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The human microbiome is a key player in regulating human physiology and disease. There is now compelling evidence from preclinical and clinical studies suggesting that the gut microbiome plays a key role in affecting host immunity and therapeutic response in cancer. The landscape of microbiome-based therapy will be instrumental in providing therapeutic strategies for several disease states, including cancer immunotherapy.
Introduction Often referred to as our second genome, the microbiome comprises of over 1,000 species with 100 trillion microbes that include bacteria, fungi, viruses, and protozoa. In recent years, research in the microbiome has increased, particularly relating to its role in human health. The human microbiome has a complex ecosystem that is inextricably interlinked with our immune system and must stay balanced and nurtured to remain healthy. Since 70% of the immune system is located in the gut, where the microbiome resides, there are many benefits to the host, especially relating to immune homeostasis. It is now well established that several diseases, including metabolic, neoplastic, and psychiatric disorders, are influenced by microbiome composition. Microbial dysbiosis refers to how the microbiome influences organs that are in direct contact and those that are distally located. Although it is known that the gut microbiota may alter the efficacy of chemotherapy and radiation therapy for cancer, there is now accumulating evidence that the intestinal microbiota composition has a profound impact on influencing the therapeutic efficacy of immunotherapies. Human Microbiome and Cancer Immunotherapy Tumorigenesis is a multistep and complex process involving both genetic and epigenetic changes within the tumor cell in addition to supportive conditions within the tumor microenvironment (TME). Cancer immunotherapy is a novel biotherapy designed to enhance immune responses against cancer and spans a wide spectrum of immune modulation. Of all the immunotherapy drugs developed and utilized for cancer treatment immune checkpoint inhibitors (ICIs) are the most widely used and have shown impressive efficacy in several cancer types. Numerous studies have reported that the intestinal microbiota composition has a profound impact not only on the therapeutic efficacy of immunotherapies, but also the efficacy of conventional chemotherapy in combination with immunotherapy. The link between microbial composition and clinical response suggests a direct mechanistic influence on immunotherapy in cancer patients. Moreover, the mounting evidence linking the gut microbiome to immunotherapy efficacy indicates that this relationship is causal rather than correlative based on the preclinical and clinical evidence. In addition to its utility as a complementary predictive biomarker of treatment outcomes, interventional strategies manipulating the microbiome will likely enhance the therapeutic efficacy of ICI therapy. Other approaches include modulation of the dietary changes that promote beneficial or deprive detrimental bacteria of their required nutrients. For example, polyphenols and high fiber foods have been shown to promote antitumor immunity. Summary Accumulating evidence has demonstrated the importance of the gut microbiota in oncogenesis and the response to treatment modalities. As a result, microbiota modulation for effective anticancer therapeutics has emerged as a new strategy, particularly with respect to ICIs. A better understanding of the correlation between the tumor microenvironment and the host immune system will help mitigate the side effects of cancer immunotherapies. Future strategies of precision medicine integrating companion diagnostics with therapeutic tools, to both identify and modulate the microbiome, should facilitate enhanced therapeutic outcomes. References
Introduction
Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that are capable of killing virally infected and physiologically stressed cells, like tumor cells. In addition to their ability to directly kill cancer cells, NK cells are capable of enhancing both antibody and T-cell responses. Moreover, ex vivo activation, expansion, and genetic modification of NK cells can greatly enhance their anti-tumor activity and equip them to overcome resistance. As a result of these observations, NK cells are currently the focus of intense investigation with the potential to become a key therapeutic modality in the next wave of cancer treatments. Natural Killer Cells NK cells are lymphocytes from the same family as B- and T-cells. Since they are cells of the innate immune system, they are classified as innate lymphocytes (ILCs) and represent 5-20% of all circulating lymphocytes in humans. Their name derives from the fact that they can target cells without the need for prior activation. NK cells are essential for the management of immunological responses and for innate immunity. Although they are primarily responsible for killing virally infected cells, they are also useful for detecting and arresting early signs of cancer. Tumor infiltrating NK cells function within a hypoxic environment, such as the tumor microenvironment (TME). They are unique in that they have the ability to recognize and kill stressed cells without the need for the major histocompatibility complex (MHC) or antibodies (Murphy, 2022). The surface of NK cells consists of different activating and inhibitory receptors that recognize different membrane proteins. The presence of NK cells within several different cancers, including squamous cell lung, gastric, and colorectal cancers have been reported to be a positive prognostic factor for these patients (Gillgrass et al 2015). There is a correlation between the presence of NK cells in a tumor and a positive clinical benefit for cancer patients, and have the potential to kill parts of the tumors resistant to other therapies. NK cells can swiftly kill multiple adjacent cells that express surface markers associated with oncogenic transformation, a unique trait among immune cells. Moreover, their capacity to enhance antibody and T-cell responses support a role for NK cells as anticancer agents (Shimasaki et al 2020). Cellular Immunotherapy Cellular Immunotherapy, also known as adoptive cell therapy, is an innovative treatment approach that harnesses the body's immune system to eliminate cancer, has long been considered an attractive therapeutic approach (Murphy, 2020). NK cells secrete cytokines like interferon-g (IFN-g), tumor necrosis factor-a (TNF-a), chemokines, and other factors that modulate the functions of other immune cells. A main challenge for NK cells is that tumors develop several different strategies to avoid NK cell attack. For example, mature NK cells express the PD-1 receptor, and engagement with the programmed death-ligand 1 (PD-L1) ligand results in impaired antitumor NK cell activity (Del Zotto et al 2017). Tumors may develop several mechanisms to resist attacks from endogenous NK cells. However, ex vivo activation, expansion, and genetic modification of NK cells can greatly increase their anti-tumor activity and ability to overcome resistance. Some of the ex vivo expansion and activation methods used have translated into clinical-grade platforms, and clinical trials of NK cell infusions in patients have yielded promising results so far (Daher et al, 2021). Several companies are currently focusing on NK cells to develop technologies and methods that increase their expansion and activation. Using cells from both the patient and donor-derived sources renders autologous or allogeneic NK cell therapy an attractive therapeutic option. Advantages of NK Cells Over T-cells Both NK cells and CD8+ cytotoxic T-cells can kill target cells through similar cytotoxic mechanisms. Over the last few years, chimeric antigen receptor (CAR) T-cell therapy has shown spectacular success for treating hematological malignancies. Currently there is a growing interest in developing CAR-engineered NK (CAR-NK) cells for cancer therapy as they potentially confer a number of advantages over the CAR-T therapies (Xie et al, 2020). Some of these advantages include safety, multiple mechanisms, reduced alloreactivity, as outlined here. Safety: Due to the limited life-span of CAR-NK cells there is less risk of on-target/off tumor toxicity. Allogeneic CAR-NK therapy has reduced the risk of graft versus host disease (GVHD) due to the amount of cytokine release. Whereas activated CAR-NK cells normally release IFN-g and granule-macrophage colony-stimulating factor (GMCSF), CAR-T cells can produce multiple cytokines that include interleukin (IL)-1a, IL-1Ra, IL-2, IL-2Ra, IL-6, IL-8, IL-10, IL-15, and TNF-α, which are associated with severe neurotoxicity. Multiple mechanisms: CAR-NK cells, not alone kill tumor cells in a CAR-dependent manner, but can also eliminate cancer cells in a CAR-independent manner. In addition to eliminating tumor cells through CD16 mediated antibody-dependent cell-mediated toxicity (ADCC), CAR-NK cells also possess their natural cytotoxic activity that can be activated through CAR-independent mechanisms. Reduced alloreactivity: The reduced risk for alloreactivity potentially allows CAR-NK cells to be generated from multiple sources, including NK92 cell lines, peripheral blood mononuclear cells (PBMCs), umbilical cord blood (UCB), and induced pluripotent stem cells (iPSCs). Therefore, CAR-NK cells potentially offer an “off-the-shelf” allogeneic product, eliminating the need for a personalized and patient-specific product associated with current CAR-T cell therapies. Summary The field of NK cell-based cancer therapy currently constitutes a major area of immunotherapy research. Two of the major focal points include optimizing the source of cells and enhancing the cell toxicity/persistence in vivo. They are emerging as both safe and efficacious treatments for some cancers with the potential to become an off-the shelf allogeneic therapy. Some of the current challenges are enhancing both activating signals and proliferation, in addition to suppressing inhibitory signals and honing cells to tumor sites. Taken together, these observations suggest that NK cells will continue to evolve and lead to major improvements in the treatment and survival of cancer patients. References
Introduction
The recent COVID-19 pandemic has shone a spotlight on a revolutionary technology called messenger RNA (mRNA). What is not so well known is that mRNA has been in the research and development sphere for about three decades. Now that the Pfizer/BioNTech and Moderna vaccines have been shown to be both safe and effective, researchers expect to be able to use this technology to create rapid-response vaccines in the future. Not alone do the mRNA vaccines have the potential to swiftly combat viral pandemics, but also generate promising treatments in other strategic areas, such as immunology, oncology, and rare diseases. Personalized Medicine There is currently a growing emphasis on the field of personalized medicine. This concept creates treatment modalities that are tailored to a specific patient, as opposed to more conventional broad-based treatments. mRNA technology can be incorporated into this personalized medicine approach. One of the pioneering companies responsible for developing the mRNA COVID-19 vaccine, BioNTech, was originally focused on developing anti-cancer vaccines. These mRNA vaccines educate the immune system to recognize specific antigens on the cell surface. With COVID-19, this antigen is the spike protein expressed on the surface of the virus. The same reasoning is applied to training the immune system to recognize proteins on the surface of aberrant cells, such as cancer. For immunotherapy, this personalized medicine approach directs the immune system to:
Application of mRNA Technology One of the original drawbacks of the mRNA technology was that it was difficult to insert the mRNA into the cell. This problem was circumvented by using synthetic RNA and enveloping the material in lipid nanoparticles that can enter cells. Major technological innovations like this have enabled mRNA to become a more feasible vaccine candidate. Various modifications of mRNA backbone and untranslated regions make mRNA less RNase-sensitive, more stable, and highly translatable. Improved purification methods have allowed mRNA products free of double-stranded contaminations, thus reducing the non-specific activation of innate immunity. More efficient in vivo delivery of mRNA has been achieved by formulating mRNA into delivery vehicles, including but not limited to lipid nanoparticles (LNPs), polymers, and peptides. mRNA encoded neoantigens have become the frontrunner in the personalized vaccine approach. In addition to the safety and efficacy profiles of the approved vaccines, another major advantage of the mRNA vaccines is their relative simplicity to manufacture. In contrast to conventional vaccines that may require enormous bioreactors, mRNA vaccines can be produced in a test tube. It is produced in a cell-free system that does not require animal derived raw materials; therefore, the risk of contamination is lower than that observed with other complex vaccine processes. Moreover, the non-integrative nature and relatively transient expression inside the cells favors the mRNA safety profile. Summary mRNA technologies have responded successfully to the challenges of the COVID-19 pandemic. Several different vaccines are currently being developed for various diseases that are based on mRNA, with the potential to become available within a few years. Currently, over twenty mRNA-based immunotherapies have entered clinical trials with some promising outcomes in solid tumor treatments. To further improve the potency of mRNA anticancer vaccines, other clinical trials are also ongoing to evaluate the combination of mRNA vaccines with either cytokine or checkpoint inhibitor therapies. To date, the data suggest that mRNA vaccines offer a powerful platform whose continued development will dramatically strengthen our ability to combat cancer. Resources
This interesting study, published in the New England Journal of Medicine, reports the advantage of taking a third (booster) shot of the Pfizer-BioNTech mRNA COVID-19 vaccine. In this Israeli study, the booster dose was administered to high-risk populations and people over the age of 60 five months after the second dose. The data shows that the rate of infection was reduced 11‑fold and the rate of severe illness reduced by over 19‑fold. The authors state that the enhanced immunity is conferred by the dramatic 10‑fold increase in the level of neutralizing antibodies produced in response to the third dose. Their findings clearly indicate the effectiveness of a booster dose against the Delta variant. Future studies will determine the long-term effects of the booster against current and emerging variants.
https://www.nejm.org/doi/full/10.1056/NEJMoa2114255 As an immunologist with three decades experience, I have received many questions about COVID-19 and the vaccines from family and friends that are not scientists. After further research and review of the currently available data, I have compiled answers to some of the most commonly asked questions explaining the science. This article is only for informational purposes and further resources are available. What is messenger RNA (mRNA) technology? The mRNA technology has become the new buzz term pioneered by Pfizer/BioNTech and Moderna as it forms the bedrock of their new vaccines. Within each of our cells lies a nucleus that contains DNA, our fundamental building block. DNA synthesizes mRNA, the intermediate step between translating protein-encoding DNA and producing proteins essential for our survival. Essentially, mRNA is a mirror image of DNA. The vaccine does not infiltrate or become part of our DNA. How does the COVID-19 mRNA vaccine work? Think of the mRNA vaccine as a delivery system to a subset of cells containing instructions to carry out a specific task. To enter a cell, the COVID-19 virus uses a “spike protein” to bind to a specific receptor on the cell surface, similar to a key opening a lock. After the virus enters the cell, it wreaks havoc, ultimately killing the cell, replicating itself, and then spreads to other cells. These vaccines contain the mRNA code that instructs the cells to produce spike proteins on the cell surface. These spike proteins are then recognized by the immune system, triggering an immune response. This response generates highly specific antibodies against the proteins, mimicking the lock and key analogy and neutralizing the impact of the virus. In addition, the immune system is taught to recognize the spike protein specific to the virus. If this spike protein is encountered in the future, an immune response is swiftly mounted, thus preventing escalation of the virus. Keep in mind:
Is this type of vaccine safe? Although this is the first time that mRNA has been approved in a clinical setting, mRNA technology has been around for three decades in the Research and Development sphere. mRNA vaccines have elicited potent immunity against infectious disease targets in preclinical models and have been used in early clinical trials for influenza virus, Zika virus, rabies virus, and others. 44,000 people were involved in the Pfizer/BioNTech clinical trial and 30,000 people in the Moderna clinical trial. These clinical trials resulted in a greater than 94% efficacy for both vaccines. Some people have experienced severe allergic reactions, however, in most cases, minimal side-effects have been reported for either vaccine. In addition, it is too early to predict the long-term effects, with accuracy, of the vaccines; however, major safety concerns have yet to be identified. Will the vaccine prevent new strains of the virus? Preliminary data suggests that the current mutated strains are more contagious than the original strain. It is possible that the current vaccines could work, at least partially, on these mutated strains if the spike protein is similar enough. Although more research is needed, preliminary Pfizer data shows effectiveness against one of the mutations. Moreover, given that we have accumulated a lot of knowledge and developed these vaccines in a relatively short time-frame, it is feasible that future vaccines will be developed and distributed even quicker. How long does it take for the vaccine to work? It takes time for the immune system to respond to a new antigen and develop a memory whereby it can recognize and respond to a new infection. Both the Pfizer and Moderna vaccines require two doses, 21 and 28 days apart respectively. It is recommended that you wait 2-4 weeks after the second dose of either vaccine to bring protection up to a reliable level. Not everyone responds to the vaccine in a similar manner as it depends on several factors, such as age, medical conditions, and overall health. In fact, a small cohort of people, roughly 5%, may not respond to the vaccine at all. It is recommended that people continue to adhere to wearing masks, social distancing, and practicing good hygiene to curtail transmission as outlined in the CDC guidelines. How does the Astra Zeneca/Oxford vaccine differ from the mRNA vaccines? The Astra Zeneca vaccine, recently approved for distribution in the UK, utilizes a more conventional approach, referred to as a viral vector. This vaccine utilizes a harmless modified version of a common cold virus to deliver the gene encoding for the spike protein into the cell. The vaccine then operates in a similar manner to that of the mRNA vaccine. Resources
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