionally administered melphalan (via isolated limb infusion) and pembrolizumab. Both patients had recurrent disease after multiple surgical resections and radiation. Analysis of primary tumors demonstrated microsatellite stable tumors with few mutations. After combination treatment, one patient had a significant partial response of 6 months duration, the second patient had a complete response of 2 years duration. Post treatment biopsies demonstrated immune infiltration into the tumor. These promising responses in patients with multiply recurrent myxofibrosarcoma have prompted the development of an investigator-initiated clinical trial to formally study the combination of regional melphalan and pembrolizumab in a systematic fashion (NCT04332874).

Actuators ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 268
Dongyu Fan ◽  
Haikuo Shen ◽  
Lijing Dong

In many existing multi-agent reinforcement learning tasks, each agent observes all the other agents from its own perspective. In addition, the training process is centralized, namely the critic of each agent can access the policies of all the agents. This scheme has certain limitations since every single agent can only obtain the information of its neighbor agents due to the communication range in practical applications. Therefore, in this paper, a multi-agent distributed deep deterministic policy gradient (MAD3PG) approach is presented with decentralized actors and distributed critics to realize multi-agent distributed tracking. The distinguishing feature of the proposed framework is that we adopted the multi-agent distributed training with decentralized execution, where each critic only takes the agent’s and the neighbor agents’ policies into account. Experiments were conducted in the distributed tracking tasks based on multi-agent particle environments where N(N=3,N=5) agents track a target agent with partial observation. The results showed that the proposed method achieves a higher reward with a shorter training time compared to other methods, including MADDPG, DDPG, PPO, and DQN. The proposed novel method leads to a more efficient and effective multi-agent tracking.

Kristine A. Frerichs ◽  
Monique Christina Minnema ◽  
Mark-David Levin ◽  
Annemiek Broijl ◽  
Gerard MJ Bos ◽  

The efficacy of daratumumab is partially dependent on CD38 expression on multiple myeloma (MM) cells. We have previously shown that ATRA upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy and safety of daratumumab combined with ATRA in daratumumab-refractory MM patients in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty daratumumab-refractory patients were subsequently enrolled in part B, and treated with daratumumab (re-intensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR≥15%) was not met. However, the majority of patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median PFS for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS, compared to those who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 versus 1.3 months). The median OS was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and re-intensification of daratumumab had limited activity in daratumumab-refractory patients, which may be explained by the transient upregulation of CD38 expression.

2021 ◽  
Vol 22 (19) ◽  
pp. 10761
Ayano Nakamura ◽  
Susumu Suzuki ◽  
Jo Kanasugi ◽  
Masayuki Ejiri ◽  
Ichiro Hanamura ◽  

The prognosis of multiple myeloma (MM) has drastically improved owing to the development of new drugs, such as proteasome inhibitors and immunomodulatory drugs. Nevertheless, MM is an extremely challenging disease, and many patients are still refractory to the existing therapies, thus requiring new treatment alternatives. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 that shows efficacy in MM not only as a single agent but also in combination therapy, especially for MM patients with translocation t(11;14). However, many patients are refractory to this drug. Here, we treated the MM cell lines KMS12PE and KMS27 with a combination treatment of venetoclax targeting BCL-2 and daratumumab targeting CD38 to evaluate the synergistic cytotoxicity of these drugs in vitro. MM cell lines were co-cultured with natural killer (NK) cells at an effector:target ratio of 0.3:1 in the presence of serial concentrations of daratumumab and venetoclax, and the resulting apoptotic MM cells were detected by flow cytometry using annexin V. These results indicated that the antibody-dependent cell-mediated NK cytotoxicity was enhanced in KMS12PE and KMS27 cells harboring t(11;14) with a high BCL-2 expression, suggesting that the combination treatment of venetoclax and daratumumab should be especially effective in patients with these characteristics.

2021 ◽  
Andrea Marie Chambers ◽  
Kyle Byrnes Lupo ◽  
Jiao Wang ◽  
Jingming Cao ◽  
Sandra Toregrosa-Allen ◽  

Immunometabolic reprogramming due to CD73-produced adenosine is a recognized immunosuppressive mechanism contributing to immune evasion in solid tumors. Adenosine is not only known to contribute to tumor progression, but it has specific roles in driving dysfunction of immune cells, including natural killer (NK) cells. Here, we engineered NK cells to directly target the CD73-adenosine axis by blocking the enzymatic activity of CD73. In doing so, the engineered NK cells not only impaired adenosinergic metabolism driven by the hypoxic uptake of ATP by cancer cells, but also mediated killing of tumor cells due to the specific recognition of overexpressed CD73. This results in a "single agent" immunotherapy that combines antibody specificity, blockade of purinergic signaling, and killing of targets mediated by NK cells. We also showed that CD73-targeted NK cells are potent in vivo and result in tumor arrest, while promoting NK cell infiltration into CD73+ tumors and enhanced intratumoral activation.

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