WHAT IS IMMUNOTHERAPY ANYWAY AND HOW DOES IT WORK?
Our immune system is very powerful and protects us from invasion of infectious organisms, but it also protects us from cancer. We all have circulating cancer cells in our bodies every day, believe it or not, but normally our immune system will recognize these abnormal cells and destroy them before they can cause harm.
Cancer cells are sneaky though and they have mechanisms that allow them to hide from the immune system so they can keep on multiplying and spreading. Immunotherapy helps a person’s own immune system to better recognize and kill cancer cells to shrink tumors and slow or stop the spread of cancer throughout the body.
In this post I will be reviewing two immune checkpoint inhibitor drugs that are now being used more often for uterine cancer and are approved by the Food & Drug Administration in the USA. I am also going to discuss who are the best candidates for immunotherapy.
Although there is a lot of science here, I tried to make things simple to understand and hope you benefit from this information. Please stay with me!
CHECKPOINT INHIBITORS
For various reasons, see this post, our immune system can become weakened and start to miss the circulating cancer cells our body produces. Cancer cells have the ability to hide from the immune system in many ways, but sometimes through what are called “checkpoint” proteins.
Checkpoint proteins are found on normal healthy cells and are what prevent our immune system from attacking them. T-cells, a type of white blood cell, will recognize and bind to checkpoint proteins on a healthy cell. This sends an “off” signal to the T-cell so it does not destroy this normal cell.
Unfortunately, cancer cells can also express these checkpoint proteins in abundance and bind to the T-cells, sending an “off” signal, in essence mimicking a normal cell. This allows the cancer cells to evade detection by the T-cells and avoid being killed. When cancer cells are not destroyed, they can start to proliferate forming tumors and eventually spread throughout the body.
Immunotherapy using checkpoint inhibitors work by blocking these proteins on cancer cells from binding with their partner proteins on the T-cells. The off signal is prevented and the T-cell will be able to recognize the cancer cell as abnormal again and destroy it. Yay!
4 TUMOR MOLECULAR PROFILING TESTS YOU NEED TO UNDERSTAND AND WHY
1. MISMATCH REPAIR STATUS
When cells divide, the DNA replicates itself so each cell has the same genetic make-up. However, sometimes during this process, errors can occur in the DNA. Normal, healthy cells have a mechanism to find and fix these errors that is called mismatch repair or MMR for short.
- dMMR = deficient mismatch repair
In some cancer cells, genetic changes can affect these mismatch repair proteins so they don’t work. This can be tested for and these cells are called mismatch repair deficient or dMMR for short.
- pMMR = proficient mismatch repair
If the cancer cells have normal repair mechanisms that function properly they are called proficient mismatch repair or pMMR.
2. MICROSATELLITE STATUS
- A microsatellite is a repeating sequence of base pairs that make up and hold together the DNA strands. When the DNA is dividing, errors can occur in the sequence and length of these microsatellites.
- MSS = Microsatellite stable
Tumors that are MSS are sometimes called “cold” tumors, meaning they are less mutated and don’t normally trigger a strong immune response. These tumors may even suppress the immune system.
- MSI = Microsatellite instable
Tumors that are MSI, also called MSI-H for MSI high, often produce abnormal or novel (different) proteins and these attract immune cells. In fact these tumors often have a high number of immune cells within them and are sometimes called “hot”. The problem is the immune cells are often being blocked from doing their job by the cancer cells.
MSI can be inherited and is part of Lynch Syndrome, which can predispose a person to endometrial and colorectal cancers. However, MSI more often occurs sporadically due to epigenetic factors of lifestyle and environment and problems with the mismatch repair proteins.
pMMR are also expected to be MSS
dMMR are considered to be MSI-High
3. TUMOR MUTATIONAL BURDEN
TMB is the total number of genetic mutations found in a tumor.
- TMB-High – These are tumors with a tumor mutational burden >10 mut/MB. I had a TMB of 28.9 mut/MB!
- TMB-Low – Less than 10 mut/MB
4. PROGRAMMED DEATH LIGAND-1 EXPRESSION
PD-L1 is a type of checkpoint protein that is found on normal cells to prevent the T-cells from destroying them. Normally when PD-1 (on the T-cell) and PD-L1 link, the “off” signal is sent to the T-cell so it does not destroy the cell and recognizes it as normal.
Unfortunately, cancer cells also have PD-L1 on their surface and can even over express this protein in abundance. This allows the cancer cells to evade detection by the T-cells and continue to divide.
There is a test that measures what percentage of cells in the tumor are expressing PD-L1. When a tumor has a high PD-L1 expression >50%, there is a higher likelihood of a good response to immunotherapy with checkpoint inhibitors.
ANOTHER IMPORTANT MARKER YOU CAN CHECK YOURSELF
NEUTROPHIL TO LYMPHOCYTE RATIO
Neutrophils and lymphocytes are types of white blood cells with different functions. If you divide the neutrophil count by the lymphocyte count found on a routine complete blood count (CBC), you will get the NLR ratio.
This ratio should ideally be around 1-2. If it’s >3 or < 0.7, it can indicate a problem.
Surprisingly, many doctors and oncologists don’t even know about this ratio or check it. I learned about it through my naturopathic doctor.
All of these tests, except the NLR, are part of the precision tumor molecular profiling tests see this post and are so important to help direct treatments. Now I will tell you why so keep reading!
SO WHAT DOES ALL THIS HAVE TO DO WITH IMMUNOTHERAPY?
- Immunotherapy with checkpoint inhibitors does not work for everyone. Each person and their particular tumor(s) are unique even though they may be diagnosed with the same type, grade and stage of cancer.
- Endometrial cancer is unusual. It has the highest prevalence of microsatellite instability across human cancer types and about 25-31% of endometrial cancers are MSI-H and dMMR, which means many of these cancers will be susceptible to immunotherapy.
- It has been shown in multiple studies that cancers that are MSI-H, dMMR and have a high TMB are more likely to respond to immunotherapy with immune checkpoint inhibitors.
- About 48% of endometrial cancers also display PD-L1 positivity. Tumors that have a high percentage of PD-L1 expression also respond well to immunotherapy.
- In this Study they found that patients with a low NLR and high TMB before treatment were statistically more responsive to immunotherapy than those patients with a high NLR and low TMB. They also had better overall and progression free survival.
There are exceptions to every rule however and the science around these newer drugs is still evolving so do not lose hope if you do not fit into these categories.
TWO IMMUNOTHERAPY DRUGS APPROVED BY THE FDA TO TREAT UTERINE CANCER
- PEMBROLIZUMAB – Trade Name KEYTRUDA
Keytruda is a monoclonal antibody that targets the checkpoint protein on immune cells called PD-1. This drug has been around the longest.
The immune checkpoint inhibitor Keytruda blocks the interaction of PD-1 (found on T-cells) and PD-L1 found on the cancer cells. This prevents the cancer cells from sending the “off” signal to the T-cells. The T-cells can then recognize the cell as abnormal and destroy it. The immune system can then work to shrink or destroy the tumor or slow its growth.
SOME HISTORY OF KEYTRUDA AND ENDOMETRIAL CANCER
- 2014 – Keytruda was first introduced in 2014 and was limited to treating melanoma.
- June 2020 – FDA approved Keytruda as first line treatment for patients with aggressive and/or recurrent solid tumors that had a high TMB (tumor mutational burden) and no longer had alternative options for treatment.
- July 2021- FDA approved Keytruda + Lenvima (more on this drug in another post) for patients with advanced endometrial carcinoma that were pMMR/MSS. These patients had disease progression following prior standard of care treatments and were no longer candidates for surgery or radiation. This was based on a study called Keynote 775. Read More
- March 2022 – FDA approved Keytruda as a single agent for the treatment of advanced endometrial cancer. Patients had to have MSI-H or dMMR biomarker status or have had disease progression following chemotherapy. They were also no longer good candidates for curative surgery or radiation therapy. This was based on a clinical trial called Keynote 158. Read More
- June 2024 – FDA approved Keytruda, along with carboplatin and paclitaxel chemotherapy, followed by Keytruda as a single agent for primary advanced or recurrent endometrial carcinoma. Both groups pMMR and dMMR were included in this study. This was based on a clinical trial called Keynote 868. Read More
2. DOSTARLIMAB – Trade Name Jemperli
This is another monoclonal antibody, checkpoint inhibitor that targets PD-1 like Keytruda. It has been FDA approved for patients with dMMR/MSI-H endometrial cancer along with chemotherapy as a first line treatment.
CLINICAL TRIALS WITH JEMPERLI
- In August 2024, the FDA approved the use of Jemperli, along with chemotherapy, as a first line treatment for patients that have advanced or recurrent endometrial cancer that are pMMR/MSS or dMMR/MSI.
- In this clinical trial, the median overall survival with Jemperli + chemotherapy (carbo/taxol) was 44.6 months vs. 28.2 months with a placebo + chemotherapy. This was a population of patients that included both dMMR/MSI-H and pMMR/MSS.
- For dMMR/MSI-H patients, the median overall survival with Jemperli + chemo had not been reached at the 36 month mark vs. 31.4 months in the placebo group. For pMMR/MSS patients, the median overall survival with Jemperli + chemo was 34 months vs. 27 months with a placebo + chemo. Read More
- Clinical trials have also shown statistically significant better overall 2 year and 3 year survival for both groups of patients with the Jemperli + chemo group vs the placebo + chemo group.
TO SUMMARIZE ALL THIS SCIENCE!
1. Based on these studies and more, multiple experts on gynecologic cancers believe that for women with advanced or recurrent endometrial cancer who have dMMR/MSI-H tumors, adding either Pembrolizumab or Dostarlimab to the chemotherapy should be the new standard first-line of treatment.
2. For women with pMMR/MSS advanced or recurrent endometrial cancer, there are two options now. Keytruda with Lenvima or Dostarlimab with chemotherapy using carboplatin and paclitaxel.
3. I was tested and found to have dMMR (deficient mismatch repair), MSI-H (high micro satellite instability), and a high TMB (tumor mutational burden) making me a good candidate for immunotherapy. I also had a low NLR (neutrophil to lymphocyte ratio) before starting treatment. Although I refused chemotherapy, my oncologist allowed me to start Keytruda as a first line of treatment. Within 3 months of starting this drug, the tumor, that was growing in my pelvic area, had disappeared and I have been in remission ever since!
4. Immune checkpoint inhibitors are given intravenously at a set dose every 3 weeks. The time frame is variable and depends on side effects. I know some women who have been receiving immunotherapy for 4-5 years and still going. I am going into my second year and will likely keep going if I don’t experience any setbacks.
5. The standard time for administration is 12-24 months, but some clinical trials have been for 3-5 years.
6. At this time, there are clinical trials going on to test other immunotherapy drugs for endometrial cancer. Some of these are showing good success too, but they are not FDA approved for use. Hopefully these forms of targeted therapy will continue to get better and better.
WHAT ARE THE POSSIBLE SIDE EFFECTS OF IMMUNOTHERAPY USING CHECKPOINT INHIBITORS?
It is important to know these drugs are working by removing one of the safeguards that prevents the body’s immune system from attacking healthy cells. This can lead to auto-immune diseases and certain organs may be affected.
Side effects are given different grades 1-5
- Grade 1 is very mild or localized
- Grade 2 are more intense side effects, but manageable
- Grade 3 are severe, causing quality of life issues
- Grade 4 are life-threatening
- Grade 5 is death
The most common side effects include
- Diarrhea or constipation
- Coughing
- Itching and sometimes a rash
- Fatigue
- Headache
- Nausea
- Reduced appetite
- Endocrine abnormalities affecting the thyroid
Less common and more severe side effects include
- Pneumonitis (inflammation of the lungs)
- Colitis (inflammation of the colon)
- Myocarditis (inflammation of the heart)
- Hepatitis (inflammation of the liver)
- Neuropathy (pain, numbness and tingling of your hands or feet)
- Muscle and joint pain and inflammation
- Autoimmune diseases
- Autoimmune reactions affecting different organs like kidneys, lungs, intestines, liver
Although rare (~0.3-1.3% chance), fatal reactions can occur with these drugs.
I recommend discussing these options with your oncologist and finding out what your tumor profile markers are as soon as possible. Remember, these are still drugs with serious side effects like chemotherapy so you don’t want to go into treatment without all the facts.
Another important point I want to make is to look at the statistics carefully. Sometimes studies make it sound like a particular drug can really make a big difference, when it may only extend survival by a few months and is only palliative, not curative. Make sure to do your due diligence and ask lots of questions.
HERE is a list of 25 questions you can download and print to ask your oncologist.
WHAT YOU CAN DO TODAY TO CONTINUE ON YOUR HEALING JOURNEY
MAKE IT A POINT TO MOVE YOUR BODY EVERY DAY!
Today I am going to recommend that you start moving your body every day if you don’t already. Exercise is so important for healing and keeping our muscles and bones strong and healthy!
Women in menopause are at high risk for osteoporosis. Do NOT take calcium supplements. More on that later, but it is not good for cancer patients and does not improve your bone health. Exercise does!
Getting too little exercise we know is not good for us, but did you know, there is also too much exercise? Extreme activities like marathon running, triathlons, and long, intense intervals of aerobic activity can increase inflammation in the body and sometimes even suppress the immune system! Read More
I don’t recommend pushing yourself too hard during this healing phase of your life. Here is a list of simple exercises that don’t have to take a lot of time.
- Walking
- Yoga
- Rebounding on a mini trampoline, which is excellent for lymphatic drainage!
- Stretching
- Light weight lifting
- Walking with a weighted vest, called Rucking
- Pilates
- Pickleball
Just 15-20 minutes a day can make a huge difference! I started with walking and stretching. I later added in Pickleball (FUN!) and walking with a weighted vest. An easy way to get weight lifting in is to walk with light hand weights. I used 3 pound dumbbells for this.
The Lord is my strength and my shield; my heart trusts in Him, and I am helped.
~Psalm 28:7