Examples of Outcome Reporting Bias in Vaccine Studies: Illustrating ...
Why Innate Immunity Could Be The Key To Improving Cancer Care
A new generation of cancer therapies has emerged over the past few decades, including checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapies that modify or directly use T-cells to attack cancer.1
These approaches have benefited certain patients, but cancer is clever, and it can evade and suppress therapies like these that employ the adaptive immune system—one of the two interdependent arms of the immune system. This is particularly evident in "cold tumors," which lack infiltration or activation of anti-cancer immunity and do not typically respond to existing immune therapies.
Novel therapies, however, could boost the ability of immune cells to infiltrate tumors and kill cancer cells. These therapies employ a different branch of the immune system called innate immunity that can help overcome cancer's ability to evade immune recognition early in an immune response. By leveraging both arms of the immune system, researchers could give modern medicine powerful new tools to fight cancer.
The dawn of immunologyThe power of the immune system to fight disease has intrigued scientists for centuries. The earliest known reference to immunity goes back more than two millennia to the plague of Athens in 430 B.C., when the Greeks realized that people who had survived smallpox were not infected with the disease a second time.2
Fast forward 2,300-plus years to the last quarter of the nineteenth century, when Elie Metchnikoff, a Russian zoologist, identified cells that could engulf and destroy foreign pathogens, known as phagocytic cells. This discovery became the basis for immunology.3
What the Greeks and Metchnikoff observed, and what scientists continue to uncover, is the complexity of the human immune system.3 The first of the immune system's two interdependent arms, the innate immune system, consists of a variety of cell types, including natural killer (NK) cells, macrophages and dendritic cells, that serve as an initial line of defense against threats. Innate immune cells exhibit rapid cytotoxic activity against foreign pathogens and malignant cells, and they have the capacity to launch a counterpart arm, the adaptive immune system. The T-cells and B-cells in this system have receptors that recognize specific foreign antigens, and they develop long-lasting immune memory to protect against future infections or cancers.
Researchers have modulated the adaptive immune system to develop therapies for cancer, infectious diseases and autoimmune conditions. And beginning decades ago, scientists realized that they could potentially treat different illnesses by utilizing innate immunity.
The role of interferons in harnessing innate immunityOne of the earliest identified keys to unlocking the power of innate immunity was leveraging interferons, a family of inflammatory proteins that detect threats and signal the immune system, causing the awakening of innate immunity and downstream adaptive responses. After they were discovered in 1957, researchers showed that interferons had antitumor activity, and others explored using them to treat diseases.4 To date, interferons have been used to treat several chronic infectious diseases, as well as certain hematologic malignancies and solid cancers.5
Although interferons produce meaningful clinical benefit for some patients, they can result in serious side effects. This has limited their broad utility and driven researchers to explore a more nuanced approach to safely stimulate innate immunity to treat cancer.5
The cancer immunity cycleOur understanding of the immune system's ability to recognize and attack cancer is best represented by what scientists refer to as "the cancer immunity cycle," which maps the interplay between immune cells and tumors along key steps that, if productive, can lead to tumor eradication.6
The first steps in the cycle occur when specialized innate immune cells known as antigen-presenting cells are activated. This leads to triggering of the adaptive immune response through the presentation of cancer-derived signals (also known as antigens) to T-cells, typically in lymph nodes near tumor sites. These activated T-cells then migrate through blood vessels and infiltrate the tumor, subsequently killing the targeted cancer cells.7 Meanwhile, additional innate immune effector cells – including macrophages, NK cells and gamma delta (γδ) T-cells – are activated to directly attack and kill tumor cells upon contact, while critically shaping the overall tumor microenvironment to be more permissive to an effective immune response.
The innate and adaptive immune systems work together to orchestrate a productive response in the tumor microenvironment, creating a powerful cycle that results in cancer cell death. Credit: Image used with permission. © 2022 Takeda Pharmaceuticals, U.S.A., Inc. All rights reserved. The future of cancer therapy Today, researchers continue to explore how the innate immune system can outsmart cancer—work that has led to a steady increase of investigational therapies that harness innate immunity. For example, researchers at Takeda Oncology are exploring this emerging science through multiple programs that seek to address the needs of people living with cancer. These include therapeutics designed to tap into the power of interferons while avoiding the toxicities that have limited their use, cell therapies that leverage innate cell types such as NK cells and γδ T-cells, antibody-like molecules that engage immune cells to attack cancer cells, and other novel modalities.
By harnessing innate immunity, which helps to drive adaptive immunity, researchers aim to enhance a powerful immune defense mechanism that achieves a robust and durable attack on tumors at different tissue locations, thereby outsmarting cancer in ways never seen before.
To learn more about how innate immunity can be leveraged in cancer therapeutics, visit .Https://www.Takedaoncology.Com/science-research/innate-immunity/.
References
Coevolutionary Interplay: Helminths-trained Immunity And Its Impact On The Rise Of Inflammatory Diseases
Chronic inflammatory and autoimmune disorders are characterized by the immune system's assault on its own tissues, affecting millions worldwide. With over 80 recognized autoimmune diseases, including IBD, MS, RA, and type 1 diabetes (T1D), the global health (10%) and economic burden is immense. Addressing this growing epidemic requires innovative approaches to prevent and treat autoimmune diseases (Smallwood et al., 2017; Gutierrez-Arcelus et al., 2016; Hayter and Cook, 2012). Although genetic predisposition influences susceptibility, some environmental and lifestyle factors are likely crucial in triggering or exacerbating these conditions as dysbiosis and loss of helminths interaction, which promote immunoregulatory mechanisms that could benefit the host by protecting them from severe inflammatory pathologies (Rook, 2023; Scudellari, 2017; Smallwood et al., 2017). Many micro and macro organisms responsible for regulating the immune system are derived from our mothers, families, and the natural environment (including animals), see Figure 1. These organisms, often symbiotic members of a healthy host biome, contribute to a balanced immune response (Rook, 2023; Scudellari, 2017).
Type 2 immune responses, rooted in ancient defense mechanisms, play a crucial role in protecting against metazoan endo- and ectoparasites, regulating metabolism, and promoting tissue repair. While these responses are essential for health, dysregulation can lead to allergic disorders, impaired tissue healing, and metabolic disturbances (Maizels and Gause, 2023; Gause et al., 2013). The diversity of these macroparasites and their manifold evasion strategies has demanded a corresponding diversification of defense mechanisms for host survival that are fine-tuned to each threat (Maizels and Gause, 2023). Most attention in recent years has been given to the pathways of type 2 induction and its regulation in immunological disorders (Gause et al., 2020; Hammad and Lambrecht, 2015; McDaniel et al., 2023).
It was once logical to postulate evolved dependence on helminths in the past (Bilbo et al., 2011; Maizels, 2020); however, it now seems more likely that the adaptation of the developing immune system to the presence of helminths was largely epigenetic and was lost after a few generations without them. These reversible epigenetic mechanisms help us to understand the conflicting and disappointing results of helminth therapy trials. Clinical trials may not yield helpful results, and face significant challenges until we can precisely identify the optimal combination of patient characteristics, genetic factors, disease stage, and specific helminth species, ESPs, or metabolic byproducts for effectively train immune system (Rook, 2023; Smallwood et al., 2017; Ryan et al., 2020; Loke et al., 2022). To mitigate risks associated with live parasite infections, exploring helminth-derived anti-inflammatory molecules or ESPs delivered through EVs offers a promising avenue for developing safer and more controlled therapeutics for chronic inflammatory diseases.
Completed and ongoing therapeutic clinical trials using helminth products in various human disease contexts are summarized by Ryan et al in their Table 1 (Ryan et al., 2020), focusing on safety, tolerability, and efficacy. Some examples of the therapeutic potential of helminth exposure or helminth-derived products for conditions like IBD, MS, and asthma are discussed below.
Inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, progressive, inflammatory conditions of the gastrointestinal tract. Nowadays, it is clear that an imbalance in the gut microbial community, or dysbiosis, represents a critical environment factors, that results in IBD. Several animal models have shown the beneficial effect of helminth infections or their products on the microbiota and the immune regulation of IBD (Atagozli et al., 2023; Shi et al., 2022; Ryan et al., 2022; Rapin et al., 2020). Thus, IBD-associated dysbiosis, marked by a loss of beneficial Bacteroides and Firmicutes and an increase in pro-inflammatory Enterobacteriaceae, is a key feature of the disease. Within this IBD-microbiota-dysbiosis framework, helminths are of increasing interest due to their capacity to modulate gut microbiota composition, enhance cecal bacterial diversity, and ameliorate IBD in animal models. A novel discovery and validation pipeline, detailed by Ryan et al., 2022, led to the identification of numerous anti-inflammatory biologics from the recombinant secretome of gut-dwelling hookworms. These proteins, representing distinct families, demonstrated protective effects against inducible colitis in mice, suggesting they are safe and promising drug candidates.
Deworming trials have revealed an increased likelihood of developing various autoimmune and metabolic diseases with the use of antihelminthic drugs. This underscores the importance of considering the evolutionary context of human-parasite interactions and the potential risks of disrupting these ancient relationships (Tahapary et al., 2017; Sanya et al., 2020; Flohr et al., 2010; Shute et al., 2021). In this sense, Shute et al., 2021 demonstrates the critical role of bacterial SCFAs via free fatty-acid receptor-2 (ffar2) in H. Diminuta-induced colitis improvement, the necessity of IL-10 in upregulating SCFA transporters/receptors, and butyrate's regulation of IL-10 receptor expression. The findings suggest that the failure of helminth therapy in some IBD trials may be due to patient-specific deficiencies in SCFA production, transport, or IL-10 signaling.
Several clinical trials have been run for over 15 y and have yielded early promising results but also some disappointing outcomes (Ryan et al., 2020; Atagozli et al., 2023). Furthermore, recent systematic reviews summarized the results of these studies into two categories: (a) the efficacy of helminth therapy and (b) the safety of helminth therapy. Results regarding the efficacy were mixed, and a conclusive answer could not be reached, as there was not enough evidence to rule out a placebo effect. Despite this, helminth therapy was safe and tolerable (Ryan et al., 2020; Alghanmi et al., 2024; Shields and Cooper, 2022; Axelrad et al., 2021). Nonetheless, epidemiological explorations, basic science studies, and clinical research on helminths can lead to the development of safe, potent, and novel therapeutic approaches to prevent or treat IBD (Ryan et al., 2020; Ryan et al., 2022; Shute et al., 2021; Maruszewska-Cheruiyot et al., 2023).
Multiple sclerosis (MS) is a highly disabling neurodegenerative autoimmune condition in which an unbalanced immune response plays a critical role. The etiology of MS remains elusive, but it is now known that environmental and patient-specific factors and susceptible genes (more than 200 autosomal vulnerability variants) were associated with disease pathogenesis. Accumulating evidence suggests that the clinical course of multiple sclerosis is better considered as a continuum, where both inflammatory and neurodegenerative processes occur in all disease courses and cannot be clearly assigned to separate, sequential disease stages (Kuhlmann et al., 2023; Correale et al., 2017). Accurate diagnosis of MS can be complex in populations from Latin America, Africa, the Middle East, eastern Europe, southeast Asia, and the Western Pacific. Unique environmental exposures, genetic predispositions, and varying healthcare access in these regions can significantly influence disease presentation and diagnostic criteria (Correale et al., 2024). One of the most striking illustrations of the importance of the environment in MS pathogenesis is its geographic distribution; prevalence rates are increased in high-latitude regions yet uncommon near the equator (Melcon et al., 2014). The gut biome is recognized as a critical regulator of immune and nervous system function, significantly impacting both the onset and progression of MS. It may contribute to and influence the production of soluble metabolites and immune and neuroendocrine factors (Correale et al., 2022). The potential role of epigenetics may explain the inconsistent outcomes of helminth therapy trials in MS (Charabati et al., 2020; Ryan et al., 2020). While natural helminth infections in childhood, more frequent in South American regions like Argentina (Correale and Farez, 2007; Correale and Farez, 2011), can halt disease progression, therapeutic helminth administration in populations without a history of such infections has yielded disappointing results (Ryan et al., 2020; Tanasescu et al., 2020). The treatment of relapsing MS patients with larvae of the nematode Necator americanus was proved to be safe and well tolerated and induced a significant increase in peripheral blood Tregs. Still, the number of new/enlarged brain lesions was not different from the placebo group (Tanasescu et al., 2020). Similarly, results were obtained using eggs from the nematode Trichuris suis, where MS patients tolerated the helminth infection, but it didn't show beneficial effects (Voldsgaard et al., 2015). In other recent study, MS patients receiving TSO treatment established a T. Suis-specific T- and B-cell response; however, with varying degrees of T cell responses and cellular functionality across individuals, which might account for the overall miscellaneous clinical efficacy in the studied patients (Yordanova et al., 2021).
Asthma and allergic airway inflammation are described as IgE-mediated diseases, characterized by a Th2-driven inflammation where environmental exposures and host factors synergistically contribute to its pathogenesis. The escalating global prevalence of these conditions (20%) is a consequence of complex gene-environment interactions that modulate the immune system, and are strongly linked to modern westernized lifestyles (Murrison et al., 2019). A substantial body of evidence obtained from experimental studies in mice points towards a protective role due to the regulatory pathways induced by the parasites that help counteract the immune hyperresponsiveness present in allergy and asthma (Smits et al., 2010). Moreover, several ESP derived from different helminth species have been shown to reduce or suppress allergic airway eosinophilia and inflammation in mice (Chauché et al., 2022; Zhang et al., 2019; Pitrez et al., 2015; Xu et al., 2025). However, other studies have shown an exacerbation of allergic asthma in response to the administration of helminth antigens, unveiling the complexity of the interaction between these type 2 immunity inducers (Ghabdian et al., 2022). On the other hand, the evidence on humans remains more conflicting. As seen with autoimmune diseases, epidemiological data suggests an inverse correlation between helminth infections and those of asthma and allergy (Logan et al., 2018); however, when considering the parasite species, some like A. Lumbricoides have been associated with an increased risk of asthma and disease severity (Cruz et al., 2017; Arrais et al., 2022). Clinical trials have been conducted to assess the efficacy of helminth therapy for asthma and allergic rhinitis, using N. Americanus and T. Suis ova, respectively. Even though they were proven to be safe and well tolerated, clinical benefits were minimal. It is speculated that the discrepancy between human and animal studies could be explained by the fact that helminths are effective at preventing the development of allergy, not treating it (Evans and Mitre, 2015). Despite the lack of positive results in humans thus far, further investigations with improved approaches and protocols are necessary for the treatment of type 2 inflammatory diseases.
Several inflammatory diseases are associated with the biome depletion theory, and increased inflammatory diseases and helminth-mediated protection are not restricted to autoimmune and allergic diseases (Smallwood et al., 2017; Maizels, 2020). There is an inverse relationship observed between human helminth infection, insulin resistance, and type 2 diabetes, and it has been proposed that chronic helminth infection results in long-term beneficial effects on host metabolism, especially on white adipose tissue, intestines, and liver (van der Zande et al., 2019; Wiria et al., 2014).
In developed countries, the successful application of helminth therapy may ultimately depend on precise patient selection and the careful matching of specific helminth species (Rook, 2023; Smallwood et al., 2017). Furthermore, the identification and characterization of helminth molecules and vesicles and the molecular pathways they target in the host represent the most valuable opportunity to develop tailored drugs inspired by nature that are efficacious, safe, and have minimal immunogenicity (Maizels and Gause, 2023; Maizels et al., 2018; Ryan et al., 2020; Drurey and Maizels, 2021), Figure 3.
The impressive molecular diversity of helminth excretory/secretory products, including a wide range of proteins and miRNAs, underscores their potential as therapeutic agents. While the development of recombinant expression systems for these molecules is crucial, challenges remain in optimizing production and delivery. The natural delivery of helminth miRNAs via EVs is a particularly intriguing strategy, and efforts to mimic this process using synthetic exosomes could revolutionize miRNA-based therapies (Ryan et al., 2020), see Figure 3.
The scientific community calls on the industry to make long-term investments in research aimed at deciphering and capitalizing on the extraordinary and diverse modes of action exhibited by these products. By unlocking the full potential of these natural compounds, we can pave the way for developing a new generation of innovative therapeutics.
Research Results
Professor Akira's discovery has already proven useful in the research and development of pharmaceuticals targeting innate immunity: for example, in the development of drugs to treat hayfever, which with 20 million sufferers across Japan has been described as Japan's national disease, as well as atopic eczema and more.
It has also found partial practical applications in medication for infectious diseases such as herpes, among others. In the scant 10+ years since Professor Akira's discovery, the field of immunology has evolved at great speed. In future, clearer understanding of immune mechanisms is expected to enable treatments not only for diseases linked to abnormal immune responses, but also for intractable diseases such as cancer.
This research, which started with Toll receptors discovered in fruit flies, has garnered immense interest worldwide as research that could critically influence humanity's future.
Subsequent research has determined that toll receptors and toll-like receptors are structurally similar, but significantly different in function. There remains no doubt that a huge diversity of living creatures found on earth is protected by such advanced innate immunity systems.
* A gene knockout mouse of which a specific gene is artificially damaged so as not to function
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