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In 1998 the biotech company Genentech launched Herceptin for the treatment of certain types of breast cancer. Herceptin was an example of a ‘therapeutic antibody’ and was the first of its type for cancer treatment. Antibodies are proteins in our immune system that can target abnormal cells (or bacteria, toxins, viruses, etc.) in the body, and on arriving at the target can set in motion a whole set of biological events that in principle can remove or degrade to a non-dangerous state the abnormal cells.

Frequently, antibodies that we should produce as a natural response to cancer cells that may develop in an organ or tissue are somehow either inhibited from forming, or where they do form are poorly effective at destroying the cancer. To combat this ineffectiveness, specific antibodies against targets on the cancer cell can be made in the laboratory and then reintroduced into the human body, causing the cancer cell to ‘self-destruct’, or become sensitized to natural immune processes that aid the cancer cell killing.

In commenting on the efficacy of such antibodies in the treatment of cancer, delivered to an international antibody conference in San Diego in December 2012, Professor Dane Wittrup (MIT) reminded the audience how limited the response rate (~10%) of current antibody therapies has been. While there may be different views on the reasons for this, we can be reasonably certain that it is due, in part, to some or all of the following: the development of tumor resistance after repeated therapy, the presence of side effects serious enough to warrant interruption or even cessation of treatment, or limited antibody efficacy in the real tumor environment. Despite the investment of billions of dollars in antibody research it is clear that the human immune system still retains many secrets, the decoding of which has been, and continues to be, a long and complex process.

Current antibody therapies target specific ‘circuits’ in cancer cells that are important for the growth of the cancer, either shutting down or blocking key points in specific cellular circuitry, thereby reducing the cancer cell viability. Unfortunately, a cancer is a population of cells and as the inhibitory antibodies move into attack mode, biological changes within the cancer cells over time can activate alternative survival circuits that allow the cancer to evade the antibody effects, effectively becoming ‘resistant’. (For example, some breast cancers are known to become resistant over time to repeated treatment with Herceptin.) To counteract this effect, therapeutic modalities have been developed where two antibodies targeting different sites (circuits) within the cells, or an antibody coupled with a highly toxic drug or toxin molecule, are being adopted. While more effective than the single antibody approach, there is still a heavy hitting part of the immune system, the so-called Cytotoxic T-lymphocyte, or CTL (‘T’ for thymus-derived) mediated response, that often stands idle while the antibody arm of the immune system goes about its work. Why might that be?

In the late 1980s and early 1990s, research groups working at research laboratories in Marseille and a pharmaceutical company in Princeton described two new proteins associated with cells of the immune system that appeared to regulate their activity, allowing them to discriminate between normal tissues and abnormal tissues such as cancer cells. These new proteins were named ‘immune checkpoint receptors’ and are now known to be instrumental in deciding whether or not CTLs become active. When CTLs receive the correct activation signal, they are primed to engage an abnormal target with a view to destroying it in what is part of the ‘adaptive immune response’. Within the cells of the immune system, these checkpoint receptors are part of a complex activating and damping signaling system involving a receptor and a second molecule (or ‘ligand’) that interacts with the receptor in a sort of pas de deux. When the two find each other, as in normal tissues, a CTL attack is prevented (if this did not happen, an autoimmune response could be initiated). So, if the same ligand signal is somehow offered by a tumor cell masquerading as a normal cell, the ‘call to attack’ signals will be overridden and a CTL assault will not occur. In many tumors, just such biochemical changes are known to occur that fool the immune system into ‘thinking’ that the tumor consists of normal human cells thus avoiding attack by CTLs.

As with many aspects of biological systems, the adaptive immune system is a balancing act between allowing effective immune responses to alien agents, such as bacteria, viruses, toxic molecules, and the like, and at the same time avoiding mounting similar responses to our own tissues, organs, and cells that could lead to ‘autoimmunity’. Immunologists use the term ‘tolerance’ to describe this protection that self-tissues and organs experience as the immune system goes about its work. Lupus erythematosus and multiple sclerosis are two examples of autoimmune responses where the normal regulatory controls have been interrupted and immune antibodies or cells have attacked normal, healthy tissues with often debilitating effects. It is currently thought that checkpoint receptors and their partner ligands play an important role in maintaining this tolerance state in normal healthy persons, preventing unwanted autoimmune responses.

But what if antibodies could be targeted to these checkpoint receptors, blocking the ability of the tumor cell to interact with the receptors on CTLs, and hijacking their deceptive “I am normal” signal? (see Figure 1). This would mean, of course, that in theory, any cell, normal or abnormal, could be a target for CTL killing since both types of cell would have their “I am normal” signal blocked. Dangerous? Possibly, if not controlled. Desirable? If a tumor is so aggressive (e.g. melanoma, pancreatic cancer, etc.) that some autoimmune side effects could be tolerated or clinically managed in order to rid the body of the cancer, perhaps the therapeutic modality would be justified.

Well, we can do better than ‘in theory’. In a recent study of patients with advanced melanoma, one of the most aggressive tumors known and refractory to most therapeutic regimes, two different antibodies against each of the two most characterized immune checkpoint receptors showed spectacular results. In summary, the Phase I/II clinical trial results showed that 40% of patients treated with the combined antibody therapy experienced tumor shrinkage, and 65% of patients experienced shrinkage or stable disease. While these results truly are impressive we cannot yet declare that the war against cancer is approaching resolution, despite the claims of some enthusiasts.

As I noted above, immune checkpoint receptors are important in avoiding immune responses to our own tissues and organs. If their regulatory role is undermined by antibody blockade then autoimmune effects could be anticipated. In fact, in all clinical trials so far conducted with antibodies against these targets, autoimmune responses have been seen, including colitis, dermatitis, hypophysitis, pneumonitis, and hepatitis. These are classes of side effects the clinical community is not accustomed to seeing during antibody therapy, and will require stringent observation during treatment while improved therapeutic regimes are developed that manage these autoimmune effects.

Despite the embryonic nature of this approach, we have truly entered a new age for antibody therapy. As with all checkpoints, two way traffic is ever present, and while in one direction there may be freedom, in the other may lie painful experiences that have to be managed. The key for the future success of this approach will be the development of immune strategies that allow the benefits of immune checkpoint inhibition in cancer treatment to be counterbalanced by clever therapy designs that avoid, or at least minimize, the associated disadvantages.

Header image: Breast cancer cell. Public domain via Wikimedia Commons.

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By Katie L. Flanagan

Despite the huge body of evidence that males and females have very different immune systems and responses, few biomedical studies consider sex in their analyses. Sex refers to the intrinsic characteristics that distinguish males from females, whereas gender refers to the socially determined behaviour, roles, or activities that males and females adopt. Male and female immune systems are not the same leading to clear sexual dimorphism in response to infections and vaccination.

In 2010, Nature featured a series of articles aimed at raising awareness of the inherent sex bias in modern day biomedical research and, yet, little has changed since that time. They suggested journals and funders should insist on studies being conducted in both sexes, or that authors should state the sex of animals used in their studies, but, unfortunately, this was not widely adopted.

Even before birth, intrauterine differences begin to differentially shape male and female immune systems. The male intrauterine environment is more inflammatory than that of females, male fetuses produce more androgens and have higher IgE levels, all of which lead to sexual dimorphism before birth. Furthermore, male fetuses have been shown to undergo more epigenetic changes than females with decreased methylation of many immune response genes, probably due to physiological differences.

The X chromosome contains numerous immune response genes, while the Y chromosome encodes for a number of inflammatory pathway genes that can only be expressed in males. Females have two X chromosomes, one of which is inactivated, usually leading to expression of the wild type gene. X inactivation is incomplete or variable, which is thought to contribute to greater inflammatory responses among females. The immunological X and Y chromosome effects will begin to manifest in the womb leading to the sex differences in immunity from birth, which continue throughout life.

MicroRNAs (miRNAs) regulate physiological processes, including cell growth, differentiation, metabolism and apoptosis. Males and females differ in their miRNA expression, even in embryonic stem cells, which is likely to contribute to sex differences in the prevalence, pathogenesis and outcome of infections and vaccination.

Females are born with higher oestriol concentrations than males, while males have more testosterone. Shortly after birth, male infants undergo a ‘mini-puberty’, characterised by a testosterone surge, which peaks at about 3 months of age, while the female effect is variable. Once puberty begins, the ovarian hormones such as oestrogen dominate in females, while testicular-derived androgens dominate in males. Many immune cells express sex hormone receptors, allowing the sex hormones to influence immunity. Very broadly, oestrogens are Th2 biasing and pro-inflammatory, whereas testosterone is Th1 skewing and immunosuppressive. Thus, sex steroids undoubtedly play a major role in sexual dimorphism in immunity throughout life.

Sex differences have been described for almost every commercially available vaccine in use. Females have higher antibody responses to certain vaccines, such as measles, hepatitis B, influenza and tetanus vaccines, while males have better antibody responses to yellow fever, pneumococcal polysaccharide, and meningococcal A and C vaccines. However, the data are conflicting with some studies showing sex effects, whereas other studies show none. Post-vaccination clinical attack rates also vary by sex with females suffering less influenza and males experiencing less pneumococcal disease after vaccination. Females suffer more adverse events to certain vaccines, such as oral polio vaccine and influenza vaccine, while males have more adverse events to other vaccines, such as yellow fever vaccine, suggesting the sex effect varies according to the vaccine given. The existing data hint at higher vaccine-related adverse events in infant males progressing to a female preponderance from adolescence, suggesting a hormonal effect, but this has not been confirmed.

If male and female immune systems behave in opposing directions then clearly analysing them together may well cause effects and responses to be cancelled out. Separate analysis by sex would detect effects that were not seen in the combined analysis. Furthermore, a dominant effect in one of the sexes might be wrongly attributed to both sexes. For drug and vaccine trials this could have serious implications.

Given the huge body of evidence that males and females are so different, why do most scientific studies fail to analyse by sex? Traditionally in science the sexes have been regarded as being equal and the main concern has been to recruit the same number of males and females into studies. Adult females are often not enrolled into drug and vaccine trials because of the potential interference of hormones of the menstrual cycle or risk of pregnancy; thus, most data come from trials conducted in males only. Similarly, the majority of animal studies are conducted in males, although many animal studies fail to disclose the sex of the animals used. Analysing data by sex adds the major disadvantage that sample sizes would need to double in order to have sufficient power to detect significant sex effects. This potentially means double the cost and double the time to conduct the study, in a time when research funding is limited and hard to obtain. Furthermore, since the funders don’t request analysis by sex, and the journals do not ask for it, it is not a major priority in today’s highly competitive research environment.

It is likely that we are missing important scientific information by not investigating more comprehensively how males and females differ in immunological and clinical trials. We are entering an era in which there is increasing discussion regarding personalised medicine. Therefore, it is quite reasonable to imagine that females and males might benefit differently from certain interventions such as vaccines, immunotherapies and drugs. The mindset of the scientific community needs to shift. I appeal to readers to take heed and start to turn the tide in the direction whereby analysis by sex becomes the norm for all immunological and clinical studies. The knowledge gained would be of huge scientific and clinical importance.

Dr Katie Flanagan leads the Infectious Diseases Service at Launceston General Hospital in Tasmania, and is an Adjunct Senior Lecturer in the Department of Immunology at Monash University in Melbourne. She obtained a degree in Physiological Sciences from Oxford University in 1988, and her MBBS from the University of London in 1992. She is a UK and Australia accredited Infectious Diseases Physician. She did a PhD in malaria immunology based at Oxford University (1997 – 2000). She was previously Head of Infant Immunology Research at the MRC Laboratories in The Gambia from 2005-11 where she conducted multiple vaccine trials in neonates and infants.

Dr Katie Flanagan’s editorial, ‘Sexual dimorphism in biomedical research: a call to analyse by sex’, is published in the July issue of Transactions of the Royal Society of Tropical Medicine and Hygiene. Transactions of the Royal Society of Tropical Medicine and Hygiene publishes authoritative and impactful original, peer-reviewed articles and reviews on all aspects of tropical medicine.

The post Why are sex differences frequently overlooked in biomedical research? appeared first on OUPblog.

        

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By William Firshein

It is almost impossible to read a daily newspaper or listen to news reports from television and radio without hearing about an outbreak of an infectious disease. On 13 March 2014, the New York City Department of Health investigated a measles outbreak. Sixteen cases including nine pediatric cases were detected, probably caused by a failure to vaccinate the victims. On 12 February, an outbreak of a common microbial pathogen known as C.difficile occurred in several hospitals in Great Britain. This pathogen induces severe cases of gastrointestinal distress including diarrhea, fever, and stomach cramps. One of the main problems with a number of microbial pathogens like C.difficile is that they have become completely resistant to many known drugs.

How did this occur? Antibiotics, complex substances produced by certain types of microbes that destroy other microbes, were hailed as miracle drugs when the first one (penicillin) was discovered more than 70 years ago by Alexander Flemming. Although over 70 useful antibiotics have been discovered since penicillin, many can no longer be used because microbial pathogens have become resistant to them through evolution. In fact, over two million people in the United States become infected with antibiotic resistant pathogens every year, leading to 23,000 deaths according to the Centers for Disease Control and Prevention (CDC). New non-antibiotic drugs are always being sought to treat infectious diseases (mostly microbial because viral diseases are not susceptible to antibiotics). One such new discovery is a commonly used pain medication called Carprofen which inhibits antibiotic resistant pathogens. Thus, the “war against” infectious diseases remains an ongoing focus of medical research.

Of course there are many other pathogens (both microbial and viral) besides those mentioned above that assault us and our body defenses constantly. They include pneumonia, dysentery, tuberculosis, tetanus, diphtheria, scarlet fever, ulcers, typhoid, meningitis, plague, cholera (bacterial), polio, HIV (AIDS), rabies, influenza, measles, mumps, the common cold, yellow fever, and chicken pox (viral). Nevertheless, all of us are not equally “susceptible” to each infectious disease — a poorly understood term that determines why some of us get one disease but not another, or why some diseases occur in the winter while others occur in the summer.

This brings us to an important concept, namely, that there is no way to be free of microbes that inhabit every “nook and cranny” of our bodies. Of the approximately ten million cells that make up the human body, there are billions of microbes that come along with them. Most microbes that inhabit our bodies are necessary for our existence. Together they make up what is called the “microbiome” consisting of a diverse group of microbes that help keep each of us healthy. Most of them are found in the gastrointestinal tract where they aid digestion; synthesize vitamins and other necessary biochemicals our cells cannot make; attack and destroy pathogens; and stimulate our immune system to act in the same way.

Nevertheless, with this constant assault, one might wonder how it is possible we have survived for so long. There are a number of other variables besides the “microbiome’ that are responsible and that are still poorly understood. These include an ability of a host (us) to coexist with a pathogen (we keep them at bay or limit their spread internally like tuberculosis), an ability to mount a furious immunological attack on the pathogen to destroy them, or an innate ability to remain “healthy” (a vague term that really signifies the fact that all of our metabolic systems are operating optimally most of the time like digestion, excretion, blood circulation, neurological or brain function, and healthy gums and teeth among other systems).

Where does this innate ability come from? Simply put, genetic phenomena (both in microbes and in humans). These traits are not only inherited under the control of genes but their functions are also controlled by such genes. Different pathogens have different sets of genes which act to produce a specific disease in a susceptible host. However, it is also why individual hosts (humans) are more or less resistant to such infectious diseases.

How does the body interact with these “foreign” entities? The immune system must protect the body from attack by pathogens and also from the formation of abnormal cells which could turn cancerous. Two types of immune responses exist. One is under the control of antibodies (proteins which circulate in the blood stream) that resist and inactivate invading pathogens by binding to them. The other is mediated by a certain type of white blood cell called a lymphocyte that destroys abnormal (potentially cancerous) cells and viral infected cells. Together, with other white blood cells, they present a formidable defense against infection and abnormality.

It takes time for an immune response by antibodies to develop during a pathogenic invasion because there are many components involved in the activity. They are usually divided into primary and secondary responses. The primary response represents the first contact with the antigen which after a period of time results in an increased production of specific antibodies that react only to that antigen (which by the way are also produced by certain lymphocytes called “B” or plasma cells). Once the infection is controlled, antibody levels fall considerably. If, however, another infection occurs in the future by the same pathogen, a much more vigorous response will result (called the secondary response) producing a much faster development and a higher level of antibodies. Why is the secondary response so much faster and vigorous? This phenomenon is due to a remarkable property of the immune system in which the primary response is “remembered” after its decrease by the preservation of “memory” “B” lymphocytes that circulate until the secondary response occurs, no matter how long it takes.

William Firshein is the Daniel Ayers Professor of Biology, Emeritus and author of The Infectious Microbe. He chaired the Biology Department at Wesleyan University for six years and published over 75 original research papers in the field of Molecular Microbiology of Pathogens. He was the recipient of several million dollars of grant support from various public and private research agencies and taught over 6,000 graduate and undergraduate students during his 48 year career.

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The post The never-ending assault by microbes appeared first on OUPblog.

        

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By Jonathan Crowe Each day of our lives is a battle for survival against an army of invaders so vast in size that it outnumbers the human population hugely. Yet, despite its vastness, this army is an invisible threat, each individual so small that it cannot be seen with the naked eye. These are the microbes – among them the bacteria and viruses – that surround us every day, and could in one way or another kill us were it not for our immune system, an ingenious defence mechanism that protects us from these invisible foes.