Browsed by
Author: Stephen J. Klemawesch, MD

TIL:  Tumor Infiltrating Lymphocyte Therapy 

TIL:  Tumor Infiltrating Lymphocyte Therapy 

TIL is a recently FDA approved therapy for treating certain types of metastatic cancer.  It has been referred to as a “living drug” as it is made up of the individual patients T lymphocytes.  It does so by taking cancer-targeting T cells from the patient’s own tumor and then growing them into billions more of the same cells in the lab and then re-infusing them into the patient.   This massive influx of warrior T cells can destroy the tumor whereas the previous small number of T cells were just holding it at bay.  

The initial FDA approval is for metastatic melanoma but it’s used for other solid tumors such as breast, pancreas and colon cancers.   

TIL is not the first use of immune cells to fight cancer.  CAR T-Cell therapy is another FDA approved method to fight certain “liquid” cancers, primarily leukemia, lymphoma, and multiple myeloma.  So far it has not proven effective for solid cancers.  CAR T-Cell therapy is so named because it involves making a chimeric antigen receptor (CAR) on T-cells.  It uses genetic engineering to modify the patient’s own T-cells so they can recognize (and then destroy) a specific cancer cell signal (antigen).  CAR-T therapy has helped and cured thousands of patients but one drawback of its use is that it is tricky to find a molecular signal (antigen) that is totally unique to the cancer.  Since healthy cells may also share this molecular signal, they can sometimes be damaged by the chimeric T-cells.  TIL on the other hand doesn’t modify the innate targeting system of the T-cells it simply uses a normal immune cytokine IL-2 (interleukin-2) to boost cell growth.  As it turns out one “target” that the TIL cells seem to pick out is the mutated protein that would otherwise control healthy cell growth.  Once this protein undergoes a Jekyll-Hyde transformation it allows uncontrolled cell growth otherwise known as cancer.   

HANE (HAE) 

HANE (HAE) 

A recent New England Journal of Medicine had three articles and an editorial about hereditary angioedema previously called hereditary angioneurotic edema.   

By way of reminder, HAE causes recurrent episodes of swelling that can affect various parts of the body:  face, tongue, throat, abdomen, extremities.  It is caused by a gene mutation in SERPING 1 which controls the production of C1-inhibitor.  In type 1 HAE there is a deficiency of the inhibitor, in type 2 the inhibitor protein is present but non-functional.  Lack of C1-inhibitor leads to excess levels of bradykinin which causes the tissue swelling.   

Current treatment of HAE is two pronged:  prevention and rescue.   This strategy is very similar to the approach to chronic asthma; that is, using a daily controller medicine but also having a rescue inhaler.  There are several preventative therapies available.  There are two types (one IV and one injected sub-Q) of purified C-1 inhibitor.  There are drugs that inhibit the procession of brady kinin kallikrein.  (An injectable monoclonal antibody and also an oral kallikrein inhibitor).     There are injectable kallikrein inhibitors and injectable brady kinin receptor blockers.  These medications can be used for both prevention and for rescue from acute attacks.   

One of the new medicines discussed in the journal is donidalorsen (an antisense oligonucleotide) that inhibits the messenger RNA that would otherwise stimulate excess kallikrein production.  Donidalorsen is an injected medication but unlike other kallikrein drugs that require more frequent injection, it can be given every two months.   

The other new drug that was discussed in the journal is sebetralstat an oral kallikrein inhibitor designed to treat acute attacks.  Currently the only rescue medicines for acute attacks are all either IV or injected.  Being IV or injected leads to barriers to compliance:  effort needed to transport, store and prepare the medication and reluctance to self-injection or infusion.  Also, if the swelling involves the hands the patient is incapable of self-administration.  These issues are especially problematic in teenagers and have led to withholding of treatment and subsequent hospitalization or death.  This makes an oral rescue medication a welcome option.   

For the sake of completeness there is a third type of HAE with normal C-1 inhibitor but excess brady kinin that can occur due to other protein abnormalities.  This group is very rare.   

Chronic Pruritis 

Chronic Pruritis 

A recent issue of JAMA the Journal of the American Medical Association had a review article of this condition.    Chronic pruritis is defined as an itch that lasts 6 weeks or longer.  It occurs in 22% of people during their lifetime and it accounts for 1% of doctor visits in the US.  Chronic pruritis can be classified as either inflammatory or neuropathic.   

The inflammatory causes are myriad.  Believe it or not a very common cause of inflammatory itch is dry skin.  Dry skin can occur due to overzealous use of soap and due to aging.  When the skin is dry it releases an inflammatory molecule (cytokine) called interleukin 33.  In eczema other interleukins (IL-4, IL-13 and IL-31) are the inflammatory cytokines.   These various interleukins activate another mediator of inflammation:  Janus Kinase (JAK).   

In people with hives, it is the tissue release of histamine that is the main cause of pruritis.  Contact dermatitis (poison ivy, nickel allergy) and insect bites are also inflammatory causes of itching.  Neuropathic causes for itch are also myriad.  Two very specific examples are due to nerve impingement:  notalgia paresthetica which is a chronic itch on the shoulder blade and brachioradial pruritis which is a chronic itch on one arm.  Chronic itch can also occur due to nerve injury from a previous case of shingles.  The patient will have itching only in the area where he/she had shingles.   

Some neuropathic itch conditions are due to amplification of the itch/scratch cycle.  Scalp pruritis and scrotal pruritis (watch out baseball players) are common examples.  The seminal event that led to initial scratching is often lost to memory but repetitive scratching strengthens the neural circuit to produce a greater sense of itch and therefore more scratching.  An especially problematic condition in this genre is prurigo nodularis.  In this condition the itch/scratch cycle is so severe that patients develop calloused nodules from the repetitive scratching.  The nodules themselves strongly stimulate the cutaneous nerves leading to a greater sensation of itch.   

Sometimes the nerve irritation is generalized.  In its most severe form it causes formication, a sensation that bugs (formic refers to ants) are crawling under the skin.  Diabetic neuropathy can do this.  Narcotic medications are another common cause.  And amphetamine-based stimulants including medications used to treat ADHD are known causes.   

Sometimes chronic itch is due to serious underlying health conditions including hepatitis, renal failure, lymphoma or other cancers, hyper-thyroidism and polycythemia (too many red blood cells).   

Obviously, the treatment needs to be directed at the cause.  Moisturizing the skin is always a good first step.  There are a variety of anti-inflammatory therapies starting with OTC hydrocortisone on up to prescription drugs that target the interleukins or Janus Kinase.  For neuro pathic issues therapies that break the itch/scratch cycle are important and include topical anesthetics, capsaicin, menthol, nerve blocks, acupuncture and neuroleptics.  Neuroleptics are medications that reduce aberrant nerve transmission (for example gabapentin and SSRI’s).   

Dear Dr. K; 

Dear Dr. K; 

I’ve modified my diet to include lots of anti-oxidants and I take vitamin E, vitamin A and beta carotene supplements.  Now I’ve recently heard they don’t reduce inflammation.  What’s the truth and, oh by the way, why can’t scientists get things straight? 

Well, first of all, scientists are people and therefore fallible.  But, science itself can be thought of as a ratchet to the truth moving forward one cog at a time.  And the complete truth/understanding may not become apparent early in the process.  Such is the case with free radicals and antioxidants.   

There has been intensive global research on inflammation and aging.  Early on it was discovered that reactive oxygen species and free radicals cause inflammation and speed up aging.  It was only later on that it was realized that amount matters.  This is based on a phenomenon called hormesis, which means small amounts are beneficial and large amounts are harmful.  Or as Friedrich Nietzsche said “what doesn’t kill you makes you stronger”. 

As it turns out small levels of reactive oxygen and free radicals stimulate the production of detoxifying enzymes and repair proteins for our individual cells and most importantly our mitochondria.  Whereas large levels have the opposite effect.   

Inflammation and aging encompass a spectrum of physiologies but mitochondrial function seems to be a lynch pin factor.  By way of reminder mitochondria are our “cellular batteries” providing life and energy for all of our cells through the production of ATP.  It’s hard to conceptualize but every 24 hours our mitochondria produce an amount of ATP equivalent to our body weight.  So, any perturbation of this system can have significant ramifications.  Because our mitochondria are so active they do break down and fall into disrepair.  That is why the detoxifying enzymes and repair proteins generated by low level free radicals are critical to mitochondrial wellness.    

Having too many broken or fragmented mitochondria not only reduces the numerical workforce but also disrupts cell function by another mechanism dubbed “inflammaging”.  Inflammaging owes its existence to our mitochondria‘s ancient bacterial origins (yes, our mitochondria are due to cells co-opting bacteria internally).  As the mitochondria spill their “bacterial origins” our immune systems mistake these fragments for actual bacterial invaders and attack the cells.  This is why low levels of reactive oxygen are critical to stimulate repair of mitochondria before this occurs.   

Thus, the “Goldilocks” niche of allowing some reactive oxygen for its goodness (all your supplements can interfere with this) but not having too much reactive oxygen (which can be accomplished through healthy diet and exercise).   

Immune Memory Cells 

Immune Memory Cells 

Scientists at McMaster University in Canada and at Mount Sanai in the US have co-discovered the cells that remember an allergy.  The Canadians call it MBC2 while the Americans call it a type 2 Memory B cell.   

B cell refers to a type of lymphocyte critical to immune function.  B cells are the factory for producing immune proteins called immunoglobulins (Ig’s).  Ig’s have a finite life span, but the B cells are much longer lived.  This is important in terms of providing for long-term immunity.  It’s our memory B cells that keep producing Ig’s (AKA antibodies) for all the illnesses we have caught and for all the vaccines we have received.  IgG is especially important in its role of providing durable immunity.   

IgE is the immune protein that causes allergy.  When B cells switch from making IgG (the protective antibody) to making IgE (the allergic antibody) it’s called an isotype switch.  You might ask why in the world would our B cells change from helping to harming?  As it turns out, other than causing allergy, IgE attacks parasites.  Our distant human ancestors all had one or another parasite in their GI tracts.  So, we evolved as a species to have a protective mechanism for this problem.  Fast forward to proper sanitation, safe drinking water and universal footwear and the worms are gone.  So now the IgE is segued to causing allergy.   

Although many people find that their allergies improve over time, many do not.  Peanut allergy is particularly known to be a persistent allergy.  So, the researchers used peanut allergic individuals to find these new memory B cells that weren’t found in non-allergic people.   

It is known that RNA (ribonucleic acid) instructs the B cells to switch from IgG production to IgE.  It does this through a protein called JAK (Janus Kinase).  So, new research is targeting this JAK signaling to see if the long-term memory can be switched off. 

Islet Cell Transplant 

Islet Cell Transplant 

The FDA has recently approved the first pancreatic islet cell transplant for some type I diabetics.  By way of clarification, type I diabetes is due to loss of the pancreatic islet cells and therefore a lack of insulin.  Whereas; type II diabetes is due to insulin resistance because the islet cells are over producing insulin due to obesity.   

Most type I diabetics can be treated with insulin, either by injection or continuous infusion.  But in a small minority safe control cannot be established with insulin.  It is this group of fragile diabetics where the transplant has value.   

The islet cells are obtained from a single deceased donor pancreas and infused into the portal vein of the liver.  Since they are from an unrelated donor, immunosuppressant drugs are required as in other organ transplants.  So far, the procedure has had long term (>5 years) success in only 1/3 of recipients.  But the concept is a novel one and improvements are likely to occur.   

Immune & Nervous Systems Interact 

Immune & Nervous Systems Interact 

Twenty years ago, if someone had said that the nervous system and the immune system interfaced with one another I probably would have scoffed.  I would have done so because with that era’s science I would have found it hard to conceive how brain and nerve cells could control individual immune cells and protein molecules and vice versa.  Boy, I would have been very wrong. 

With the sophisticated molecular biology developed over the past five years or so scientists have a new understanding of this interplay. 

Our immune systems protect us from infections and work to heal damaged tissue after infection or injury.  New science has come to realize that the nervous system and immune system work in concert to achieve these goals.  Our sensory nerves detect injury, infection and inflammation which results in a signal of pain and/or itch.  In fact, direct stimulation of peripheral sensory nerves can drive inflammatory changes in the skin.   

Our immune cells have receptors for numerous neurotransmitters (chemicals released by nerve endings) that allow direct communication between the nervous and immune systems.  And, as it turns out the immune cells can also produce neurotransmitters that communicate with nerve cells.  Depending on which neurotransmitter is released it can either activate or suppress the immune response.   

The immune to nerve communication can lead to a diverse array of unwanted symptoms: amplification of the itch sensation from eczema and hives, hyperresponsiveness of the airways in asthma, loss of sense of smell with nasal allergy and dysphagia (impaired nerve controlled esophageal motion) in eosinophilic esophagitis.   

Now that this interplay is understood, scientists are busy doing research to find ways to modify things in a favorable way to better treat cancer, allergy, autoimmune diseases and infections.   

Dear Dr. K; 

Dear Dr. K; 

I’ve lived in Florida my whole life and had tons of mosquito bites, but now they are swelling way more and lasting a week or longer.  What’s up with that? 

It means it’s time for you to leave Florida and lessen our traffic jams….no, just kidding.  Most likely it means you have developed an allergy, but a rare cause for strong reactions to arthropod bites is as an early sign of leukemia or myeloma.   

Mosquitos have been around for over 100 million years (specimens found in amber date to 100 million years ago).  Homo sapiens are a new addition to the planet.  Scientists estimate that there have been 110 billion humans and that half of us have died from mosquito borne diseases.   

A few additional facts about mosquitos are cogent.  Only female mosquitos bite.  They need blood to nourish their eggs and larvae.  Male mosquitos eat pollen.  When a mosquito bites us, she uses six mouth parts.  There are two serrated “knives” that cut our skin, then two “retractors” to open the rent and one retractable “sucking needle” to extract blood and one “saliva needle” to insert the saliva.   And the saliva she injects as an anti-coagulant contains proteins that can lead to the development of allergy.  In experimental models, the best way to induce an allergic reaction to a substance is by discreet but intermittent exposure.  So, if that is what has happened to you over time, your immune system has “learned” to dislike the salivary protein.  Depending on the severity of the reaction, various therapies can be used.  Oral antihistamines help.  Topical steroid (either OTC or prescription) applied quickly and under occlusion (a band aid makes the steroid penetrate better) works even better.  For more severe cases an allergy shot for mosquito can be done.   

On a different note, in terms of mosquito borne diseases, malaria has garnered the most attention.  Several standard types of vaccine strategies have been tried with modest and mixed results.  More recent trials with a monoclonal antibody are looking much more promising.   

Mosquitos do bite some individuals more than others.  Women are more attractive to mosquitos than men.  Pregnant women even more so, as during pregnancy women exhale 20% greater carbon dioxide than non-pregnant women.  Mosquitos are attracted by carbon dioxide, type O blood, scents/perfumes, certain skin bacteria and bright clothing.  Beer also seems to attract them.   

Dear Dr. K;

Dear Dr. K;

I recently underwent food allergy testing at the behest of my gastroenterologist to see if food allergies are causing or contributing to my irritable bowel syndrome.  It turns out I’m allergic to five foods.  My question is how do I determine if all five are causing my symptoms or just one or two?

That is a great question.  The guidelines I’m going to share with you were worked out in clinical research units.  In these settings patients are kept in a controlled environment (typically a hotel appended to the university hospital) and avoid the implicated (food allergy test positive) foods for two weeks.  It seems to take this long to fully “clean the system”.  Then, one food at a time is re-introduced.  In the research setting this is done double blinded and placebo controlled by putting the food to be tested inside gel-caps.  On a given day the patient may receive a placebo or an actual food.  Now, obviously this is a very tedious and protracted protocol.  But it has led to some basic rules to be used at home.

So, first of all, you need to avoid all five foods at the same time for two weeks.  If food allergy is causing your IBS, you will feel better at the end of two weeks. 

Then start adding a single food. You should have this food in “a usual portion size” and have it at least three days in a row.  If you have “tummy troubles” the very first day it could be due to the food or serendipity.  So, you need to repeat the experiment to verify. 

Now here is the hard part.  If you have symptoms you need to go back to the elimination diet until you feel well again before you try the next food.  Unfortunately, this could take up to two weeks again.  But you need a symptom reduced baseline to have clarity. 

Once you’ve tested all the foods there is another step you might need to take.  But this is necessary only if all the individual tests were negative.  This step involves testing food combos.  By way of example let’s say you tested positive to cheese, tomato and wheat.  Tested individually: no issue.  But tested together might reveal synergism.  So, pizza would be a mechanism to test all three.  Good luck, be patient. 

Omalizumab for Food Allergies

Omalizumab for Food Allergies

The FDA recently approved omalizumab (Xolair) to treat patients with food allergy including children as young as one year.  The approval came from several research trials including one recently published in the New England Journal of Medicine (NEJM) that was conducted at John’s Hopkins.  This particular study looked at allergy to peanut, cashew, egg, milk, walnut, hazelnut and wheat.  In the case of peanut allergy 67% of the test patients were able to consume 600 mg of peanut (equivalent to four peanuts) without adverse symptoms. 

The current recommendation is to only consider this therapy in people with severe (anaphylactic) food allergy.  In addition, the intent is not to enable ongoing ingestion of the food but to protect against anaphylaxis due to accidental exposure.  

An accompanying editorial in the NEJM was a bit of a devil’s advocate pointing out that the treatment is not curative but only works as long as the medication is continued.  It further argued that avoidance is still the lynch pin of therapy in severe food allergy.

The editorial did point out the potential safety net for children who otherwise run the risk of anaphylaxis from accidental exposure.