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Background KISIMATM platform allows the development of protein-based cancer vaccines able to induce a potent, tumor-specific CD8 and CD4 T cells response. While the cell penetrating peptide and peptide agonist for Toll like receptor (TLR)-2 and TLR-4 confer, respectively, the cell delivery and self-adjuvanticity properties, the multiantigenic domain allows the targeting of different cancer antigens, resulting in anti-tumoral efficacy in different murine models. Oncolytic viruses exert their therapeutic effects by a prolonged oncolytic action and the associated intratumoral inflammation as well as general immune activation. Arming oncolytic virus with tumor associated antigens can additionally enhance the tumor-specific T cell portion and therefore positively affect the balance of antitumor versus antiviral immune responses. The protein vaccine KISIMATM and the recombinant oncolytic virus VSV-GP-TAA (vesicular stomatitis virus pseudotyped with LCMV GP expressing tumor-associated antigens) are both promising vaccine candidates that offer a new cancer vaccination opportunity when combined in heterologous prime-boost regimen. Materials and Methods Mice were vaccinated with subcutaneous (s.c.) injection of KISIMA-TAA vaccine and/or with intravenous injection of VSV-GP-TAA in different settings. Immunogenicity was assessed by measuring the peripheral antigen-specific response. Anti-tumoral efficacy as well as in depth monitoring of TILs and tumor microenvironment modulation were assessed following therapeutic vaccination in different tumor models. Additionally, transcriptome and immunohistochemistry analyses of the TC-1 tumor have been performed. Combination of heterologous prime-boost with checkpoint blockade PD-1 therapy has been assessed. Results Priming with KISIMA-TAA followed by VSV-GP-TAA boost induced a large pool of polyfunctional and persistent antigen-specific cytotoxic T cells in the periphery as well as within the tumor in several tumor models. Frequencies of antigen specific T cells are significantly higher than the respective homologous vaccinations. Additionally, transcriptome analysis of a cold tumor model revealed profound changes in the tumor microenvironment upon heterologous vaccination, including a strong upregulation of gene signatures of several pro-inflammatory cytokines and chemokines required for antitumor immunity along with dendritic and T cell trafficking and activation. This was corroborated by flow-cytometric analysis of tumor-infiltrating leukocytes showing massive CD8+ and CD4+ T cell infiltration as well as repolarization of M2-like macrophages towards M1-phenotype. The presence of the CD8+ T cells within the tumor core was confirmed by immunohistochemistry analysis. Moreover, combining heterologous vaccination with checkpoint blockade further improved its therapeutic efficacy and the number of long-term survivors. Conclusions The KISIMA/VSV-GP heterologous prime-boost approach holds great promise for patients with primary or acquired resistance to checkpoint blockade due to its ability to induce tumor-specific T cell, improve T cell infiltration and increase tumor inflammation, even in tumors with limited permissivity for the oncolytic virus. Disclosure Information E. Belnoue: A. Employment (full or part-time); Significant; AMAL Therapeutics SA. K. Das: None. M. Rossi: A. Employment (full or part-time); Significant; AMAL Therapeutics SA. T. Hofer: None. S. Danklmaier: None. T. Nolden: A. Employment (full or part-time); Significant; Viratherapeutics GmbH. L. Schreiber: None. K. Angerer: None. J. Kimpel: None. S. Hoegler: None. L. Kenner: None. D. von Laer: None. K. Elbers: A. Employment (full or part-time); Significant; Viratherapeutics GmbH. G. Wollmann: None. M. Derouazi: A. Employment (full or part-time); Significant; AMAL Therapeutics SA.

Significance Oscillatory activity is prominent in the brain, and one hypothesis is that it is, in part, due to the nature of coupling or interaction patterns between brain areas. We tested this hypothesis by manipulating the strength of coupling between two brain regions (ventral premotor cortex, PMv, and motor cortex, M1) in two directions (increase or decrease) while carefully controlling for the impact each manipulation had on activity in each area. We looked at the PMv–M1 connection because it is the major cortical route by which prefrontal cortex might influence, inhibit, and curtail action-related activity in M1. Manipulating PMv–M1 coupling in accordance with Hebbian-like spike-timing–dependent plasticity resulted in changes in beta and theta frequencies linked to action control., The origins of oscillatory activity in the brain are currently debated, but common to many hypotheses is the notion that they reflect interactions between brain areas. Here, we examine this possibility by manipulating the strength of coupling between two human brain regions, ventral premotor cortex (PMv) and primary motor cortex (M1), and examine the impact on oscillatory activity in the motor system measurable in the electroencephalogram. We either increased or decreased the strength of coupling while holding the impact on each component area in the pathway constant. This was achieved by stimulating PMv and M1 with paired pulses of transcranial magnetic stimulation using two different patterns, only one of which increases the influence exerted by PMv over M1. While the stimulation protocols differed in their temporal patterning, they were comprised of identical numbers of pulses to M1 and PMv. We measured the impact on activity in alpha, beta, and theta bands during a motor task in which participants either made a preprepared action (Go) or withheld it (No-Go). Augmenting cortical connectivity between PMv and M1, by evoking synchronous pre- and postsynaptic activity in the PMv–M1 pathway, enhanced oscillatory beta and theta rhythms in Go and No-Go trials, respectively. Little change was observed in the alpha rhythm. By contrast, diminishing the influence of PMv over M1 decreased oscillatory beta and theta rhythms in Go and No-Go trials, respectively. This suggests that corticocortical communication frequencies in the PMv–M1 pathway can be manipulated following Hebbian spike-timing–dependent plasticity.

Simple Summary Oncolytic viruses can be a potent tool in the fight against cancer. However, in clinical settings their ability to replicate in and kill tumors is often limited. Combinations with specific small molecule compounds can address some of these limitations and help oncolytic viruses reach their full potential. The aim of this review is to provide an overview of the different types of small molecules with which oncolytic viruses can achieve therapeutic synergy. We focus on the underlying mechanisms in three functional areas: combinations that increase viral replication, enhance tumor cell killing and improve antitumor immune responses. Abstract The focus of treating cancer with oncolytic viruses (OVs) has increasingly shifted towards achieving efficacy through the induction and augmentation of an antitumor immune response. However, innate antiviral responses can limit the activity of many OVs within the tumor and several immunosuppressive factors can hamper any subsequent antitumor immune responses. In recent decades, numerous small molecule compounds that either inhibit the immunosuppressive features of tumor cells or antagonize antiviral immunity have been developed and tested for. Here we comprehensively review small molecule compounds that can achieve therapeutic synergy with OVs. We also elaborate on the mechanisms by which these treatments elicit anti-tumor effects as monotherapies and how these complement OV treatment.

Introduction: Oncolytic viruses (OVs), which selectively replicate in and destroy tumor cells, form a highly promising class of cancer therapeutics with a strong immune stimulatory potential. VSV-GP, a chimeric Vesicular Stomatitis Virus (VSV) pseudotyped with the glycoprotein of the lymphocytic choriomeningitis virus (LCMV) can selectively replicate and express therapeutic cargos in the tumor microenvironment. Lymphotoxin alpha (LTα) - a member of the TNF superfamily - may present as a potent therapeutic cargo based on its immune stimulatory and cell death modulatory characteristics.In this study, we explore the immune promoting and tumor cell death inducing properties of VSV-GP-LTα, a next generation variant with an NF-κB facilitated mode of action. We further investigate clinically relevant combination therapies with “second mitochondria-derived activator of caspases” mimetic compounds (SMCs). Experimental Procedures: Viral fitness, cargo expression and test substance quality were assessed using growth kinetic, ELISA, RT-qPCR and titration assays. Therapeutic efficacy and safety of VSV-GP-LTα, with or without SMC co-treatment, were assessed in vivo in syngeneic C57BL/6 mice bearing subcutaneous LLC1-IFNAR-/- or B16F10-OVA tumors. To shed further light into the VSV-GP-LTα treatment effects, we applied immunohistochemistry, flow cytometry, multiplex ELISA and Nanostring® assays. Data Summary: VSV-GP-LTα induced stronger anti-tumor effects and increased overall survival compared to VSV-GP. It was also better tolerated than VSV-GP armed with TNF-α, a therapeutic cargo from the same class. Histological and gene expression analysis confirmed widespread cell killing within the tumor and activation of innate and adaptive immune response markers. However, further characterization of the adaptive immune compartment did not show significant changes induced by the expressed LTα. Building on the observed therapeutic strengths of VSV-GP-LTα, we further explored a treatment combination with SMC. This resulted in a therapeutic synergy with improved treatment-induced tumor cell death, especially in a less permissive tumor setting. Conclusion: Together, here we show that arming VSV-GP with LTα resulted in a strong inflammation of the tumor microenvironment and enhanced levels of tumor cell death induction. This effect could be further enhanced by the co-treatment with SMC. Citation Format: Bart Spiesschaert, Philipp Müller, Katharina Angerer, Krishna Das, Tobias Nolden, Carles Urbiola, Judy Ng, Fabian Heinemann, Birgit Stierstorfer, Patrik Erlmann, Guido Wollmann. Lymphotoxin-alpha-armed oncolytic VSV-GP synergizes with SMAC mimetics to induce enhanced tumor cell death and regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4193.

This article argues that the dual-process position can be a useful first approximation when studying human mental life, but it cannot be the whole truth. Instead, we argue that cognition is built on association, in that associative processes provide the fundamental building blocks that enable propositional thought. One consequence of this position is to suggest that humans are able to learn associatively in a similar fashion to a rat or a pigeon, but another is that we must typically suppress the expression of basic associative learning in favour of rule-based computation. This stance conceptualises us as capable of symbolic computation but acknowledges that, given certain circumstances, we will learn associatively and, more importantly, be seen to do so. We present three types of evidence that support this position: The first is data on human Pavlovian conditioning that directly support this view. The second is data taken from task-switching experiments that provide convergent evidence for at least two modes of processing, one of which is automatic and carried out “in the background.” And the last suggests that when the output of propositional processes is uncertain, the influence of associative processes on behaviour can manifest.