Can HIV be used as therapy for cancer?

Diagram of the HIV virus.

Diagram of the HIV virus. (Photo credit: Wikipedia)

Every so often, a report comes out in the news that grabs our attention.  Here is one of them.  The virus responsible for AIDS, a deadly disease with no real cure, has been successfully used to treat a few people with certain types of cancer.  Now wait a minute, you mean we are giving someone HIV?  Are we replacing one fatal disease (viral) for another fatal disease (cancer)?  No and no. Let me explain.

Human viruses that cause disease have successfully evolved to infect and survive in human tissues and cells.  HIV has evolved so well that it infects humans cells and avoids immune elimination and of course eventually causes death.  Other viruses are also very effective at infecting human cells and surviving to the extent that they replicate (or divide) very well in the body.  Viruses, although extremely simple in their makeup, have also evolved clever ways to manipulate the human cell’s own machinery for itself.  One of the things that the HIV viruses does very well is to integrate it’s genetic material into the human cells.  So, why not modify the virus so that it no longer kills you (we call this removing the virulent properties) but still has all the infective, survival and genetic integration properties. This is exactly what is being done.

For many years, a virus known as adenovirus has been modified to remove it’s harmful properties and keep it’s infective and replication processes.  This has been done rather successfully, but using these ‘modified viruses’ has proven rather difficult…do to a host of reasons.  What is new now is that the HIV virus was used as a viral vector in this case.  Thus, the properties that allow HIV to kill humans were removed, but the properties that allow HIV to infect human cells and integrate their genetic elements were kept.  It is perhaps not surprising that after nearly 15 years of HIV research and trillions of dollars being spent, we have now reached a stage where we know enough about the virus to start modifying it for use as therapy.

OK, so how is it being used.  Let’s first look at the cancer in question.  Leukemia is a cancer of the blood…often it is a cancer of the B cells specifically.  These B cells, instead of protecting you from pathogens by making B cells and then dying like normal cells, become transformed and keep dividing uncontrollably.  Mutations in the genome of the B cells result in a cancer of these cells that grows to such a large extent that they start preventing the normal function of the blood and the immune system.  These cancerous B cells start to overtake the body.  Getting rid of them permanently is difficult as bone marrow transplants are the best way to permanently remove them.  However, this can only be done with individuals who are healthy, and who have their cancer in remission (one must have a good heart, have a functioning normal immune system, etc.). BM transplants are still high risk and have many side effects and are very expensive, but can be life saving.  Not everyone can qualify for this procedure.  Chemotherapy often fails but is used to try and control the disease, but often as a temporary measure for many leukemias.  So, other therapies are often needed.

Using a modified and non lethal form of the HIV virus that infects T cell, scientists mixed a these cells.  However, the HIV itself was engineered to express a modified protein that allows the T cells to recognize the B cell, and then to kill it.  So, a mix of this genetically engineered HIV was allowed to infect the patients own T cells and those T cells are now able to recognize and destroy the B cells in the patient.  Confusing…yes, but don’t worry too much about the details.  In general HIV plus the patients own T cells were used to allow the T cells to kill the cancer cells.

Sounds sexy sure.  However a few things to recognize before getting too ahead of ourselves.  1) All B cells are killed not only the cancerous B cells and thus treatment makes you VERY sick as your immune system is shot for quite some time after the procedure (but this is only temporary as your immune system will recover but the cancer wont).  2) This may not work on everyone and only a small amount of people have been tested.  3) This is an example of personalized medicine and is very costly.  4) It may be years, if ever, before the FDA recognizes and approves of this type of therapy.  5) No one knows the potential dangers if any with using HIV as an infection tool.

So, interesting…let’s hope they can expand their trial and show long term studies that ‘prove’ that this works.  But for now, its a small step in the right direction!!!

 

Thank you

Dr C

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Gene therapy finally gets its day!

DNA vaccine and Gene therapy techniques are si...

DNA vaccine and Gene therapy techniques are similar. (Photo credit: Wikipedia)

It is finally real.  One very specific form of gene therapy has been approved by the European drug authorities.  Actually, China has allowed some forms of gene therapy since 2003, but regulatory authority in Chinese Healthcare is not as rigorous as other countries.

What exactly constitutes gene therapy.  It is a form of treatment for any disease in which a defective gene is replaced by a functional gene through a very a specific protocol.  Simply injecting genes or using gold particle coated with gene(s) (units of DNA which code for a protein) is not enough.  Genes must be delivered into cells through certain vehicles before they can work properly.  Viruses make excellent carriers of genes because of their unique properties of 1) infecting cells and 2) getting gene products to be converted into protein products in an efficient manner.

The US and other countries with active medical research capabilities have been certainly keen to adopt gene therapy in the past.  However, as of date, there are currently NO gene therapy approved protocols/nor products in the US.  Why?  In 2000-2001 the entire human genome was sequenced and we technically at least know all the genes that humans have.  So, the issue of the gene itself is solved (theoretically).  The problem is in the delivery.  How do we get cells (and the right cells in fact) to take up the genes and most importantly convert the gene into a useful product?

That is where viruses come in.  The most useful and somewhat safe viral system developed so far is something called the adenovirus.  This virus will infect human cells and allow the inserted gene to be converted into useful protein product.  Also importantly, the virus itself does not insert the gene into the human genome.  In this way the new gene does not disrupt the existing genes or DNA material that is inside the cell.

Sounds good.  So what the problem?  Well all viruses are pathogens.  That means that part of the definition of a virus is that it infects human and has the potential to cause an infection.  Secondly, even if it has been modified extensively, it is still a virus and thus a foreign entity or organism.  One fundamental tenant of the human immune system is that foreign proteins or entities are immunoreactive.  Thus, the human immune system can mount an aggressive  response.  That response is normal, but can actually kill the patient if strong enough.  In fact, that is exactly what happened in a very well publicized gene therapy trial for a teenage boy with a very rare disease (ornithine transcarbamylase deficiency) in 1999, who was killed after mounting a huge immune response against the viral carrier of the gene being replaced.  There have been a number of other accidents and failures to various gene therapy trials and the US regulatory authorities have been extremely cautious to grant approval of any new forms of gene therapy.

There are over 2000 different types of diseases which are potentially treatable with gene therapy.   Generally any deficiency in which a single gene is responsible can be treated with gene therapy.  All one technically has to do is make sure that the cell type which carries and produced the defective gene (like the gene responsible for the disease cystic fibrosis) and use gene therapy with a corrected version of the gene that is targeted to that cell using some kind of modified virus.  The gene needs to be produced over a long time in order to be effective as a treatment.  In the case of this newly approved gene therapy by the company called uniQure Glybera allows for the expression of the new gene that codes for a lipid processing enzyme that is deficient in the patient receiving the treatment.  The gene is introduced into the muscle tissue with an adenoviral associated virus (AAV).  As the virus does not insert the gene into the human genome itself the gene only lasts in the nucleus of the cells for as long as 12 weeks and seems to minimize the diseases for almost two years.  This new therapy relied on a AAV that has been modified to be non-pathogenic, thus not causing disease.  So, the parts of the virus that causes disease has been removed, the the parts that allows the virus to act like the virus has been kept (e.g. the viral coat proteins).  Only one case of fever (often a result of immune reaction) has been reported so far, thus this new viral vector may indeed hide itself from recognition by the immune system.

So, finally gene therapy gets its share of the limelight.  Generally, it takes one successful trial of a certain drug class (in this case gene therapy using AAV) to get other agencies to approve that therapy or to get the same agency to approve of use of that therapy in different disease.  In clinical trials at the moment is this type of gene therapy for Parkinson’s disease and others.  So, who knows this approval for this one disease may point the way to more approval for other countries and other diseases where single gene replacement is curative.

Thank you and please do support me by going to my web page….www.cancermadesimple.com

Dr. C

Why medical community still doubts herbal remedies

English: Herbal remedies for sale in San Juan ...

English: Herbal remedies for sale in San Juan de los Lagos, Mexico (Photo credit: Wikipedia)

We have all heard it:  herbal remedies can’t be wrong, they have been used for thousands of years.  In fact, it’s true…many cultures, tribes, medicine men, etc. have been using and in essence prescribing natural plant based herbal remedies for many many years….in fact, much longer than that of modern medicine/pharmaceuticals.
So why then is the medical community reluctant to embrace herbal medicines and remedies.  Although it’s fun to poke fun of doctors, medical administrators, insurance companies, and pharmaceutical executives, the universal distrust in these types of remedies is not unfounded.  Here is a small list of reasons: 1) Many herbal remedies were found to have good affects on one particular ailment (such as stomach discomfort) and then prescribed and suggested to work in other organ system (the liver, lungs, etc.) with little or no evidence.  2) Many herbal remedies have been linked to visual cues in how they were assigned to work.  For example, it is common to find that red fruits or seed products are often given to women for bleeding conditions as blood is red and so is the remedy.  3) Many herbal remedies over the years are assigned to work on various parts of the bodies as they were harvested in certain ways- functional links.  For example, the Cantonese believe that eating pig brain will make you smart, or if you have impotency- eating of dried and ground up ox testicles will help.  Although these are not plant remedies, these types of functional or anatomical links have dominated traditional remedies.  4) The vast majority of remedies, even though many have commonalities from independent groups around the world and have been used by millions, have no properly controlled studies to show that they actually work. 5) They are prescribed and administered in widely varying fashion. The list goes on and on and these objections are fair.  That does not mean that herbal remedies don’t work, it just means we have a long way to go before modern practitioners will embrace them.

The last time that a medical compound was successfully derived from a plant and used in clinical medicine was in 1967.  That agent/drug was Taxol.  That was a long time ago?  For a while people just stopped looking for them.  However, many are now pursuing this newly popular science; namely plant medicinal chemistry with newer techniques.  Who knows, maybe one of our next blockbusters will come from a herb, plant or natural product.   It might not only save lives but also teach us identify the chemical component that works in the plant itself.

The placebo effect or the placebo response

Placebo Effect (Doctor Who)

Image via Wikipedia

Evidence-based medicine for all it’s ugly by products, is here to stay.  This means that any therapies/medicines/approaches to helping patients with illness must be proven by outcomes in a controlled and documented manner.  That means just simply saying, ‘see it works’ will not cut it.  Since 1993, when the Cochrane Collaboration was formed and recommended that all studies be conducted as full ‘ Randomized Control Studies’, evidence-based medicine has dominated Western thinking.  Those who have promoted that we treat patients the same way as we have always done without properly conducting trials when possible are of course not happy with this type of medicine.  Those who promote ‘complimenary and alternative medicine or CAM‘ are also not too happy, as many state that the effectiveness of that type of therapy is based on hundreds of years of experience. However, many supporters of CAM have been conducting randomized control trials to address these concerns about real efficacies.  So far, no CAM therapies have been proven effective after these trials are done.

So this is where placebos come in to play.  A placebo is an agent that is given to a patient that does NOT contain the active ingredient or ‘device’ being tested in the experimental arm.  So, if for asthma medication treatment study that could be the inhaled drug albuterol as the experimental agent and inhaled air as a placebo.  A placebo is designed to act as a type of control.  However, it is not a true control as if it is inhaled (even air) it may be perceived to provide some benefit by the patient.  A true control would be non-intervention or nothing.  So inhaled albuterol, inhaled air as a placebo and nothing as a true negative control is a great example of a randomized control trial design.  The patient does not know which one he/she is given (the placebo or albuterol) but will know if they are in the nothing treatment arm. 

This is actually a true study designed to look at the placebo effect.  This particular study published in the New England Journal of Medicine and compared the effects of inhaled asthma drug, placebo, acupuncture, and no treatment conditions.  The interesting thing is that when all of these were compared the placebo, the acupuncture and even the no treatment conditions all showed strong subjective responses.  This means that when patients were asked how these treatments made them feel about their asthma, they were very positive in their answers.  The drug was slightly higher at about 50% subjective responses while the acupuncture and placebo were both at about 45%, not much lower.  The lowest response came from those with no intervention; 21% of those folks felt that no treatment made them feel much better.  Seems good right?  Wow, seems like we can avoid expensive drugs and just take inhaled air or go see an acupuncturist right?

No, it turns out that the second set of data is what really makes people stand up and take notice.  When you actually measure the amount of air that gets in through the lungs (by an accepted lung air measuring medical device) the data looks completely different. When they actually measure physiologic response; ONLY the inhaled drug works well and gives a measurable response.  Whereas all three other treatment (or lack of it) gave the same low response.  So, the body really does react to the drug and only very little to the non drugs (or the placebo effect). There was actually no difference in physiologic or objective responses between the non-intervention or the placebo or acupuncture.  They were the same.  The body derives zero benefit from these as compared to no treatment.  

So, not to trash the CAM believers in any way…this is only one study on Asthma and not the definitive study on all other indications where traditional chinese medicine or other CAMs may have some effects (positive not negative).  But, this is fairly drastic news for those who propose that the placebo effect may explain how CAM works…as the placebo effect (in this case) is a fallacy.  It also underscores something else very important….that is, subjective responses (I feel, he feel, she feels) are very dangerous and recording them may not be the best measurement when looking at medications and treatments.  This is a big issue now?  Do we look at objective or subjective measurements?  For evidence-based medicine, the answer is clearly objective outcomes. 

Thank you for reading…Dr. G Cancer Made Simple  

Old drugs get a new lease on life: cancer!

Age-standardised death rates from Breast cance...

Image via Wikipedia

When drug companies make new drugs they often spend million and millions of dollars on them.  Due to regulatory issues, new drugs can only be used for one very specific purpose (that at which is was designed and tested for).  However, if the drug is included in the treatment cycle and FDA approved it can ear a company billions of dollars in income.  As you might imagine the incentive to discover new areas of treatment for the new drug is huge.  This is not a bad thing.  There are conditions here one’s immune system is too active and needs to be suppressed.  For example, for transplantation where a donors organ or blood is put into a patient, large amounts of immunosuppressant drugs are used.  These drugs often inhibit the growth or activation of immune cells in the patient.  It turns out that the very same pathways that some of these drugs work in blocking the immune system also work fairly well in blocking cancer cells.  This is where the link is now being pursued by many drug companies.  I will just bring up one example here below but in the future I will introduce other examples.

Recently, Novartis (a big pharmaceutical company) had good success with an immunosuppressant for Breast Cancer.  The drug Afinitor (R) is a type of drug known as Everolimus which was originally designed to block a protein pathway in the cell known as MTOR.  This pathway if blocked prevents activation and proliferation of T cells and is thus acts to prevent immune responses.  Over the years it has also been approved by the FDA to be used to treat late stage kidney cancer, certain metastatic pancreatic cancers and a few other conditions. 

Recently, ver strong clinical data has encouraged the maker of Afinitor (R), Novartis to file for worldwide approval for the use of this mTOR inhibitor in breast cancer patients.  Phase III clinical trials with 700 patients have shown that patients who took this drug plus a hormone inhibitor in advanced breast cancer settings had delayed tumor growth in comparison to estrogen inhibitor therapy alone.  This combination of the two drugs allowed patients who had breast cancer delay their treatment with chemotherapy and slows down the hormone resistance that develops after a time in many of these women.  If awarded, this drug will make over a billion dollars for Novartis. 

So, this is just one example of re-use of a drug that had once been used only for inhibiting the immune system and now used in breast cancer.  It’s an example of an old drug with a new target.    

Thanks …Dr C

Cancer Made Simple

Drug companies and cancer

The graph shows the annual number of cases of ...

Image via Wikipedia

So….where are we now with new therapies that are actually saving lives for people with cancer?  As I have discussed before, have we seen any progress in the last ten years?  We have certainly advanced our knowledge of cancer and signaling pathways and have even come up with new strategies to target cancer.  Let me make a quick list of the things we have learned in the last ten to 15 years…

1.  We have now started looking for mutations in patients with certain kinds of cancer such as advanced melanoma (BRAF mutation V600E) as a means of identifying patients who should respond favorably to drugs that target those mutations.

2. Immunotherapy has potential to work (and does so in rare cases) but still not well against some cancers.   Antibody therapy is used against some cancers such as B cell cancer and even now in skin cancer with some success.  Things that help boost the immune system do show limited efficacy in some cancers. 

3.  Drug companies have developed some interesting other types of therapies that rely on dendritic cell vaccines and a few others.  A vaccine is a bit different from antibodies in that they are material that you can use that comes from the cancer cell itself or from a newly designed product (e.g. human dendritic cells given bits of tumor antigens) to patients to help them boost their anti cancer immunity.  These have limited effects and only work with certain patients and we can’t always anticipate who will benefit and who won’t.  Other approaches include the use of cancer RNA, DNA, cytokine stimulated dendritic cells, etc.  Only one drug in this class has been approved by the FDA so far and that is against very advanced protate cancer.

4. Small peptides (proteins) and other small molecules are being developed now that target various newly discovered cancer specific pathways (again we have learned a great deal about pathways in cancer that don’t exist in normal cells).  In melanoma (skin cancer) about 45 different cancer specific peptides have been identified (ones that the immune system recognizes and trials or pre clinical research is being conducted with many of them). 

5.  We have learned that treating cancers with drugs that target specific mutations (a classic example is Gleevec(R) that targets the BCR:ABL protein in a cancer called CML) have the potential of driving the cancer to become resistant to that drug (via further mutations).  This is somewhat similar to the anti-viral therapy for AIDS (HIV-1 disease).

  6.  We can sub-classify cancer better and stage it better.  It is not clear that this helps with treatment, but it certainly helps to give the patient individualized prognosis (e.g. give them with more accuracy his/her life expectancy with a cancer at a specific stage).  In some cases it does help to prolong life.

7.  Some drugs on the market can now be analyzed for long-term efficacies.  For example, for some drugs that have been used for 10 years or more for the same patient (same cancer) we can come up with better 10 year survival rates, etc.  This, of course, can be done on patients who were treated with a cancer therapy (even immunotherapy) ten years ago, even if the drug was stopped.  We can and have gotten better numbers now at longer term survival (perhaps in the future cure rates will be measured at longer time points than 5 years).

8.  Viral vaccines against papilloma virus for teens (females only) is going to revolutionize the HPV associated cancers.  These vaccines (initiated in many countries now) are going to reduce significantly the risk of getting certain cancer in women…the biggest of which is cervical cancer.  It will be interesting to see if the same can be done in the future for other viral associated cancers such as liver cancer (HCV or HBV), stomach cancer, and a few others (e.g. EBV and NPC). 

Anyhow, there is much we have learned (and this was not comprehensive).  However, it is not clear that we are truly extending the lives of many patients with cancer (better than we were ten years ago).  It seems that for advanced cancer patients we are in the same position as we were years ago.  Certainly for newly diagnosed cancers such as prostate cancer, we can do more now than ever to get most patients to continue to live cancer free lives.  We have a long way to go…we have got to find treatments that work for patients with cancers that have metastasized for example.  We have got to figure out how to keep costs low.  We have got to figure out how to do better screening or if screening is really necessary. Other avenues that are gaining interest are treatment that do not rely on “western medical” interventions.  This area will continue to grow.

Thanks for reading….please leave me comments!

Cancer made simple! 

Cancer treatments: traditional or not?

Logo of the Natural Products Association.

Image via Wikipedia

There seems to be a battle between those who passionately believe in traditional (evidence based) medical treatment and those who believe in non traditional (less evidence and sometimes no science-based) treatments.  Usually people are polarized one way or the other.  I would love to get a nice dialogue with folks who support one or the other and what the reasons are.  So let me start off by getting some of the terms spelled out and trying to categorize various types of treatments.

Pharmaceutical versus naturaceuticals:  The former is chemical based products designed and manufactured by pharmaceutical companies while the later is non-chemical based natural products (of course they can be chemical in principal, but not made synthetically) or extracts from natural products (such as seaweed, plants, oils, etc.). .

Traditional versus non-traditional (alternative medicine).  This is the western defined definition…traditional refers to surgery, radiation and chemotherapy while non traditional refers to things outside of this.  Traditional methods requires clinicians while non traditional may not.  Examples of non traditional treatment include vitamin C therapy, coffee enema, vegetable soups, etc.

Western versus Eastern medicine:  This usually refers to drugs and treatments designed to be used in modern health care and include drugs dispensed by trained cancer doctors while the later refers to things such as traditional chinese medicine, indian healing and traditional indian herbs, etc.  These might be dispensed by trained TCM practitioners but often given by parents and relatives of patients.  Some of these have many years of experience behind them but often have limited scientific studies behind them.

There are many other classes of treatment that do not have such nice and neat categories.  For example, I have a colleague who promotes holistic healing using energy (eg. from ones own self or from other sources).  Others believe that psychotherapy can help and some fo the techniques used include hypnosis.  Others belive that specific diets can starve cancer cells while normal cells grow well.  I have another colleague who calls himself Doc (not to be confused with Dr.) who uses a technique that analyzes hair samples and helps to identify (again using some interesting energy source) the cancer a person has but more importantly the source of the illness (e.g he belive that cancer is a result of other imbalances of the body).  He then embarks on a treatment plant (diet and natural products and alignment techniques) that corrects the underlying deficiency in the body that cures the patient.  There are many other types of proposed therapies and this only scratches the surface.  I would love to hear from you…the reader as to any treatments that you know about, swear works, or have suspicion about.

Let me finish by discussing some things that people tend to criticise about these types of therapies.  First of all major criticisms about modern therapies such as pharmaceutical based drugs and treatments include the following: 1) They are too expensive, 2) They don’t work- well they only target the cancer cell but not the underlying conditions that made the cancer grow in the first place, 3) They are not natural and thus inherently toxic, 4) Drug companies are in cahoots with Doctors and hospitals to milk the customer (the cancer patient) for as much money as possible so these companies can get larger and richer and 5) These companies spend so much on making these drugs (hundreds of millions) that many of these drugs can’t fail and the investment is too big and thus the claims for their effectiveness are exaggerated.  Common criticisms of other therapies include: 1) They are not tested well and have almost no scientific or clinical evidence for efficacy, 2) People who say they work base their assumptions on the one or two people who claim that they work but ignore the hundreds of people who they don’t know who had witnessed no recovery using these methods, 3) The few people who say these methods work could have gotten better for reasons we don’t know, 4) Some of the natural products that people take can actually be toxic in large amounts (especially for the liver or kidney), 5) Like pharmaceutical companies, companies that sell these so-called natural products for cancer treatment are also very biased, hide negative data, and try to sell inexpensive natural products at high prices to make a profit and have no real care for the patient. 

Despite how you feel there are likely to be real pros and cons for any type of treatments that you use if you have cancer.  No one is likely to be able to provide you with the miracle cure.  The comfort level and the background fo the patient is always going to play an important role and education can never hurt.  So, please do comment on this and let me know what you think!  Would love to see an active discussion going?  What do you favor or disfavor and why?  Can you challenge the status quo?  Do you have stories to share of how you may have changed your views about treatments?

Thanks for reading….. Dr. C

Cancer made Simple