Search

Most anti-cancer modalities are designed to directly kill cancer cells deploying mechanisms of action (MOAs) centered on the presence of a precise target on cancer cells. The efficacy of these approaches is limited because the rapidly evolving genetics of neoplasia swiftly circumvents the MOA generating therapy-resistant cancer cell clones. Other modalities engage endogenous anti-cancer mechanisms by activating the multi-cellular network (MCN) surrounding neoplastic cells in the tumor microenvironment (TME). These modalities hold a better chance of success because they activate numerous types of immune effector cells that deploy distinct cytotoxic MOAs. This in turn decreases the chance of developing treatment-resistance. Engagement of the MCN can be attained through activation of immune effector cells that in turn kill cancer cells or when direct cancer killing is complemented by the production of proinflammatory factors that secondarily recruit and activate immune effector cells. For instance, adoptive cell therapy (ACT) supplements cancer cell killing with the release of homeostatic and pro-inflammatory cytokines by the immune cells and damage associated molecular patterns (DAMPs) by dying cancer cells. The latter phenomenon, referred to as immunogenic cell death (ICD), results in an exponential escalation of anti-cancer MOAs at the tumor site. Other approaches can also induce exponential cancer killing by engaging the MCN of the TME through the release of DAMPs and additional pro-inflammatory factors by dying cancer cells. In this commentary, we will review the basic principles that support emerging paradigms likely to significantly improve the efficacy of anti-cancer therapy. [ABSTRACT FROM AUTHOR]

Advancing personalized medicine in brain cancer relies on innovative strategies, with mRNA vaccines emerging as a promising avenue. While the initial use of mRNA vaccines was in oncology, their stunning success in COVID-19 resulted in widespread attention, both positive and negative. Regardless of politically biased opinions, which relate more to the antigenic source than form of delivery, we feel it is important to objectively review this modality as relates to brain cancer. This class of vaccines trigger robust immune responses through MHC-I and MHC-II pathways, in both prophylactic and therapeutic settings. The mRNA platform offers advantages of rapid development, high potency, cost-effectiveness, and safety. This review provides an overview of mRNA vaccine delivery technologies, tumor antigen identification, combination therapies, and recent therapeutic outcomes, with a particular focus on brain cancer. Combinatorial approaches are vital to maximizing mRNA cancer vaccine efficacy, with ongoing clinical trials exploring combinations with adjuvants and checkpoint inhibitors and even adoptive cell therapy. Efficient delivery, neoantigen identification, preclinical studies, and clinical trial results are highlighted, underscoring mRNA vaccines' potential in advancing personalized medicine for brain cancer. Synergistic combinatorial therapies play a crucial role, emphasizing the need for continued research and collaboration in this area. [ABSTRACT FROM AUTHOR]

Liver steatosis, inflammation, and variable degrees of fibrosis are the pathological manifestations of nonalcoholic steatohepatitis (NASH), an aggressive presentation of the most prevalent chronic liver disease in the Western world known as nonalcoholic fatty liver (NAFL). Mitochondrial hepatocyte dysfunction is a primary event that triggers inflammation, affecting Kupffer and hepatic stellate cell behaviour. Here, we consider the role of impaired mitochondrial function caused by lipotoxicity during oxidative stress in hepatocytes. Dysfunction in oxidative phosphorylation and mitochondrial ROS production cause the release of damage-associated molecular patterns from dying hepatocytes, leading to activation of innate immunity and trans-differentiation of hepatic stellate cells, thereby driving fibrosis in NASH. [ABSTRACT FROM AUTHOR]

Mammalian cells responding to specific perturbations of homeostasis can undergo a regulated variant of cell death that elicits adaptive immune responses. As immunogenic cell death (ICD) can only occur in a precise cellular and organismal context, it should be conceptually differentiated from instances of immunostimulation or inflammatory responses that do not mechanistically depend on cellular demise. Here, we critically discuss key conceptual and mechanistic aspects of ICD and its implications for cancer (immuno)therapy. [ABSTRACT FROM AUTHOR]

In the last decade, Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach to fight cancers. This approach consists of genetically engineered immune cells expressing a surface receptor, called CAR, that specifically targets antigens expressed on the surface of tumor cells. In hematological malignancies like leukemias, myeloma, and non-Hodgkin B-cell lymphomas, adoptive CAR-T cell therapy has shown efficacy in treating chemotherapy refractory patients. However, the value of this therapy remains inconclusive in the context of solid tumors and is restrained by several obstacles including limited tumor trafficking and infiltration, the presence of an immunosuppressive tumor microenvironment, as well as adverse events associated with such therapy. Recently, CAR-Natural Killer (CAR-NK) and CAR-macrophages (CAR-M) were introduced as a complement/alternative to CAR-T cell therapy for solid tumors. CAR-NK cells could be a favorable substitute for CAR-T cells since they do not require HLA compatibility and have limited toxicity. Additionally, CAR-NK cells might be generated in large scale from several sources which would suggest them as promising off-the-shelf product. CAR-M immunotherapy with its capabilities of phagocytosis, tumor-antigen presentation, and broad tumor infiltration, is currently being investigated. Here, we discuss the emerging role of CAR-T, CAR-NK, and CAR-M cells in solid tumors. We also highlight the advantages and drawbacks of CAR-NK and CAR-M cells compared to CAR-T cells. Finally, we suggest prospective solutions such as potential combination therapies to enhance the efficacy of CAR-cells immunotherapy. [ABSTRACT FROM AUTHOR]

Abnormal gene expression level or expression of genes containing deleterious mutations are two of the main determinants which lead to genetic disease. To obtain a therapeutic effect and thus to cure genetic diseases, it is crucial to regulate the host's gene expression and restore it to physiological conditions. With this purpose, several molecular tools have been developed and are currently tested in clinical trials. Genome editing nucleases are a class of molecular tools routinely used in laboratories to rewire host's gene expression. Genome editing nucleases include different categories of enzymes: meganucleses (MNs), zinc finger nucleases (ZFNs), clustered regularly interspaced short palindromic repeats (CRISPR)- CRISPR associated protein (Cas) and transcription activator-like effector nuclease (TALENs). Transposable elements are also a category of molecular tools which includes different members, for example Sleeping Beauty (SB), PiggyBac (PB), Tol2 and TcBuster. Transposons have been used for genetic studies and can serve as gene delivery tools. Molecular tools to rewire host's gene expression also include episomes, which are divided into different categories depending on their molecular structure. Finally, RNA interference is commonly used to regulate gene expression through the administration of small interfering RNA (siRNA), short hairpin RNA (shRNA) and bi-functional shRNA molecules. In this review, we will describe the different molecular tools that can be used to regulate gene expression and discuss their potential for clinical applications. These molecular tools are delivered into the host's cells in the form of DNA, RNA or protein using vectors that can be grouped into physical or biochemical categories. In this review we will also illustrate the different types of payloads that can be used, and we will discuss recent developments in viral and non-viral vector technology. [ABSTRACT FROM AUTHOR]

The horizon of immunotherapy using CAR-T cells is continuously extending to treat solid tumors beyond the success in the treatment of liquid tumors. Precise in-vitro evaluations of CAR-T cells for their phenotypes, quantity and quality of activation in various tumor microenvironments including different antigen densities, and the resulting effector functions are critical for the successful development of CAR-T therapies and safe translation to clinics. Unfortunately, the development of methods and tools to accommodate these needs have been lagging behind. Here, we developed a novel biomaterial platform, acellular artificial target particles (aaTPs) against CAR-T cells, using magnetic microbeads that are already widely employed in the manufacturing of T cell products. By devising a simple and standardized procedure, we precisely controlled the antigen surface densities presented on the aaTPs for a wide range. By co-incubation of aaTPs with CAR-T cells followed by flow cytometry and cytokine assays, we quantitatively determined the antigen-specific and dose-dependent activation of anti-HER2 CAR-T cells. We also demonstrated that the aaTP can serve as a clean target cell in in-vitro assays to prove the proposed mechanism of action of a next-generation CAR-T product. Overall, the simple, inexpensive, modular and precisely controllable synthetic nature of aaTPs enables the development of clean and standardized in-vitro assays for CAR-T cells, which provides critical advantages over the conventional assays using target cell lines. The design of aaTPs can be extended to include other tumor antigens and relevant surface molecules of physiological target cells. Thus, the aaTP platform has great potential as a standardized tool for the development and evaluation of both conventional and new CAR-T products in the context of approval from regulatory agencies and clinical translation. [ABSTRACT FROM AUTHOR]

A cancer immune phenotype characterized by an active T-helper 1 (Th1)/cytotoxic response is associated with responsiveness to immunotherapy and favorable prognosis across different tumors. However, in some cancers, such an intratumoral immune activation does not confer protection from progression or relapse. Defining mechanisms associated with immune evasion is imperative to refine stratification algorithms, to guide treatment decisions and to identify candidates for immune-targeted therapy. Molecular alterations governing mechanisms for immune exclusion are still largely unknown. The availability of large genomic datasets offers an opportunity to ascertain key determinants of differential intratumoral immune response. We follow a network-based protocol to identify transcription regulators (TRs) associated with poor immunologic antitumor activity. We use a consensus of four different pipelines consisting of two state-of-the-art gene regulatory network inference techniques, regularized gradient boosting machines and ARACNE to determine TR regulons, and three separate enrichment techniques, including fast gene set enrichment analysis, gene set variation analysis and virtual inference of protein activity by enriched regulon analysis to identify the most important TRs affecting immunologic antitumor activity. These TRs, referred to as master regulators (MRs), are unique to immune-silent and immune-active tumors, respectively. We validated the MRs coherently associated with the immune-silent phenotype across cancers in The Cancer Genome Atlas and a series of additional datasets in the Prediction of Clinical Outcomes from Genomic Profiles repository. A downstream analysis of MRs specific to the immune-silent phenotype resulted in the identification of several enriched candidate pathways, including NOTCH1, TGF- |$\beta $|⁠ , Interleukin-1 and TNF- |$\alpha $| signaling pathways. TGFB1I1 emerged as one of the main negative immune modulators preventing the favorable effects of a Th1/cytotoxic response. [ABSTRACT FROM AUTHOR]

Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies. [ABSTRACT FROM AUTHOR]

Successful implementation of adoptive cell therapy (ACT) of cancer requires comprehensively addressing biological and practical challenges. This approach has been largely overlooked, resulting in a gap between the potential of ACT and its actual effectiveness. We summarize the most promising technical strategies in creating an "ideal" ACT product, focusing on chimeric antigen receptor (CAR)-engineered cells. Since many requirements for effective ACT are common to most cancers, what we outline here might have a broader impact. [ABSTRACT FROM AUTHOR]