Tuesday, October 30, 2012

SpA, RA, and OA Criteria

In class yesterday some of us were wondering what the criterion was for spondylarthritis (SpA), rheumatoid arthritis (RA), and osteoarthritis (OA) in the article titled "Mediation of the Proinflammatory Cytokine Response in Rheumatoid Arthritis and Spondylarthritis by Interactions Between Fibroblast-like Synoviocytes and Natural Killer Cells." I went and found the articles which listed the criteria  by which the patients were accepted into the study. 

SpA was defined by the criteria of the European Spondylarthropathy Study Group in 1991. The full article was not able to be accessed, but the material I have found is from the abstract of the original article. "Based on statistical analysis and clinical reasoning, we propose the following classification criteria for spondylarthropathy: inflammatory spinal pain or synovitis (asymmetric or predominantly in the lower limbs), together with at least 1 of the following: positive family history, psoriasis, inflammatory bowel disease, urethritis, or acute diarrhea, alternating buttock pain, enthesopathy, or sacroiliitis as determined from radiography of the pelvic region."

RA was defined by the criteria according to the American College of Rheumatology, formerly known as the American Rheumatism Association. This criteria was also published years prior to the publishing of the article discussed in class. The definition of RA, according to "The American Rheumatism Association 1987 Revised Criteria For The Classification of Rheumatoid Arthritis," is as follows: "1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3)swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid facto; and 7) radiographic erosions and/or periarticular osteopenia in hands and/or wrist joints. Criteria 1 through 4 must be present for 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or lists of exclusions are required."

OA was also defined by ACR criteria, though from 1986. The data was put into a table and put into three categories: Clinical and Laboratory, Clinical and Radiographic, and Clinical t. 

Under Clinical and Laboratory criteria, knee pain and at least 5 of 9 criteria must be met: age > 50, stiffness < 30 minutes, crepitus, bony tenderness, bony enlargement, no palpable warmth, erythrocyte sedimentation rate (ESR) < 40 mm/hour, rheumatoid factor (RF) < 1:40, and synovial fluid signs of osteoarthritis (SF OA).

Under Clinical and Radiographic criteria, knee pain and at least 1 of 3 criteria must be met: age > 50, stiffness < 30 minutes, and crepitus + osteophytes.

Under Clinical t criteria, knee pain and at least 3 of 6 criteria must be met: age > 50, stiffness < 30 minutes, crepitus, bony tenderness, bony enlargement, and no palpable warmth.


I find it strange that a scientific article submitted in 2007 is using criterion published in 1986, 1988, and 1991, while there is much more recently published criteria for OA, RA, and SpA available. Anyone have any thoughts?

Resources:

1. Altman R, Asch E, Bloch D, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification  
    of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association.  
    Arthritis Rheum 1986;29(8):1039-49.  

2. Arnett FC, Edworthy SM, Bloch DA, et. al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315-24. 

3. Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor B, Calin A, Cats A, Dijkmans B, Olivieri I, Pasero G. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum. 1991;34:1218-1227.


Monday, October 29, 2012

Arthritis Facts and Myths, Can You Tell Them Apart?

As I was perusing the first page of the 2,630,000 results from my most recent Google search, "arthritis myths", I came upon a quiz that entailed sorting out some common facts from myths about arthritis. Tapping into my inner competition seeker, I eagerly accepted the challenge. Be cautioned fellow science bloggers, I use the word "challenge" loosely as the 20 question quiz was hardly a deviation from common sense (for the most part). Although I would like to point out that there were a couple of questions that sparked my interest. 

SPOILER ALERT: This next section will delve deeper into the logic behind a few of the quiz questions and the answer(s) may be revealed. Take the quiz first here: Arthritis Quiz - Myth or Fact. or just read on.



Exhibit A: Knuckle-cracking can cause arthritis.  

I must admit that knuckle-cracking has never been a habit of mine until recently. It could be that I was constantly reprimanded by my grandparents who believed that cracking knuckles inevitably leads to arthritis. Considering grandparents only ever have your best interests at heart, I thought nothing of it and would even pass what I thought to be such a great piece of knowledge off onto my classmates at school. Needless to say the validity of a statement drops significantly with age of the person saying it. Not only did I receive strange looks, but nobody even took my advice! To this day I still am not sure as to whether they actually knew arthritis isn't associated with knuckle-cracking or if they just didn't care. Back then though, I couldn't help but be entertained with the thought that all those persistent knuckle-crackers were in for the worst arthritis of their lives come 50 years from then. I had warned them, but I was wrong. This led me to dig deeper into this myth and here is what I found.
Knuckle-cracking is done for a variety of reasons. Most might say they find it relieves pressure that has built up from frequent use of the fine motor skills, like perhaps writing for long periods of time. While others may simply find enjoyment in the so-called "cracking" sound we are all too familiar with.  The actual "cracking" sound heard comes from the popping of an air bubble that forms within the synovial fluid (joint lubricant) when the joints are pulled apart.1
Those who write or type frequently may find relief in the popping of that air bubble to, say, relieve pressure within joints. Furthermore, as some of you knuckle-crackers may have experienced, it takes some force in order to produce the desired cracking sound and/or relief, and as one study found, knuckle-cracking can lead to swelling and minor pain due to the mechanical nature of the cracking.2 Similarly, another study looked at the potential metacarpal-phalangeal osteoarthritic changes in geriatric patients with a history of knuckle-cracking and found no conclusive evidence of degenerative changes.3 As I continued my search to crack this myth I stumbled upon a man named Donald Unger, a medical doctor who authored a scientific paper on a study he performed on himself. He made it a point to crack the knuckles on only his left hand for half a century, leaving his right hand uncracked as a control and after analyzing his data, or his hands rather, he found no apparent difference between the two.4 So for all you knuckle-crackers, there is no need to rush to break the habit as no clear link between knuckle-cracking and arthritis has been found.

Myth = busted.

Exhibit B: Cold, damp weather causes arthritis.

This second myth caught my attention because it is another one of those that a good amount of people have heard of even though it's not actually true, at least not entirely. What do I mean by that? Well, we know that arthritis is a condition involving the loss of cartilage in the joints and can be categorized into three types: traumatic arthritis in which onset is triggered by injury, osteoarthritis in which onset is triggered by normal everyday wear and tear, and rheumatoid arthritis in which onset is triggered when the body makes antibodies that attack cartilage.5 Regardless of the type, those with arthritis usually experience pain, swelling and stiffness of joints due to the degeneration of the cartilage. This then, becomes the preface for those who believe that weather is indeed having a detrimental effect.

 -->As I was searching for some scientific facts to support this claim, a search bar that Weather.com has implemented immediately caught my attention. The idea is that you input your current location and the results will give you not only a forecast, but also "Today's Aches and Pains Index", a numerical scale they've developed that "forecasts the potential for weather-related aches and pains, especially in people with chronic health conditions (such as migraines or arthritis) that might make them sensitive to changes in weather conditions" and is defined as follows: Very High (9, 10), High (7, 8), Moderate (5, 6), Low (3, 4), Minimal (1, 2).-->6 Given a number on their scale, you can then infer how bad your symptoms of a chronic health condition may be that day. They also specify that the top three weather conditions that may be having this effect on symptoms are, chance of precipitation, humidity change, and temperature change.6 It could be that the change in pressure within the atmosphere could cause a change in pressure within the joints and thus swelling and/or pain. And the same could be said in regards to humidity and temperature with respect to joint pain, but whether or not these conditions are having a significant effect, has not scientifically been proven.7 
Despite the fact that no direct link has been found, research in this area is difficult in general due to the mere fact that pain is relative. It is hard to determine that a high of 32 degrees with a 50% chance of rain is significantly causing a person's arthritis to worsen thus causing pain when pain tolerance between people can be very variable. Two people meeting the same criteria, with the same history may report two very different levels of pain under the same conditions making a completely controlled experiment invalid. Although as with anything, people will believe what they believe and just because the science can't back them up doesn't mean they are going to change their minds or ways. So, does the weather actually cause arthritis? No, but there is a slight chance that it could be worsening the symptoms.

Myth = mostly busted.
 
Sources:.
  1. Bonafede, Peter. "Ask an Expert: Knuckle cracking and arthritis." Providence Health & Services. N.p., n.d. Web. 24 Oct. 2012. <http://oregon.providence.org/patients/programs/providence-medical-group-arthritis-center/pages/askanexpertlanding.aspx?templatename=ask+an+expert%3A+knuckle+cracking+and+arthritis&templatetype=askanexpert>. 
  2. Castellanos, J, and D Axelrod. "Effect of habitual knuckle cracking on hand function.." Annals of Rheumatic Diseases 49.5 (1990): 308-309. BMJ Journals. Web. 24 Oct. 2012.
  3. Swezey, Robert, and Stuart Swezey. "The Consequences of Habitual Knuckle Cracking." Western Journal of Medicine 122.5 (1975): 377-379. National Center for Biotechnology Information. Web. 24 Oct. 2012. 
  4. Cracking joints. (2012, October 16). In Wikipedia, The Free Encyclopedia. Retrieved 06:29, October 25, 2012, from http://en.wikipedia.org/w/index.php?title=Cracking_joints&oldid=518120930
  5. Lum, Grant. "Aches & Pains: Cold weather and effects on arthritis - The Weather Network." Current Weather - The Weather Network. N.p., n.d. Web. 25 Oct. 2012. <http://www.theweathernetwork.com/achespains/coldwx_arthritis>.  
  6. "weather.com - Aches & Pains - Local Forecast." National and Local Weather Forecast, Hurricane, Radar and Report. N.p., n.d. Web. 29 Oct. 2012. <http://www.weather.com/outlook/health/achesandpains/weather/tenday/USWA0395?x=0&lswe=&lswa=&GO=GO&whatprefs=&from=aches_welcome&y=0>. 
  7. Griffin, J. Morgan. "Arthritis and Weather." WebMD - Better information. Better health.. WebMD, 9 June 2003. Web. 29 Oct. 2012. <http://www.webmd.com/osteoarthritis/guide/arthritis-weather?page=3>. 
 

Sunday, October 28, 2012

Don't Believe Everything You See: Is Tanezumab Really the Greatest Treatment for Arthritis?



Lets say that I have arthritis and I am unhappy with the medication I am currently taking so I decide to search the Internet for clinical trials or other “cures” that could improve the state of my arthritis…  The first thing I came across was an article by the Wall Street Journal titled, “Did Pfizer’s Experimental Arthritis Drug Work Too Well?”  After reading this article it seemed to be that the drug tanezumab was incredible enough that those who were taking it were able to be so active (due to the decrease in their pain) that these actions then lead them back to the progression of their arthritic symptoms. This idea seems to be a little far-fetched to me. 
1.                     The article does not state how fast the symptoms are relieved once the tanezumab is taken.   Seeing as people who have osteoarthritis (which was the type of arthritis mainly focused on in the text) tend to be upwards of 50 years old, and have  had degenerative issues accumulating for large portions of their lives, how fast could a drug really alleviate all of these problems to the point where arthritic people are able to go about living their normal lifestyles again?  
2.                     If it’s the older generations who are diagnosed with osteoarthritis, is the mass majority of this population going to be running, hiking, biking, white-water rafting, anything of this sort so much that they are going to re-injure themselves? 
In my opinion, it is absurd to claim that this drug works too well.   If a drug was working well enough, then there shouldn’t be a progression of symptoms due to the usage of the joints.  People with arthritis are taking this drug to be able to use the joints in order to live their lives normally, so what’s the point in taking it and still not being able to do the activities they love?  If the drug was really that amazing, then it should reduce the symptoms of osteoarthritis and prevent further progression of the illness no matter what kind of activities are performed.  However, the “wear and tear” on joints is inevitable whilst using them; therefore I do understand how being active could still affect those with arthritis.
As a person with arthritis, I might read this article and think that there is potential solution for my condition.  Although it does say that Pfizer was forced to take the drug off of the market for right now, there are clinical trials underway, which could lead to tanezumab’s re-release.   I think this article is used more as a type of promotion for tanezumab if it is released, instead of being more inquisitive of any of the negative effects that could result from taking it. 
I researched ‘Pfizer’s tanezumab’ and found another article from Emax Health that was published about three months prior that states that the drug’s trials had to be taken stopped abruptly when there were cases of tanezumab worsening the symptoms of the subjects taking it.  This article gives a more in-depth description of how the trials are performed and what exactly tanezumab is.  For example, “Tanzumab is a humanized monoclonal antibody that targets nerve-growth factor, a protein that mediates the pain response to injury. It is administered by infusion every eight weeks” (Reynolds).    This article seemed to lack a bias in either direction, which contrasts how the Wall Street Journal was written.  Also, a third article that was published only a few months ago claims that tanezumab is the Pfizer drug farthest away from being put back on to the market.   This statement contrasts the positive out look that is portrayed via the WSJ article.  I have realized in Dr. Cohen’s class that it is important that we read publications with a critical eye and to not believe everything we read even though it is published.   It is especially important for people with any type of illness to make sure that they check all of the facts; using tanezumab as a cure for arthritis is only one example.

Crowley, John. "FDA Recommendations Bode Well For Pfizer - Seeking Alpha." FDA
Recommendations Bode Well For Pfizer - Seeking Alpha. Seeking Alpha, 10 May 2012. Web. 26 Oct. 2012. <http://seekingalpha.com/article/577981-fda-recommendations-bode-well-for-pfizer>.

Loftus, Peter. "Did Pfizer’s Experimental Arthritis Drug Work Too Well?"
WSJ.com. Wall Street Journal, 29 Sept. 2010. Web. 26 Oct. 2012. <http://blogs.wsj.com/health/2010/09/29/did-pfizers-experimental-arthritis-drug-work-too-well/>.

Reynolds, Denise, RD. "Pfizer Immediately Halts Tanezumab Osteoarthritis Trials."
Pfizer Immediately Halts Tanezumab Osteoarthritis Trials. Emax Health, 24 June 2010. Web. 26 Oct. 2012. <http://www.emaxhealth.com/1506/pfizer-immediately-halts-tanezumab-osteoarthritis-trials>.

Friday, October 26, 2012


Vaccine vs. Arthritis Medication, Which Would you Chose?
With flu season about to be in full swing, and Dr. Cohen encouraging the students to go get their vaccinations, I began to wonder how getting an inoculation would affect those diagnosed with Rheumatoid Arthritis.  If this autoimmune disease occurs because the patient’s body has an over-active immune system, which causes anti-IgG IgM to be secreted from B cells, then should people with RA who are taking immunosuppressive drugs receive vaccinations?
I was able to do some research on Enbrel.com and found that before taking Enbrel people should talk to a doctor if they “[h]ave recently received or are scheduled for any vaccines. All vaccines should be brought up-to-date before starting ENBREL. Patients taking ENBREL should not receive live vaccines.”  This drug is taken over the course of several years in order to prevent the progression of the disease.  With this immunosuppressor being a long-term treatment, clearly the drug is being used over the course of many flu seasons.
Doing further research on other forums, it seemed to be that there are two types of influenza vaccines: dead or live.  The killed virus strain was the form of inoculation that was recommended for those who have chronic illnesses; however, the Center for Disease Control stated that there is a “high risk from flu complications” for those who take Enbrel, among other immunosuppressive prescriptions.
Is it worth the risk to stop taking immunosuppressors for a few months in order to get a vaccine: keeping in mind that there could be a progression in the rheumatoid arthritis? Or, is it less risky to continue with the drugs when there is a chance of contracting a virus? In the later case, the immune system would not be as strong as it could be when trying to fight off the virus.

Eustice, Carol. "Flu Shot - Should People With Rheumatoid Arthritis or Other Rheumatic Diseases Get a Flu Shot?." Arthritis and Joint Conditions - About.com. About.com, 14 Oct. 2009. Web. 18 Oct. 2012. <http://arthritis.about.com/od/arthqa/f/flushots.htm>.

"What is Enbrel® (etanercept)?." Moderate to Severe Plaque Psoriasis and Rheumatoid Arthritis Treatment - Enbrel® (etanercept). Enbrel etanercept, n.d. Web. 18 Oct. 2012. <http://www.enbrel.com/what-is-ENBREL.jspx?WT.z_co=P&WT.z_in=OTH&WT.z_ch=PDS&WT.z_se=G&WT.srch=1&WT.z_ag=enbrel&WT.mc_id=P_OTH_PDS_G_enbrel>.

Thursday, October 25, 2012

Cancer Vaccines effective? I don't know.


Hi everyone,

I work in a lung cancer lab and came across this article in a search after hearing that there are vaccinations being experimented with for cancer. Though the article has interesting points and is backed up with reliable manuscripts, I feel like it can be misleading. There are many variables simply within the genetics and habits of a person for which I believe that one vaccine could not address. Cancer is heavily involved with the tumor microenvironment. A solid tumor is an ecosystem composed of tumor cells, resident and infiltrating non-tumor cells, and molecules present in proximity to these cells. Both the tumor cells as well as the neighboring non-tumor cells take part in establishing the specific milieu of the microenvironment. Therefore, I do not foresee effective vaccines being developed for cancer. Especially in highly metastatic cancers (pancreatic) and cancers that involve a highly abused substance, such as tobacco (lung), due to the huge genetic diversity and the microenvironment that plays a delicate role in cancer progression and metastasis.  Even in treatment now, one drug might work for a person with a certain type of cancer, and not work at all for another person with the same stage of the same cancer. I don't mean to be a pessimist, and I would be amazed if something of significance developed from these vaccination experiments, but I believe that there are just too many variables. But I wanted to know what you all think?? 



Cancer Vaccines

Key Points

  • Cancer vaccines are designed to boost the body’s natural ability to protect itself, through the immune system, from dangers posed by damaged or abnormal cells such as cancer cells.
  • The U.S. Food and Drug Administration (FDA) has approved two types of vaccines to prevent cancer: vaccines against the hepatitis B virus, which can cause liver cancer, and vaccines against human papillomavirus types 16 and 18, which are responsible for about 70 percent of cervical cancer cases.
  • The FDA has approved one cancer treatment vaccine for certain men with metastatic prostate cancer.
  • Researchers are developing treatment vaccines against many types of cancer and testing them in clinical trials.
  1. What are vaccines?


    Vaccines are medicines that boost the immune system's natural ability to protect the body against “foreign invaders,” mainly infectious agents, that may cause disease.
    The immune system is a complex network of organstissues, and specialized cells that act collectively to defend the body. When an infectious microbe invades the body, the immune system recognizes it as foreign, destroys it, and “remembers” it to prevent another infection should the microbe invade the body again in the future. Vaccines take advantage of this response.
    Traditional vaccines usually contain harmless versions of microbes—killed or weakened microbes, or parts of microbes—that do not cause disease but are able to stimulate an immune response against the microbes. When the immune system encounters these substances through vaccination, it responds to them, eliminates them from the body, and develops a memory of them. This vaccine-induced memory enables the immune system to act quickly to protect the body if it becomes infected by the same microbes in the future.
    The immune system’s role in defending against disease-causing microbes has long been recognized. Scientists have also discovered that the immune system can protect the body against threats posed by certain damaged, diseased, or abnormal cells, including cancercells(1).
  2. How do vaccines stimulate the immune system?


    White blood cells, or leukocytes, play the main role in immune responses. These cells carry out the many tasks required to protect the body against disease-causing microbes and abnormal cells.
    Some types of leukocytes patrol the circulation, seeking foreign invaders and diseased, damaged, or dead cells. These white blood cells provide a general—or nonspecific—level of immune protection.
    Other types of leukocytes, known as lymphocytes, provide targeted protection against specific threats, whether from a specific microbe or a diseased or abnormal cell. The most important groups of lymphocytes responsible for carrying out immune responses against such threats areB cells and cytotoxic (cell-killing) T cells.
    B cells make antibodies, which are large secreted proteins that bind to, inactivate, and help destroy foreign invaders or abnormal cells. Most preventive vaccines, including those aimed athepatitis B virus (HBV) and human papillomavirus (HPV), stimulate the production of antibodies that bind to specific, targeted microbes and block their ability to cause infection. Cytotoxic T cells, which are also known as killer T cells, kill infected or abnormal cells by releasing toxic chemicals or by prompting the cells to self-destruct (a process known as apoptosis).
    Other types of lymphocytes and leukocytes play supporting roles to ensure that B cells and killer T cells do their jobs effectively. These supporting cells include helper T cells and dendritic cells, which help activate killer T cells and enable them to recognize specific threats.
    Cancer treatment vaccines are designed to work by activating B cells and killer T cells and directing them to recognize and act against specific types of cancer. They do this by introducing one or more molecules known as antigens into the body, usually by injection. An antigen is a substance that stimulates a specific immune response. An antigen can be a protein or another type of molecule found on the surface of or inside a cell.
    Microbes are recognized by the immune system as a potential threat that should be destroyed because they carry foreign or “non-self” antigens. In contrast, normal cells in the body have antigens that identify them as “self.” Self antigens tell the immune system that normal cells are not a threat and should be ignored (2).
    Cancer cells can carry both self antigens and cancer-associated antigens. The cancer-associated antigens mark the cancer cells as abnormal, or foreign, and can cause B cells and killer T cells to mount an attack against them.
    Cancer cells may also make much larger amounts of certain self antigens than normal cells. Because of their high abundance, these self antigens may be viewed by the immune system as being foreign and, therefore, may trigger an immune response against the cancer cells (1–6).
  3. What are cancer vaccines?


    Cancer vaccines are medicines that belong to a class of substances known as biological response modifiers. Biological response modifiers work by stimulating or restoring the immune system’s ability to fight infections and disease. There are two broad types of cancer vaccines:
    • Preventive (or prophylactic) vaccines, which are intended to prevent cancer from developing in healthy people; and
    • Treatment (or therapeutic) vaccines, which are intended to treat an existing cancer by strengthening the body’s natural defenses against the cancer (7).
    Two types of cancer preventive vaccines are available in the United States (see Question 5), and one cancer treatment vaccine has recently become available (see Question 8).
  4. How do cancer preventive vaccines work?


    Cancer preventive vaccines target infectious agents that cause or contribute to the development of cancer (8). They are similar to traditional vaccines, which help prevent infectious diseases, such as measles or polio, by protecting the body against infection. Both cancer preventive vaccines and traditional vaccines are based on antigens that are carried by infectious agents and that are relatively easy for the immune system to recognize as foreign.
  5. What cancer preventive vaccines are approved in the United States?


    The U.S. Food and Drug Administration (FDA) has approved two vaccines, Gardasil® andCervarix®, that protect against infection by the two types of HPV—types 16 and 18—that cause approximately 70 percent of all cases of cervical cancer worldwide. At least 17 other types of HPV are responsible for the remaining 30 percent of cervical cancer cases (9). HPV types 16 and/or 18 also cause some vaginalvulvaranalpenile, and oropharyngeal cancers (10).
    In addition, Gardasil protects against infection by two additional HPV types, 6 and 11, which are responsible for about 90 percent of all cases of genital warts in males and females but do not cause cervical cancer.
    Gardasil, manufactured by Merck & Company, is based on HPV antigens that are proteins. These proteins are used in the laboratory to make four different types of “virus-like particles,” or VLPs, that correspond to HPV types 6, 11, 16, and 18. The four types of VLPs are then combined to make the vaccine. Because Gardasil targets four HPV types, it is called a quadrivalent vaccine (11). In contrast with traditional vaccines, which are often composed of weakened whole microbes, VLPs are not infectious. However, the VLPs in Gardasil are still able to stimulate the production of antibodies against HPV types 6, 11, 16, and 18.
    Cervarix, manufactured by GlaxoSmithKline, is a bivalent vaccine. It is composed of VLPs made with proteins from HPV types 16 and 18. In addition, there is some initial evidence that Cervarix provides partial protection against a few additional HPV types that can cause cancer. However, more studies will be needed to understand the magnitude and impact of this effect.
    Gardasil is approved for use in females to prevent cervical cancer and some vulvar and vaginal cancers caused by HPV types 16 and 18, and for use in males and females to prevent anal cancer and precancerous anal lesions caused by these HPV types. Gardasil is also approved for use in males and females to prevent genital warts caused by HPV types 6 and 11. The vaccine is approved for these uses in females and males ages 9 to 26. Cervarix is approved for use in females ages 9 to 25 to prevent cervical cancer caused by HPV types 16 and 18.
    The FDA has also approved a cancer preventive vaccine that protects against HBV infection.Chronic HBV infection can lead to liver cancer. The original HBV vaccine was approved in 1981, making it the first cancer preventive vaccine to be successfully developed and marketed. Today, most children in the United States are vaccinated against HBV shortly after birth (12).
  6. Have other microbes been associated with cancer?


    Many scientists believe that microbes cause or contribute to between 15 percent and 25 percent of all cancers diagnosed worldwide each year, with the percentage being lower in developed than developing countries (4813).
    The International Agency for Research on Cancer (IARC) has classified several microbes as carcinogenic (causing or contributing to the development of cancer in people), including HPV and HBV (14). These infectious agents—bacteriaviruses, and parasites—and the cancer types with which they are most strongly associated are listed in the table below.
    Infectious AgentsType of
    Organism
    Associated Cancers
    hepatitis B virus (HBV)virushepatocellular carcinoma (a type of liver cancer)
    hepatitis C virus (HCV)virushepatocellular carcinoma (a type of liver cancer)
    human papillomavirus (HPV) types 16 and 18, as well as other HPV typesviruscervical cancer; vaginal cancer; vulvar cancer; oropharyngeal cancer (cancers of the base of the tongue, tonsils, or upper throat); anal cancer; penile cancer; squamous cell carcinoma of the skin
    Epstein-Barr virusvirusBurkitt lymphomanon-Hodgkin lymphoma;Hodgkin lymphomanasopharyngealcarcinoma (cancer of the upper part of the throat behind the nose)
    Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8)virusKaposi sarcoma
    human T-cell lymphotropic virus type 1 (HTLV1)virusadult T-cell leukemia/lymphoma
    Helicobacter pyloribacteriumstomach cancer; mucosa-associated lymphoid tissue (MALT) lymphoma
    schistosomes (Schistosoma hematobium)parasitebladder cancer
    liver flukes (Opisthorchis viverrini)parasitecholangiocarcinoma (a type of liver cancer)
  7. How are cancer treatment vaccines designed to work?


    Cancer treatment vaccines are designed to treat cancers that have already developed. They are intended to delay or stop cancer cell growth; to cause tumor shrinkage; to prevent cancer from coming back; or to eliminate cancer cells that have not been killed by other forms of treatment.
    Developing effective cancer treatment vaccines requires a detailed understanding of how immune system cells and cancer cells interact. The immune system often does not “see” cancer cells as dangerous or foreign, as it generally does with microbes. Therefore, the immune system does not mount a strong attack against the cancer cells.
    Several factors may make it difficult for the immune system to target growing cancers for destruction. Most important, cancer cells carry normal self antigens in addition to specific cancer-associated antigens. Furthermore, cancer cells sometimes undergo genetic changes that may lead to the loss of cancer-associated antigens. Finally, cancer cells can produce chemical messages that suppress anticancer immune responses by killer T cells. As a result, even when the immune system recognizes a growing cancer as a threat, the cancer may still escape a strong attack by the immune system (15).
    Producing effective treatment vaccines has proven much more difficult and challenging than developing cancer preventive vaccines (16). To be effective, cancer treatment vaccines must achieve two goals. First, like traditional vaccines and cancer preventive vaccines, cancer treatment vaccines must stimulate specific immune responses against the correct target. Second, the immune responses must be powerful enough to overcome the barriers that cancer cells use to protect themselves from attack by B cells and killer T cells. Recent advances in understanding how cancer cells escape recognition and attack by the immune system are now giving researchers the knowledge required to design cancer treatment vaccines that can accomplish both goals (1718).
  8. Has the FDA approved any cancer treatment vaccines?


    In April 2010, the FDA approved the first cancer treatment vaccine. This vaccine, sipuleucel-T(Provenge®, manufactured by Dendreon), is approved for use in some men with metastaticprostate cancer. It is designed to stimulate an immune response to prostatic acid phosphatase(PAP), an antigen that is found on most prostate cancer cells. In a clinical trial, sipuleucel-T increased the survival of men with a certain type of metastatic prostate cancer by about 4 months (19).
    Unlike some other cancer treatment vaccines under development, sipuleucel-T is customized to each patient. The vaccine is created by isolating immune system cells called antigen-presenting cells (APCs) from a patient’s blood through a procedure called leukapheresis. The APCs are sent to Dendreon, where they are cultured with a protein called PAP-GM-CSF. This protein consists of PAP linked to another protein called granulocyte-macrophage colony-stimulating factor (GM-CSF). The latter protein stimulates the immune system and enhances antigen presentation.
    APC cells cultured with PAP-GM-CSF constitute the active component of sipuleucel-T. Each patient’s cells are returned to the patient’s treating physician and infused into the patient. Patients receive three treatments, usually 2 weeks apart, with each round of treatment requiring the same manufacturing process. Although the precise mechanism of action of sipuleucel-T is not known, it appears that the APCs that have taken up PAP-GM-CSF stimulate T cells of the immune system to kill tumor cells that express PAP.
  9. What types of vaccines are being studied in clinical trials?


    Vaccines to prevent HPV infection and to treat several types of cancer are being studied in clinical trials.
    The list below shows the types of cancer that are being targeted in active cancer prevention or treatment clinical trials using vaccines. If you are accessing this fact sheet online, the cancer names are links to search results from NCI’s clinical trials database.
    Active Clinical Trials of Cancer Treatment Vaccines by Type of Cancer:
    Active Clinical Trials of Cancer Preventive Vaccines by Type of Cancer:
  10. How are cancer vaccines made?


    All cancer preventive vaccines approved by the FDA to date have been made using antigens from microbes that cause or contribute to the development of cancer. These include antigens from HBV and specific types of HPV (see Question 5). These antigens are proteins that help make up the outer surface of the viruses. Because only part of these microbes is used, the resulting vaccines are not infectious and, therefore, cannot cause disease.
    Researchers are also creating synthetic versions of antigens in the laboratory for use in cancer preventive vaccines. In doing this, they often modify the chemical structure of the antigens to stimulate immune responses that are stronger than those caused by the original antigens.
    Similarly, cancer treatment vaccines are made using antigens from cancer cells or modified versions of them. Antigens that have been used thus far include proteins, carbohydrates(sugars), glycoproteins or glycopeptides (carbohydrate-protein combinations), and gangliosides(carbohydrate-lipid combinations).
    Cancer treatment vaccines are also being developed using weakened or killed cancer cells that carry a specific cancer-associated antigen or immune cells that are modified to express such an antigen. These cells can come from a patient himself or herself (called an autologous vaccine, such as sipuleucel-T) or from another patient (called an allogeneic vaccine).
    Other types of cancer treatment vaccines are made using molecules of deoxyribonucleic acid(DNA) or ribonucleic acid (RNA) that contain the genetic instructions for cancer-associated antigens. The DNA or RNA can be injected alone into a patient as a “naked nucleic acid” vaccine, or researchers can insert the DNA or RNA into a harmless virus. After the naked nucleic acid or virus is injected into the body, the DNA or RNA is taken up by cells, which begin to manufacture the tumor-associated antigens. Researchers hope that the cells will make enough of the tumor-associated antigens to stimulate a strong immune response.
    Scientists have identified a large number of cancer-associated antigens, several of which are now being used to make experimental cancer treatment vaccines. Some of these antigens are found on or in many or most types of cancer cells. Others are unique to specific cancer types (1,5618–22).
  11. Can researchers add ingredients to cancer vaccines to make them work better?


    Antigens and the substances discussed in Question 10 are often not strong enough inducers of the immune response to make effective cancer treatment vaccines. Researchers often add extra ingredients, known as adjuvants, to treatment vaccines. These substances serve to boost immune responses that have been set in motion by exposure to antigens or other means. Patients undergoing experimental treatment with a cancer vaccine sometimes receive adjuvants separately from the vaccine itself (23).
    Adjuvants used for cancer vaccines come from many different sources. Some microbes, such as the bacterium Bacillus Calmette-Guérin (BCG) originally used as a vaccine against tuberculosis, can serve as adjuvants (24). Substances produced by bacteria, such as Detox B, are also frequently used. Biological products derived from nonmicrobial organisms can be used as adjuvants, too. One example is keyhole limpet hemocyanin (KLH), which is a large protein produced by a sea animal. Attaching antigens to KLH has been shown to increase their ability to stimulate immune responses. Even some nonbiological substances, such as an emulsified oil known as montanide ISA–51, can be used as adjuvants.
    Natural or synthetic cytokines can also be used as adjuvants. Cytokines are substances that are naturally produced by white blood cells to regulate and fine-tune immune responses. Some cytokines increase the activity of B cells and killer T cells, whereas other cytokines suppress the activities of these cells. Cytokines frequently used in cancer treatment vaccines or given together with them include interleukin 2 (IL2, also known as aldesleukin), interferon alpha (INF–a), and GM–CSF, also known as sargramostim (see Question 8).
  12. Do cancer vaccines have side effects?


    Vaccines intended to prevent or treat cancer appear to have safety profiles comparable to those of traditional vaccines (6). However, the side effects of cancer vaccines can vary among vaccine formulations and from one person to another.
    The most commonly reported side effect of cancer vaccines is inflammation at the site of injection, including redness, pain, swelling, warming of the skin, itchiness, and occasionally a rash.
    People sometimes experience flu-like symptoms after receiving a cancer vaccine, including fever, chills, weakness, dizziness, nausea or vomiting, muscle ache, fatigue, headache, and occasional breathing difficulties. Blood pressure may also be affected.
    Other, more serious health problems have been reported in smaller numbers of people after receiving a cancer vaccine. These problems may or may not have been caused by the vaccine. The reported problems have included asthma, appendicitis, pelvic inflammatory disease, and certain autoimmune diseases, including arthritis and systemic lupus erythematosus.
    Vaccines, like any other medication affecting the immune system, can cause adverse effectsthat may prove life threatening. For example, severe hypersensitivity (allergic) reactions to specific vaccine ingredients have occurred following vaccination. However, such severe reactions are quite rare.
  13. Can cancer treatment vaccines be combined with other types of cancer therapy?


    Yes. In many of the clinical trials of cancer treatment vaccines that are now under way, vaccines are being given with other forms of cancer therapy. Therapies that have been combined with cancer treatment vaccines include surgerychemotherapyradiation therapy, and some forms oftargeted therapy, including therapies that are intended to boost immune system responses against cancer.
    Several studies have suggested that cancer treatment vaccines may be most effective when given in combination with other forms of cancer therapy (2125). In addition, in some clinical trials, cancer treatment vaccines have appeared to increase the effectiveness of other cancer therapies (2125).
    Additional evidence suggests that surgical removal of large tumors may enhance the effectiveness of cancer treatment vaccines (25). In patients with extensive disease, the immune system may be overwhelmed by the cancer. Surgical removal of the tumor may make it easier for the body to develop an effective immune response.
    Researchers are also designing clinical trials to answer questions such as whether a specific cancer treatment vaccine works best when it is administered before chemotherapy, after chemotherapy, or at the same time as chemotherapy. Answers to such questions may not only provide information about how best to use a specific cancer treatment vaccine but also reveal additional basic principles to guide the future development of combination therapies involving vaccines.
  14. What additional research is under way?


    Although researchers have identified many cancer-associated antigens, these molecules vary widely in their capacity to stimulate a strong anticancer immune response. Two major areas of research aimed at developing better cancer treatment vaccines involve the identification of novel cancer-associated antigens that may prove more effective in stimulating immune responses than the already known antigens and the development of methods to enhance the ability of cancer-associated antigens to stimulate the immune system. Research is also under way to determine how to combine multiple antigens within a single cancer treatment vaccine to produce optimal anticancer immune responses (26).
    Perhaps the most promising avenue of cancer vaccine research is aimed at better understanding the basic biology underlying how immune system cells and cancer cells interact. New technologies are being created as part of this effort. For example, a new type of imaging technology allows researchers to observe killer T cells and cancer cells interacting inside the body (27).
    Researchers are also trying to identify the mechanisms by which cancer cells evade or suppress anticancer immune responses. A better understanding of how cancer cells manipulate the immune system could lead to the development of new drugs that block those processes and thereby improve the effectiveness of cancer treatment vaccines (28). For example, some cancer cells produce chemical signals that attract white blood cells known as regulatory T cells, or Tregs, to a tumor site. Tregs often release cytokines that suppress the activity of nearby killer T cells (2129). The combination of a cancer treatment vaccine with a drug that would block the negative effects of one or more of these suppressive cytokines on killer T cells might improve the vaccine’s effectiveness in generating potent killer T cell antitumor responses.
Selected References
  1. Pardoll DM. Cancer immunology. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, editors. Abeloff's Clinical Oncology. 4th ed. Philadelphia: Churchill Livingstone, 2008.
  2. Murphy KM, Travers P, Walport M, editors. Janeway's Immunobiology. 7th ed. New York: Garland Science, 2007.
  3. Waldmann TA. Effective cancer therapy through immunomodulation. Annual Review of Medicine2006;  57:65–81. [PubMed Abstract]
  4. Emens LA. Cancer vaccines: on the threshold of success. Expert Opinion on Emerging Drugs2008; 13(2):295–308. [PubMed Abstract]
  5. Sioud M. An overview of the immune system and technical advances in tumor antigen discovery and validation. Methods in Molecular Biology 2007; 360:277–318. [PubMed Abstract]
  6. Pazdur MP, Jones JL. Vaccines: an innovative approach to treating cancer. Journal of Infusion Nursing 2007; 30(3):173–178. [PubMed Abstract]
  7. Lollini PL, Cavallo F, Nanni P, Forni G. Vaccines for tumour prevention. Nature Reviews Cancer2006; 6(3):204–216. [PubMed Abstract]
  8. Frazer IH, Lowy DR, Schiller JT. Prevention of cancer through immunization: prospects and challenges for the 21st century. European Journal of Immunology 2007; 37(Suppl 1):S148–S155. [PubMed Abstract]
  9. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clinical Science 2006; 110(5):525–541. [PubMed Abstract]
  10. Parkin DM. The global health burden of infection-associated cancers in the year 2002.International Journal of Cancer 2006; 118(12):3030–3044. [PubMed Abstract]
  11. Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. Journal of Clinical Investigation 2006; 116(5):1167–1173. [PubMed Abstract]
  12. U.S. Centers for Disease Control and Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part 1: immunization of infants, children, and adolescents. Morbidity and Mortality Weekly Report 2005; 54(No. RR–16):1–31. [PubMed Abstract]
  13. Mueller NE. Cancers caused by infections: unequal burdens. Cancer Epidemiology, Biomarkers & Prevention 2003; 12(3):237s. [PubMed Abstract]
  14. International Agency for Research on Cancer (2011). Agents Classified by the IARC Monographs Exit Disclaimer, Volumes 1–100. Retrieved November 15, 2011.
  15. Rivoltini L, Canese P, Huber V, et al. Escape strategies and reasons for failure in the interaction between tumour cells and the immune system: how can we tilt the balance towards immune-mediated cancer control? Expert Opinion on Biological Therapy 2005; 5(4):463–476. [PubMed Abstract]
  16. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines.Nature Medicine 2004; 10(9):909–915. [PubMed Abstract]
  17. Renkvist N, Castelli C, Robbins PF, Parmiani G. A listing of human tumor antigens recognized by T cells. Cancer Immunology and Immunotherapy 2001; 50(1):3–15. [PubMed Abstract]
  18. Parmiani G, Russo V, Marrari A, et al. Universal and stemness-related tumor antigens: potential use in cancer immunotherapy. Clinical Cancer Research 2007; 13(19):5675–5679. [PubMed Abstract]
  19. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. New England Journal of Medicine 2010; 363(5):411–422. [PubMed Abstract]
  20. Parmiani G, De Filippo A, Novellino L, Castelli C. Unique human tumor antigens: immunobiology and use in clinical trials. The Journal of Immunology 2007; 178(4):1975–1979. [PubMed Abstract]
  21. Finn OJ. Cancer immunology. The New England Journal of Medicine 2008; 358(25):2704–2715.[PubMed Abstract]
  22. Curigliano G, Spitaleri G, Dettori M, et al. Vaccine immunotherapy in breast cancer treatment: promising, but still early. Expert Review of Anticancer Therapy 2007; 7(9):1225–1241. [PubMed Abstract]
  23. Chiarella P, Massi E, De Robertis M, Signori E, Fazio VM. Adjuvants in vaccines and for immunisation: current trends. Expert Opinion on Biological Therapy 2007; 7(10):1551–1562.[PubMed Abstract]
  24. Herr HW, Morales A. History of Bacillus Calmette-Guérin and bladder cancer: an immunotherapy success story. The Journal of Urology 2008; 179(1):53–56. [PubMed Abstract]
  25. Emens LA. Chemotherapy and tumor immunity: an unexpected collaboration. Frontiers in Bioscience 2008; 13:249–257. [PubMed Abstract]
  26. Schlom J, Arlen PM, Gulley JL. Cancer vaccines: moving beyond current paradigms. Clinical Cancer Research 2007; 13(13):3776–3782. [PubMed Abstract]
  27. Ng LG, Mrass P, Kinjyo I, Reiner SL, Weninger W. Two-photon imaging of effector T-cell behavior: lessons from a tumor model. Immunological Reviews 2008; 221:147–162. [PubMed Abstract]
  28. Garnett CT, Greiner JW, Tsang KY, et al. TRICOM vector based cancer vaccines. Current Pharmaceutical Design 2006; 12(3):351–361. [PubMed Abstract]
  29. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nature Reviews Immunology2006; 6(4):295–307. [PubMed Abstract]

Reference

http://www.cancer.gov/cancertopics/factsheet/Therapy/cancer-vaccines#r7