Biology subjects

Eitan, R.

Publications and source records attributed to Eitan, R..

5 recordsLinked to original sources

bioRxiv2024

Novel immunotherapy for multiple solid cancers using an Anti-HVEM blocking monoclonal antibody

INTRODUCTIONImmune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet their efficacy remains limited. Therefore, there is a clear need for new anti-tumor agents. HVEM (Herpes Virus Entry Mediator) plays a regulatory role in immunity, making it a promising cancer therapeutic target. EXPERIMENTAL DESIGNWe have developed Anti-4CB1, a fully human HVEM-BTLA and HVEM-CD160 blocking mAb and tested its anti-tumor activity in various in-vitro, ex-vivo and in-vivo models, alone or in combination with Anti-PD1. Finally, we analyzed HVEM expression in serum samples and melanoma tumor tissues and its correlation with HVEM and PD1 blockade treatment response. RESULTSIn-vitro assays demonstrated enhanced melanoma cell killing by autologous TILs in the presence of Anti-4CB1. In addition, Anti-4CB1 significantly increased cytotoxicity by up to 233% in a variety of ex-vivo cancer tissue samples of different indications. Notably, Anti-4CB1 demonstrated effectiveness in samples where Anti-PD1 was ineffective. In addition, significant anti-tumor activity at 10 mg/kg in combination with Anti-PD1 (TGI 95% p=0.0001) or at 25 mg/kg as monotherapy (TGI 50% p=0.0096) was demonstrated in a colon carcinoma transgenic mice model. Moreover, significant anti-tumor activity was observed in a mouse ImmunoGraft model (TGI 53% p=0.0102 as monotherapy). Finally, we demonstrated that HVEM expression correlated with response to Anti-HVEM and Anti-PD1 treatments. DISCUSSIONWe describe the development of Anti-4CB1, a fully human anti-HVEM mAb, blocking HVEM-BTLA and HVEM-CD160 human interactions and enhancing lymphocytes cytotoxicity against various cancer cells ex-vivo. In-vivo, Anti-4CB1 showed promising anti-tumor effects, particularly in combination with Anti-PD1, suggesting its therapeutic potential. Finally, HVEM expression may serve as a predictive marker for Anti-HVEM and Anti-PD1 treatments response, offering potential diagnostic utility in patient selection for these immunotherapies. These results support Anti-4CB1 potential as an anti-cancer therapeutic agent. Translational RelevanceThe discovery of immune checkpoint inhibitors (ICIs), marks a significant breakthrough in cancer therapy. However, despite the remarkable success of current ICIs targeting CTLA4 and PD1/PD-L1 pathways, a significant proportion of patients fail to respond or develop resistance. Therefore, the search for novel ICIs is crucial for advancing cancer immunotherapy. Anti-HVEM emerged as a promising candidate, as we demonstrate in ex-vivo and in-vivo models, its ability to block the HVEM-BTLA interaction, resulting in enhanced antitumor immune responses in solid tumors, alone or in combination with existing ICIs, to improve treatment outcomes. Moreover, the correlation between HVEM expression and treatment responses highlight its potential as an attractive target for biomarker-driven therapies. Investigating HVEM as an ICI offers a promising path to expand therapeutic options, personalize treatment approaches, address the evolving challenges in cancer immunotherapy and improve patient outcomes.

cancer biology↗

bioRxiv2022

De-tensioning of collagen fibers optimizes endometrial receptivity and improves the rate of embryo implantation

Successful embryo implantation within the uterine wall requires intricate endometrial remodeling. Impaired endometrial receptivity, a common cause of infertility, often results from ineffective remodeling processes. Here, we demonstrate that a single dose of human collagenase-1 administered into the mouse uterus enhances embryo implantation rates. Mechanistically, collagenase-1 induces remodeling of the endometrial extracellular matrix (ECM), leading to the degradation of collagen fibers and proteoglycans. This process releases matrix-bound bioactive factors, such as VEGF, which facilitates local vascular permeability and angiogenesis. Furthermore, collagenase-1 treatment increases NK cell infiltration and elevates levels of the cytokine LIF, a key factor in embryo implantation. Remarkably, the overall structural integrity of the uterine tissue remains uncompromised, even in the presence of reduced tension in endometrial collagen fibers. To assess pre-clinical potential, in-uteri application of collagenase-1 successfully rescued implantation in mouse models subjected to heat stress and embryo transfer, conditions known for their adverse impact on implantation rates. Importantly, ex-vivo exposure of human uterine tissue to collagenase-1 induced collagen de-tensioning and the release of VEGF, demonstrating similar processes observed in the mouse settings, and the potential relevance of this treatment to human conditions. Our findings underscore the immense clinical potential and feasibility of collagenase treatment to enhance uterine receptivity for embryo implantation, offering a controlled and minimally invasive intervention. This innovative approach not only demonstrates the potential to enhance efficiency in livestock breeding but, more importantly, signifies a substantial promise in supporting medical interventions for human reproduction in clinical settings.

biochemistry↗

bioRxiv2020

Frequency matters: Up- and Down-Regulation of Dopamine Tone Induces Similar Frequency Shifts in Cortico-Basal Ganglia Beta Oscillations

Beta oscillatory activity (13-30Hz) is pervasive within the cortico-basal ganglia (CBG) network. Studies in Parkinsons disease (PD) patients and animal models suggested that beta-power increases with dopamine depletion. However, the exact relationship between oscillatory power, frequency and dopamine-tone remains unclear. We recorded neural activity in the CBG network of non-human-primates (NHP) while acutely up- and down-modulating dopamine levels. Further, we assessed changes in beta oscillations of PD patients following acute and chronic changes in dopamine-tone. Beta oscillation frequency was strongly coupled with dopamine-tone in both NHPs and human patients. In contrast, power, coherence between single-units and LFP, and spike-LFP phase-locking were not systematically regulated by dopamine levels. These results demonstrate via causal manipulations that frequency, rather than other properties, is the key property of pathological oscillations in the CBG networks. These insights can lead to improvements in understanding of CBG physiology, PD progression tracking and patient care.

neuroscience↗

bioRxiv2018

Human Subthalamic Nucleus Selectively Decreases its Response to the Go-Signal in a Motor Inhibition Context

To better understand the mechanism of movement facilitation and inhibition in the subthalamic nucleus (STN), we recorded subthalamic multiunit activity intra-operatively while parkinsonian patients (n=43 patients, 173 sites) performed increasingly complex oddball paradigms: auditory ( None-Go, n=7, 28), simple movement ( All-Go, n=7, 26) and movement inhibition ( Go-NoGo, n=29, 119) tasks. To enable physiological sampling of the different subthalamic nucleus domains in both hemispheres, each patient performed one of the oddball paradigms several times.\n\nThe human STN responded mainly to movement-involving tasks: movement execution at the motor STN and movement planning at the limbic-associative STN. In the limbic-associative STN, responses to the inhibitory cue (deviant tone) in the movement inhibition task were not significantly different from the simple movement task. However, responses to the go cue (frequent tone) were significantly reduced. The reduction was mainly in the negative component of the evoked response amplitude. Successful movement inhibition was correlated with higher baseline activity before the inhibitory cue.\n\nWe suggest that the STN adapts to movement inhibition context by selectively decreasing the amplitude of neuronal activity. Thus, the STN enables movement inhibition not by increasing responses to the inhibitory cue but by reducing responses to the release cue. The negative component of the evoked response probably facilitates movement and a higher baseline activity enables successful inhibition of movement. These discharge modulations were found in the ventromedial, non-motor domain of the STN and therefore suggest a significant role of the associative-limbic domains in movement planning and in global movement regulation.

neuroscience↗

bioRxiv2017

Reconstructing cancer karyotypes from short read data: the half full and half empty glass

BackgroundDuring cancer progression genomes undergo point mutations as well as larger segmental changes. The latter include, among others, segmental deletions duplications, translocations and inversions. The result is a highly complex, patient-specific cancer karyotype. Using high-throughput technologies of deep sequencing and microarrays it is possible to interrogate a cancer genome and produce chromosomal copy number profiles and a list of breakpoints (\"jumps\") relative to the normal genome. This information is very detailed but local, and does not give the overall picture of the cancer genome. One of the basic challenges in cancer genome research is to use such information to infer the cancer karyotype.\n\nWe present here an algorithmic approach, based on graph theory and integer linear programming, that receives segmental copy number and breakpoint data as input and produces a cancer karyotype that is most concordant with them. We used simulations to evaluate the utility of our approach, and applied it to real data.\n\nResultsBy using a simulation model, we were able to estimate the correctness and robustness of the algorithm in a spectrum of scenarios. Under our base scenario, designed according to observations in real data, the algorithm correctly inferred 69% of the karyotypes. However, when using less stringent correctness metrics that account for incomplete and noisy data, 87% of the reconstructed karyotypes were correct. Furthermore, in scenarios where the data were very clean and complete, accuracy rose to 90%-100%. Some examples of analysis of real data, and the karyotypes reconstructed by our algorithm, are also presented.\n\nConclusionWhile reconstruction of complete, perfect karyotype based on short read data is very hard, a large portion of the reconstruction will still be correct and can provide useful information.

bioinformatics↗