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DNA Vaccines as Immunotherapy for Cancer

General, Immune | March 22, 2016 | Author: The Super Pharmacist

Immune, cancer, general

DNA Vaccines as Immunotherapy for Cancer

It is important to understand about the human immune system to understand how vaccines work and may work with cancer patients.

The Immune System

The human immune system is a complex network of cells and organs that evolved to fight off infectious microbes. Much of the immune system’s work is carried out by an army of various specialised cells, each type designed to fight disease in a particular way.

The invading microbes first run into this army of cells, which include white blood cells called macrophages (literally, “big eaters”). The macrophages engulf as many of the microbes as they can.

How do the macrophages recognise the microbes?

All cells and microbes wear a “uniform” made up of molecules that cover their surfaces. Each human cell displays unique marker molecules unique to the individual. Microbes display different marker molecules unique to them.

How do the macrophages recognise the microbes?The macrophages and other cells of your immune system use these markers to distinguish among the cells that are part of your body, harmless bacteria that reside in your body, and harmful invading microbes that need to be destroyed. The marker molecules on a microbe that identify it as foreign are called ‘antigens.’  

Every microbe carries its own unique set of antigens, macrophages digest most parts of the microbes but save the antigens and carry them to the body’s ‘lymph nodes.’

Lymph Nodes

Lymph nodes are small, bean-shaped glands located throughout the body such as in the armpits or the groin. The lymph nodes contain the immune cells (called lymphocytes). The main lymphocytes are the B cells and the T cells.

T Cells

There are two types of T cells, the killer T cells and the helper T cells. The killer T cells can be thought of as ‘offensive.’ The killer T cells recognise cells within the body that are already diseased, having been invaded by the microbe. The killer T cells latch onto these diseased cells and release chemicals that destroy them and the microbes inside. This sequence of killer T cell activities mounted in response to cells already invaded by the microbe represents what is called “cell-mediated immunity.”

B Cells

B cells, on the other hand, only recognise antigen on invaders that are floating in the circulating fluids outside the cells of the body. Unlike killer T cells, B cells do not mount a chemical attack on the invaders.

Instead, they produce ‘antibodies’ which are proteins that detect antigens on these floating invaders and attach themselves to them. B cells are each programmed to make one specific antibody. When B cells come into contact with their matching microbial antigen, they are stimulated to divide into many larger cells, called plasma cells, which secrete mass quantities of antibodies. An antibody matches an antigen much like a key matches a lock. Whenever the antibody and antigen interlock, the antibody marks the antigen for destruction. The work of B cells is called the “humoral” immune response, or simply the “antibody” response.

The B cell forms memory cells that remember the infection or antigen exposure for life.

Vaccines

The goal of most vaccines is to stimulate this response.

In fact, many infectious microbes can be defeated by antibodies alone, without any help from killer T cells. The T cell is the primary cell responsible for direct recognition and killing of tumour cells. 

In contrast to T-cell cytotoxic immunity, humoral antibodies do not appear to confer significant protection against tumour growth.

The antibodies secreted by B cells circulate throughout the human body and attack the microbes that have not yet infected any cells but are lurking in the blood or the spaces between cells. When antibodies gather on the surface of a microbe, it becomes unable to function.

Antibodies signal macrophages and other defensive cells to come eat the microbe.  In fact, many infectious microbes can be defeated by antibodies alone, without any help from killer T cells. After the body eliminates the disease, some microbe-fighting B cells and T cells are converted into memory cells. If re-exposure to the infectious microbe occurs, the immune system will quickly recognise the microbe and will stop the infection.

Vaccines mimic a natural infection.

Human macrophages cannot tell that the vaccine microbes are weakened, so they engulf them as if they were dangerous. In the lymph nodes, the macrophages present the microbe antigen to T cells and B cells. A response from the T cells is activated, and B cells secrete antibodies. The weakened microbes in the vaccine are quickly eliminated. The ‘mock’ infection is cleared, and humans are left with a supply of memory T and B cells for future protection against that microbe.

Types of Vaccines

The first human vaccines against viruses used weaker or attenuated viruses to generate immunity. The smallpox vaccine, for example, used cowpox, a poxvirus that was similar enough to smallpox to protect against it but usually did not cause serious illness. Rabies was the first virus attenuated in a lab to create a vaccine for Types of Vaccineshumans.

Vaccines are made using several different processes. They may contain live viruses that have been attenuated (weakened or altered so as not to cause illness); inactivated or killed organisms or viruses; inactivated toxins (for bacterial diseases where toxins are generated by the bacteria, and not the bacteria themselves, cause illness); or merely segments of the pathogen (this includes both subunit and conjugate vaccines).

Live, Attenuated

  • Measles, mumps, rubella (MMR combined vaccine)
  • Herpes zoster (shingles)
  • Varicella (chickenpox)
  • Influenza (nasal spray)
  • Rotavirus

Live, attenuated vaccines contain a version of the living microbe that has been weakened in the lab so it cannot cause disease. Because a live, attenuated vaccine is the closest thing to a natural infection, these vaccines are good “teachers” of the immune system: They elicit strong cellular and antibody responses and often confer lifelong immunity with only one or two doses. Despite the advantages of live, attenuated vaccines, there are some drawbacks. One concern that must be considered is the potential for the vaccine virus to revert to a form capable of causing disease. Protection from a live, attenuated vaccine typically outlasts that provided by a killed or inactivated vaccine.3

Inactivated/Killed

  • Polio (IPV)
  • Hepatitis A
  • Rabies

Vaccines of this type are created by inactivating a pathogen, typically using heat or chemicals such as formaldehyde or formalin. This destroys the pathogen’s ability to replicate, but keeps it “intact” so that the immune system can still recognise it.3 Such vaccines are more stable and safer than live vaccines. The dead microbes cannot mutate back to their disease-causing state. Most inactivated vaccines, however, stimulate a weaker immune system response than do live vaccines. So it would likely take several additional doses, or booster shots, to maintain a person’s immunity.

Toxoid (inactivated toxin)

  • Diphtheria
  • Tetanus

Some bacterial diseases are not directly caused by a bacterium itself, but by a toxin produced by the bacterium.  Immunisations for this type of pathogen can be made by inactivating the toxin that causes disease symptoms. Immunisations created using inactivated toxins are called toxoids.3

Subunit/Conjugate

  • Hepatitis B Influenza (injection)
  • Haemophilus influenza type b (Hib)
  • Pertussis (part of DTaP combined immunization)
  • Pneumococcal Meningococcal
  • Human papillomavirus

Subunit vaccines contain only pieces of the pathogens they protect against. Instead of the entire microbe, subunit vaccines include only the antigens that best stimulate the immune system. In some cases, these vaccines use epitopes—the very specific parts of the antigen that antibodies or T cells recognize and bind to. Because subunit vaccines contain only the essential antigens and not all the other molecules that make up the microbe, the chances of adverse reactions to the vaccine are lower.

What Is So Special about DNA Vaccines?

Recently, a radically new approach to vaccination has been developed. DNA vaccination, or genetic immunisation, is a novel vaccine technology that has great potential for reducing infectious disease and cancer-induced morbidity and mortality worldwide. 

DNA vaccines take immunisation to a new tWhat Is So Special about DNA Vaccines?echnological level.

These vaccines dispense with both the whole organism and its parts and get right down to the essentials: the microbe’s genetic material. In particular, DNA vaccines use the genes that code for those all-important antigens. During the last few years, there has been immense progress in the field of DNA vaccines. This has been a result of new and better vectors, different types of delivery methods and devices, addition of immunologic adjuvants, and harnessing (or decreasing the activation of) the innate system, which is activated by the plasmid DNA itself, and can be further activated by encoded proteins.

Deoxyribonucleic acid (DNA) is a cellular molecule that carries most of the genetic instructions used in the development, functioning and reproduction of all known living organisms and many viruses. Researchers have found that when the DNA genes for a microbe’s antigens are introduced into the human body, some of the body’s cells will take up that DNA. The DNA then instructs those cells to make the antigen molecules that are found on the surface of the microbe. These antigens are produced and displayed on cell surfaces. The body’s immune cells gear up to mount an attack against the pathogen that carries those antigen molecules. In other words, the body’s own cells become vaccine-making factories, creating the antigens necessary to stimulate the immune system.

The main advantage of DNA vaccines is their ability to stimulate both the humoral and cellular arms of the adaptive immune system. 

In regards to humoral immunity, the generation of antibodies by B lymphocytes against invading pathogens is one of the most effective defences mounted by the immune system. Vaccines that utilise live-attenuated microorganisms, killed viral particles, or recombinant viral proteins elicit the production of specific antibodies that bind superficial microbial structures on the target pathogen. Unfortunately, certain pathogens accumulate mutations that reduce the effectiveness of antibodies originally generated against the pathogen. Typically, antibody responses generated by traditional vaccines target only the specific antigens found in the inoculum, and are poorly able to control similar pathogens that carry either subtle or gross changes to the antigen.

Due to the ability to genetically modify the antigen encoded by DNA vaccines, the vaccine can be designed to contain the most highly conserved regions of the superficial, antibody-generating structures on a pathogen. DNA can be injected alone into a patient as a “naked nucleic acid” vaccine, or packaged into a harmless virus. This leads to the human cells to secrete the proteins normally expressed on the surface of the pathogen. The efficacy of DNA vaccines to protect against challenge with pathogens has been demonstrated in animal models of influenza virus, malaria, mycobacterium, HIV, and Ebola. 

The Advantages of DNA vaccines

Because of a number of distinct advantages DNA vaccines can offer over existing vaccination techniques, the technology has drawn considerable interest. 

First of all, DNA vaccines do not contain an actual infectious agent, whether dead or alive. There is no risk of mutation to a more virulent agent. DNA vaccines can effectively stimulate both cellular and humoral immune responses, thereby providing a person long lasting immunity after a small number of doses. 

One of the problems with some vaccination technologies is the fact that multiple booster doses are needed for a vaccine to effectively immunise an individual, and this can pose practical problems, particularly in countries where healthcare and transport infrastructure is not well established. 

DNA vaccines also offer advantages in terms of their production. Once tested for efficiency and safety, a DNA vaccine can be generated in large volumes at a much lower cost than some traditional vaccine types. 

DNA vaccines are stable for storage and shipping. DNA vaccines may be intrinsically more safe than conventional vaccines, because they are non-life, non-replicating, and non-spreading. They also appear well-tolerated, i.e., nontoxic. Some concerns have been raised about the safety of using viral vectors for the delivery of the drug, however these vectors are carefully and designed in such a way that they do not have any effect other than to introduce pathogenic DNA into human cells. 

At present, human trials are under way with several DNA vaccines, including those for malaria, AIDS, influenza, Ebola and herpes virus.

The Facts on Cancer Vaccines

For many years, vaccines have been used to successfully prevent devastating infectious diseases such as smallpox, measles and polio. According to data from the U.S. Centres for Disease Control and Prevention, 10 infectious diseases have been at least 90 percent eradicated in the United States thanks to vaccines. But vaccines are not only for preventing infectious diseases. Some help the body fight a range of illnesses by activating the immune system to recognise and attack disease.

The Facts on Cancer VaccinesToday, biopharmaceutical research companies are developing 271 vaccines for infectious diseases, cancer, neurological disorders, allergies and other diseases. In 2010, a new cancer vaccine for the treatment of prostate cancer was approved by the U.S. Food and Drug Administration (FDA). This vaccine, sipuleucel-T (Provenge®), is approved for use in some men with metastatic prostate cancer. 

It is designed to stimulate an immune response to an antigen that is found on most prostate cancer cells. It has been shown in clinical trials to extend life for men with treatment-resistant metastatic prostate cancer. There are two broad types of cancer vaccines: preventive vaccines and therapeutic vaccines.

Cancer preventive vaccines target infectious agents that cause or contribute to the development of cancer and are intended to prevent cancer from developing in the first place.

Therapeutic vaccines are intended to treat an existing cancer by strengthening the body’s natural immune response against the cancer. Therapeutic vaccines are a type of ‘immunotherapy.’ Immunotherapy refers to treatments that restore or enhance the immune system’s natural ability to fight cancer. In just the past few years, the rapidly advancing field of cancer immunology has produced several new methods of treating cancer that increase the strength of immune responses against tumours.

Preventive Cancer Vaccines

Cancer preventive vaccines target infectious agents that cause or contribute to the development of cancer.

  • Human papilloma virus vaccine (HPV). Persistent infections with high-risk HPV types can cause cervical cancer, anal cancer, oropharyngeal cancer, and vaginal, vulvar, and penile cancers. Three vaccines are approved by the US Food and Drug Administration (FDA) to prevent HPV infection: Gardisil ® Gardasil 9®, and Cervarix®.
  • Hepatitis B vaccines (HBV). Chronic HBV infection can lead to liver cancer. The FDA has approved multiple vaccines that protect against HBV infection.

Therapeutic Cancer Vaccines

Therapeutic cancer vaccines are designed to stimulate the patient’s own immune system against tumour antigens. Antigens are proteins that help make up the outer surface of the viruses. By triggering the immune system, therapeutic vaccines can initiate a durable anti-tumour response that can attack tumour cells and lead to improved survival. It is important to recognize, however, that therapeutic cancer vaccines differ from traditional preventative vaccines, such as those for various infectious.

The primary goal of a therapeutic cancer vaccine is NOT to prevent disease, but to generate an active immune response against an existing cancer.

Autologous cancer vaccines:  Autologous means “derived from oneself” – so an autologous vaccine is a personalized vaccine made from an individual’s own cells—either cancer cells or immune system cells. To make an autologous cancer vaccine, cells from a person’s tumour are removed from the body and treated in a way that makes them a target for the immune system. They are then injected into the body, where immune cells recognize them, disable them, and then do the same to other cancer cells in the body. Another approach to autologous cancer vaccines is to use an individual’s own immune cells to make the vaccine. The FDA has licensed one autologous vaccine made from immune cells. Sipuleucel-T (Provenge®) is an autologous immune cell prostate cancer vaccine. 

Allogenic cancer vaccines: “Allo-” means other. Allogenic cancer vaccines are made from ‘non-self ‘cancer cells grown in a lab. Several allogenic cancer cell vaccines have been tested and are being tested, including vaccines to treat pancreatic cancer, melanoma (skin cancer), leukaemia, non-small cell lung cancer, and prostate cancer. Allogenic cancer vaccines are appealing because they are less costly to develop and produce than autologous vaccines. So far, none has been shown to be effective enough to be licensed.

Other Immunotherapy Research

Immunotherapy has been chosen as the "clinical cancer advance of the year" by the American Society of Clinical Oncology (ASCO) in its Clinical Cancer Advances 2016 report. Cancer vaccines are only one form of immunotherapy.

TThe Facts on Cancer Vaccineshe main types of immunotherapy now being used to treat cancer include:

Monoclonal Antibodies Antibodies are proteins that target antigens. They are produced in the body by immune system cells.  Some monoclonal antibodies work by attaching to antigens on cancer cells and marking them for destruction by other immune system cells.

Examples of monoclonal antibodies include ipilimumab (Yervoy®), pembrolizumab (Keytruda®), and nivolumab (Opdivo®).  All have been FDA approved for the treatment of metastatic melanoma. 

Immune Checkpoint Inhibitors During an immune response, the immune system turns on to attack potentially harmful agents. The immune system also has ways to turn off. This limits the immune response and prevents damage to healthy tissues. Some cancer cells bind to receptors on activated T cells and turn them off. Immune checkpoint inhibitors are drugs that prevent cancer cells from turning off T cells. This allows T cells to infiltrate a tumour and stop it from growing. The FDA has approved several immune checkpoint inhibitors for the treatment of metastatic melanoma. 

These approved drugs include ipilimumab, nivolumab, and pembrolizumab.  These 3 drugs are all ‘checkpoint blocking antibodies.’ Studies have also investigated the role of checkpoint inhibitors in lung cancer with highly promising results.

Adjuvants Substances known as adjuvants are often added to vaccines to boost their ability to induce potent anti-cancer immune responses. Non-specific immunotherapies do not target cancer cells specifically. They stimulate the immune system in a more general way, but this can still sometimes lead to a better immune response against cancer cells.

Cytokines These adjuvants are a broad category of small proteins that are important in cell ‘signaling.’  Two main types of cytokines are used to treat cancer are interferons and interleukins. 

Adoptive transfer of T cells After decades of experiments conducted on mice and other animals, scientists have shown that they can isolate antigen-specific T cells from a cancer patient, expand them to large numbers in a test-tube, and re-infuse them back into the patient to kill off the remaining tumour cells. When this technique was used in a clinical study to treat patients with metastatic melanoma, it was observed that the tumour regressed in about 34 percent of the patients. The drawback of this therapy is that the killer instinct of the transferred killer or cytotoxic T cells is rather short-lived after infusion into patients. This is because the patient cannot provide all the accessory immune molecules that the killer T cells need to be maintained and to finish the job.

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http://www.healthcentre.org.uk/vaccine/advantages-disadvantages-dna-vaccines.html   Accessed 19 Mar 2016.

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