RESUMEN

Engagement of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) can interfere with the CD28 signaling requisite for T-cell activation. While immune checkpoint inhibitors (ICIs) can relieve this suppression, they are unable to drive CD28 costimulation that may mechanistically contribute to ICI resistance. Thus, CD28 costimulation in the context of checkpoint inhibition may activate immunosuppressed T-cells in the tumor microenvironment. Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain (vIgD) designed to mediate PD-L1-dependent CD28 costimulation while inhibiting the PD-L1 and CTLA-4 checkpoints. PD-L1-restriction of davoceticept's CD28 costimulatory activity may minimize systemic T-cell activation and avoid untoward systemic toxicities. At the same time, preclinical studies have suggested that treatment with davoceticept during PD-1 inhibition may enhance antitumor activity by upregulating PD-L1, potentially synergizing with davoceticept's PD-L1-dependent costimulatory mechanism. This report details two cases of fatal cardiac events following treatment with davoceticept in combination with pembrolizumab (anti-PD-1) in the phase 1 study, NEON-2. Both events occurred in females in their 60s; one with choroidal melanoma and prior immunotherapy, the other with ICI-naïve microsatellite stable colorectal cancer. The clinical courses were fulminant with symptom onset at 2 weeks, followed by rapid decline. Cardiac autopsy from one patient confirmed immune-related myocarditis, and immunosequencing revealed expansion of a single T-cell clone that was not present in the pretreatment tumor. These cases highlight the importance of understanding risk factors that may contribute to immune-related myocarditis and other severe immune-related adverse events when CD28 agonism is targeted in the context of checkpoint inhibition.NEON-2 (NCT04920383).

Asunto(s)

Anticuerpos Monoclonales Humanizados , Inhibidores de Puntos de Control Inmunológico , Miocarditis , Femenino , Humanos , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Antígenos CD28/metabolismo , Antígeno CTLA-4/antagonistas & inhibidores , Resultado Fatal , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Miocarditis/inducido químicamente , Ensayos Clínicos Fase I como Asunto

RESUMEN

Epileptic seizure is typically characterized by highly synchronized episodes of neural activity. Existing stimulation therapies focus purely on suppressing the pathologically synchronized neuronal firing patterns during the ictal (seizure) period. While these strategies are effective in suppressing seizures when they occur, they fail to prevent the re-emergence of seizures once the stimulation is turned off. Previously, we developed a novel neurostimulation motif, which we refer to as "Forced Temporal Spike-Time Stimulation" (FTSTS) that has shown remarkable promise in long-lasting desynchronization of excessively synchronized neuronal firing patterns by harnessing synaptic plasticity. In this paper, we build upon this prior work by optimizing the parameters of the FTSTS protocol in order to efficiently desynchronize the pathologically synchronous neuronal firing patterns that occur during epileptic seizures using a recently published computational model of neocortical-onset seizures. We show that the FTSTS protocol applied during the ictal period can modify the excitatory-to-inhibitory synaptic weight in order to effectively desynchronize the pathological neuronal firing patterns even after the ictal period. Our investigation opens the door to a possible new neurostimulation therapy for epilepsy.

RESUMEN

Dopamine plays a critical role in modulating the long-term synaptic plasticity of the hippocampal Schaffer collateral-CA1 pyramidal neuron synapses (SC-CA1), a widely accepted cellular model of learning and memory. Limited results from hippocampal slice experiments over the last four decades have shown that the timing of the activation of dopamine D1/D5 receptors relative to a high/low-frequency stimulation (HFS/LFS) in SC-CA1 synapses regulates the modulation of HFS/LFS-induced long-term potentiation/depression (LTP/LTD) in these synapses. However, the existing literature lacks a complete picture of how various concentrations of D1/D5 agonists and the relative timing between the activation of D1/D5 receptors and LTP/LTD induction by HFS/LFS, affect the spatiotemporal modulation of SC-CA1 synaptic dynamics. In this paper, we have developed a computational model, a first of its kind, to make quantitative predictions of the temporal dose-dependent modulation of the HFS/LFS induced LTP/LTD in SC-CA1 synapses by various D1/D5 agonists. Our model combines the biochemical effects with the electrical effects at the electrophysiological level. We have estimated the model parameters from the published electrophysiological data, available from diverse hippocampal CA1 slice experiments, in a Bayesian framework. Our modeling results demonstrate the capability of our model in making quantitative predictions of the available experimental results under diverse HFS/LFS protocols. The predictions from our model show a strong nonlinear dependency of the modulated LTP/LTD by D1/D5 agonists on the relative timing between the activated D1/D5 receptors and the HFS/LFS protocol and the applied concentration of D1/D5 agonists.

Asunto(s)

Dopamina , Modelos Neurológicos , Teorema de Bayes , Región CA1 Hipocampal/fisiología , Dopamina/farmacología , Estimulación Eléctrica/métodos , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Plasticidad Neuronal/fisiología , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Sinapsis/fisiología

RESUMEN

Disrupting the pathological synchronous firing patterns of neurons with high frequency stimulation is a common treatment for Parkinsonian symptoms and epileptic seizures when pharmaceutical drugs fail. In this paper, our goal is to design a desynchronization strategy for large networks of spiking neurons such that the neuronal activity of the network remains in the desynchronized regime for a long period of time after the removal of the stimulation. We develop a novel "Forced Temporal-Spike Time Stimulation (FTSTS)" strategy that harnesses the spike-timing dependent plasticity to control the synchronization of neural activity in the network by forcing the neurons in the network to artificially fire in a specific temporal pattern. Our strategy modulates the synaptic strengths of selective synapses to achieve a desired synchrony of neural activity in the network. Our simulation results show that the FTSTS strategy can effectively synchronize or desynchronize neural activity in large spiking neuron networks and keep them in the desired state for a long period of time after the removal of the external stimulation. Using simulations, we demonstrate the robustness of our strategy in desynchronizing neural activity of networks against uncertainties in the designed stimulation pulses and network parameters. Additionally, we show in simulation, how our strategy could be incorporated within the existing desynchronization strategies to improve their overall efficacy in desynchronizing large networks. Our proposed strategy provides complete control over the synchronization of neurons in large networks and can be used to either synchronize or desynchronize neural activity based on specific applications. Moreover, it can be incorporated within other desynchronization strategies to improve the efficacy of existing therapies for numerous neurological and psychiatric disorders associated with pathological synchronization.