The Faces of Successful Colorectal Cancer Immunotherapies: Vol. 2

This is a blog post I had been hoping to write for a long time! The first published (today in the New England Journal of Medicine)clinically disease free” success achieved via immunotherapy & surgery in an advanced Stage IV patient with the common “Microsatellite Stable (MSS)” subtype of colorectal cancer (CRC) – the kind of CRC that I and most CRC patients have! As of right now it is only a single patient proof of concept but it is the first publication showing such high clinical efficacy in a Stage IV MSS-CRC patient achieved primarily via the immune system!

To put this news into context, I wanted to back up & walk you to today’s post via the fast pace of immunotherapy developments and strategies that I have been focusing much of my writing on the past year.  The rapid developments in immunotherapies have truly been breathtaking to behold over the past few years, as both a scientist and a patient.  CRC has unfortunately lagged behind some other cancer types but in the past year that has thankfully started to quickly change.

In early 2015, anecdotal stories started to emerge that CRC patients of the relatively rare “Microsatellite Instable (MSI-high)” sub-type of CRC were responding well to the deservedly famous new “anti-PD(L)1” immunotherapy drugs.  This is the drug class which is making continuous headlines around the world as having activity against multiple types of cancer.  Already FDA approved for melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer and Head & Neck cancer, these drugs will surely be “anchor therapies” for numerous additional cancer types in the coming years, as they wind their way through the clinical trial process – especially in many novel combinations.

Coordinated presentation at ASCO-2015 (shown below) and publication in the New England Journal of Medicine  last June officially announced high response rates in MSI-high (aka “Mismatch-repair deficient”) CRC patients in a small preliminary clinical trial.  To publicize this incredibly important news, I wrote about these immunotherapies in the post: “THE FACES OF SUCCESSFUL COLORECTAL CANCER IMMUNOTHERAPIES: VOL. 1 last Fall.  The test for MSI-status is standard and because the news was having trouble filtering down to the local level, I was excited to see my writing read by many tens of thousands of readers across multiple languages worldwide!

ASCO-2015_Anti-PD1 in MSI-High CRC_Phase 2 Results

Although very exciting news, MSI-high CRC is only about 15-20% of CRC cases and since they tend to be diagnosed in earlier stages, only about 5% of Stage IV patients.  Like most CRC survivors, I am not MSI-high.  Instead I have the much more common “MSS” subtype of CRC…

The hunt for immunotherapy success against the more common MSS-CRC subtype continued…

There are many different strategies being tested in parallel to find “the tricks” needed to achieve immunotherapy success against a “tougher” type of cancer like MSS-CRC.  I wrote about the Cancer Research Institute-Fight Colorectal Cancer Immunotherapy Roundtable convened to try to help coordinate those efforts and I made some bold predictions of future success in my “New Year’s Day 2016” post.  The first potential advance with a immunotherapy combination approach against MSS-CRC was just announced at ASCO-2016 although in the presentation activity did not hit the level of “clinically disease-free”.

Last winter,  I have written posts on the (I firmly believe) coming wave of personalized immunotherapies which I am currently exploring for my own therapy…  Although I believe there will certainly be non-personalized successful immunotherapy strategies found for MSS-CRC, I also personally believe that incorporating a personalized component will obtain the highest levels of success.

A significant step forward in the successful immunotherapy treatment of a MSS-CRC patient was just published today in the New England Journal of Medicine using just such a personalized approach – a clinical trial I tried (and failed) to get into last fall.

The name of the technology is “Adoptive Cell Transfer (ACT) of Tumor-Infiltrating Lymphocytes (TILs)” and it is a trial being run at the United States National Institutes of Health (NIH) as: NCT01174121.  I know that is a mouthful but don’t worry, I’ll explain it in an easy to understand way!  This methodology has been used with success for a number of years against Melanoma but… Melanoma is the “poster child” of cancer immunotherapies – often immunotherapy techniques work the best against it.

Achieving clinical activity against epithelial GI-solid tumors had been elusive until the first published case report of success in a cholangiocarcinoma patient (“Patient #3737”) back in 2014. Since then, scientists have been working hard to replicate this success in a more common epithelial GI-cancer: MSS-CRC.  As just announced, the hunt has finally shown signs of success. The picture below shows immune cells attacking a cancer cell.  A beautiful sight to behold huh?  🙂

T-Cells Attacking Cancer_Not Copyrighted

What is “Adoptive Cell Transfer (ACT) of Tumor-Infiltrating Lymphocytes (TILs)”?

This procedure is quite complex but I’ll break it down to its key components.  Essentially it identifies immune cells called “Tumor-Infiltrating Lymphocytes (TILs)” within a patient’s tumor that are highly reactive against specific mutations found only within the tumor’s genome (i.e. mutations not found in the patient’s normal DNA).  These mutations are called “neoantigens” and as discussed in the therapeutic vaccine strategy I previously wrote about these are personalized “drug targets” which are specific to the exact genetics of a patient’s tumor and immune system.

Once TILs are harvested from a patient’s tumor (via surgery – one of the current bottlenecks of the technology), tumor-mutation-specific TILs are identified & these are then expanded into many billions of copies.  This new batch of expanded TILs = “the drug”.  In this case we’re not talking about an old-fashioned pill… we’re talking about a living drug – a “drug” which in fact are many billions of copies of a patient’s own tumor-recognizing immune cells!

At this point, the procedure becomes even more intense (technology bottle-neck #2!).  An important goal after re-infusing the TILs back into the patient is to have as many of them survive & multiply as possible. Previous research has shown that pre-treating the patient with a form of chemotherapy (Cyclophosphamide & Fludarabine) ironically depletes the immune system in such a way that basically “sets the stage” for the re-infused TIL’s to live and multiply to a greater extent, increasing their therapeutic potential.  Along with infusion of the billions of TIL cells, Aldesleukin (IL-2) is given as an immune stimulant.  Recently, Pembrolizumab (a PD-1 inhibitor) has also been added to the overall treatment process to remove an immunosuppression trick used by many tumors, although the patient in today’s publication did not receive it.

As you can see, it is now a multi-faceted process of:

  • Surrounding the tumors with billions of tumor-specific immune cells
  • Activating the immune system with IL-2
  • Removing immunosuppression with a PD-1 inhibitor.



Science 2015_Steven Rosenberg TIL Trial Review_Current Process_Purchased

Used with permission. Rosenberg S.A. and N.P. Restifo.  Science 348(6230), 62-68 (2014)

Overall, the process requires a 3-4 week hospital stay at the NCI Hospital in Bethesda, MD, there are significant side effects endured during the treatment, and risks of very serious complications exist.

But CRC patients have been lining up (myself included) to try to get into this trial even with all of its risks and hardships for one very big reason: in Melanoma it is clinically used and it cures some Stage IV patients.


Celine Ryan_2016-04

Celine Ryan – CRC Immunotherapy Pioneer

Celine Ryan has a technical background (database programming and mechanical engineering) but she never would have guessed in a million years that her life would become the epicenter of a cancer treatment scientific breakthrough for the medical history books.

She was happily focusing on home-schooling 3 out of her 5 kids when she went in for her first colonoscopy in September, 2013. The news was not good.  Following emergency surgery, she was diagnosed with Stage IIIC CRC and she endured 6 months of the difficult FOLFOX chemotherapy cocktail, as well as radiation.  The side effects were very harsh but she pushed her way through them because for Stage IIIC CRC, these treatments are potentially a cure. She was willing to do anything for that chance of a cure.

In her own words: “Chemo was challenging for me both physically and emotionally.  My life revolved around treatments and support measures.  I had unexplainable pain in my neck and back that radiated down both arms after the majority of infusions that lasted for days.  My feet and hands were struck with neuropathy, and my eyes became painfully sensitive to light.  I was nauseous day after day, despite taking meds to prevent it.  Juggling the kids’ lessons, practices, and performances with my trips to the clinic was a logistical nightmare.”

When the 6 months of treatment ended, her friends threw her a party she would never forget. She thought she was “No Evidence of Disease (NED)Life was joyous.  But then at her 6-month CT scan, spots on her lungs had grown.  The cancer was back and Celine was now considered “currently incurable” Stage IV.

Celine’s oncologist immediately offered her standard of care chemotherapy.  She dreaded doing it again, especially now that it would not offer the possibility of cure – at least she wanted to wait until she had exhausted other options first.  A story in the New York Times earlier in May of that year had caught her eye.  It described a patient with cholangiocarcinoma who had undergone an extremely experimental personalized cellular immunotherapy at the NIH.  She was the first patient with a GI-cancer to ever respond to this type of therapy. Her story read like a medical miracle.

Most patients follow standard of care chemotherapy first, followed by clinical trials.  Looking at the new world of immunotherapies, Celine decided to flip this flowchart in reverse and first try for an unproven home run hit. Although still a rare gutsy move, in the new world order of immunotherapies – this is a strategic sentiment you hear more & more often in the Stage IV patient world. Two days after being offered chemotherapy, Celine was on the phone with the NIH.  A date she’ll never forget – December 19, 2014 – her 49th birthday.

The NIH TIL trial is not easy to get into.  Celine hit roadblocks albeit with glimmers of Hope – so she pushed & pushed & pushed.  She felt driven to get into the trial.  She eventually succeeded.  It was a fateful decision.

KRAS-G12D Driver Mutation: Meet Your TIL

Celine began the long and difficult TIL extraction and reinfusion process I described earlier in the post.  The NIH scientists made an earth-shattering discovery during her TIL testing however.  In the mixture of TILs, they identified ones which recognized and attacked her KRAS-G12D “Driver Mutation”The NIH scientists immediately started working to make BILLIONS of copies of these TIL.

What is a “driver mutation” and why is this a big deal?  It’s a big deal because: cancer cells are not identical inside a tumor.  Even if the immune system “sees” most of the tumor, parts of the tumor may escape by simply not having the mutation that is noticeable by the activated immune cells.

Driver Mutations are special. They “drive” a cancer’s growth and malignancy.  For this reason, they are likely to be contained in most of the cancer cells.   An activated immune system can achieve “bystander” cancer cell killing in the tumor but the higher the percentage of cells having the immune target, the less the reliance on this happening for clinical efficacy & potential cure.  In this setting, the Driver Mutation is the Achilles Heel of the cancer.  An activated immune cell targeting a cancer’s Achilles Heel? That is hitting the cancer cell with a sledge hammer exactly at its weakest spot.  Conceptually, this may offer an improved chance of cure.

It also offers the possibility of perhaps using the information obtained from Celine’s case to treat other KRAS-G12D patients via construction of engineered T-Cells with KRAS-G12D “TCRs”.  KRAS-G12D is a frequent driver mutation in various cancers including e.g. CRC, pancreatic cancer and non-small cell Lung cancer.   Celine’s TIL is specific for her HLA-type (HLA-C*08:02) which may limit how many other patients could potentially be directly helped via her data – but follow-up science is in progress!

The Results are In!


Pictured above are the sequential CT scans published today in the New England Journal of Medicine  Used with permission from Tran E et al. N Engl J Med 2016;375:2255-2262.

Although it wasn’t (yet!) the “clinically disease-free” homerun that Celine had been hoping for, the results were still stupendous!  Initially all seven of her tumors shrank before one (“Lesion #3”) began to progress.  All while Celine enjoyed a very good quality of life, absolutely nothing like her chemo experience.  Maybe her first at bat wasn’t a home run but she was on base and the NIH doctors were working very hard for her to run the bases & get across home plate.

Baseball Runner Being Waved Into Home Plate

Celine and her NIH doctors developed a plan to respond to the one tumor that was resisting treatment.  They surgically removed the one resistant tumor.  With that surgery, Celine is now “clinically disease-free” and has been now for months. With some of the very best scientific minds in the world focused on her case, optimism is running high!  Celine’s goal remains the same: she hopes to be the first “currently incurable” MSS-CRC patient to be cured by immunotherapy.  I for one am not arguing against her chances – someone has to go down in the history books, I would be thrilled if it is my friend Celine!

At this point it is still unknown what percentage of MSS-CRC patients will respond to this kind of therapy.  Is Celine the start of a trend or is she a rare outlier?  Although the MSS-CRC immunotherapy scientific breakthrough seen in Celine is very exciting to behold – obviously the main issue with the current TIL therapy is its complexity, high cost and low throughput.  Those are certainly big issues but they are not fatal flaws.  There are many scientists at the NIH and elsewhere with great ideas on how to address each of them, in order to bring this kind of therapy to much larger groups of patients.

The world needed a first published “proof of principle”… that this (any!) immunotherapy technology could achieve a “clinically disease-free” state in MSS-CRC, a type of cancer which desperately needs immunotherapy breakthroughs. I am beyond excited that my friend Celine is that first person.  

For current CRC patients, this trial is very small with tough criteria to get into (I tried & failed to get in myself) so the experimental therapy is not easily accessible for now.  What it is doing for ALL of us is laying the experimental research groundwork for future treatments.  If the number of responders go up (data pending but I predict will happen), the therapy will become easier to access through expanded/additional clinical trials!

Don’t mistakenly think that this means that TIL therapy is the only immunotherapy that will work against MSS-CRC.  This success has broader implications than thatIt shows that immunotherapy in general can achieve “clinically disease free” in at least some patients with MSS-CRC… there will be more tricks found.  That is how science works.  We learn from preliminary successes, the door is cracked open a bit and then we push on it with all our might to expand this success as quickly as possible to more people in need.

And we will keep pushing with all our might until a Cure is here – Celine and her TILs are helping to show us the way. 

2016-08_Celine Ryan and Tom Marsilje

12 Comments on “The Faces of Successful Colorectal Cancer Immunotherapies: Vol. 2

  1. This is fabulous post, thank you Tom, as complicated as the science is, you make it understandable for us lay people, thank you for reporting so brilliantly on this and giving us such hope!


  2. Thank you for this post Tom. This is very exciting indeed. The “field” is moving so rapidly as we search for another clinical trial for my husband Jim. He’s having a biopsy tomorrow to perhaps help us find one that will better match his needs. We just know there has to be something out there that will shrink these puppies down or just nail his “Achilles Heel” so they don’t exist any longer. I will never stop searching on behalf of my husband and he won’t stop fighting either. This feels like a win for all of us. Thank you to Celine too!


  3. Thanks, Tom for the post. My husband and I read it together. You give us such hope in the battle against this disease. It is truly amazing!!


  4. Thank you, Tom! How incredibly exciting for Celine, all CRC patients and the scientific community! That picture of the immune cells attacking the cancer cell is incredible! It would serve well as a focus for meditative visualization of ones cancer being defeated! Thank you again and all the best wishes for success in your upcoming trial as well.


  5. Great writeup Tom! When I first joined the Colon Club forum Celine was just getting started with the trial. Her progress and success has been amazing!


  6. Thank you so much Tom, you are so incredibly helpful for all mCRC patients and their families! The article is very interesting and gives hope, however it is not clear to whether this method can also work for patients without mutations. E.g. my mother has no RAS or BRAF mutations. Does this mean that it can not work for her because there is no target for the TILs?


    • Hi Sven,

      Just to correct your point: your mother may have no RAS or BRAF mutations – but “by definition” I 100% guarantee she has mutations! Cancer can not exist without mutations. Her mutations are just different than the ones tested in the simplistic 1st pass genomics panels used in/for many hospitals that only look for a SUBSET of specific mutations. For example, there is a 90% chance she has an APC mutation. That is sometimes not told to patients because it is currently considered “undruggable” with a medicine – but in theory, if the APC mutation is immuogenic, it could be targeted via a TIL strategy! Even without an APC mutations, she will have other mutations that in theory she may have TIL against… That is why for these type of projects they do something called “whole exome sequencing” which looks for EVERY mutation that results in a mutated protein for the immune system to potentially notice, whether they impact current clinical use of drugs or not.

      I hope that clarifies!



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  8. Tom,

    Do most CRC patients exhaust standard of care therapy before they move to the clinical trials or is it more common for patients to just “go for it” if something looks promising?



  9. Hi Tom,
    Thank you for all that you do! In one of your responses above, you mentioned that “if the APC mutation is immuogenic, it could be targeted via a TIL strategy!” How is it determined if one’s mutation is “immuogenic” or not?


  10. Pingback: Mother of five was diagnosed with stage 4 colon cancer - here’s how she beat it without chemo : The Hearty Soul

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