Anti-PD-1 Pathway Immunotherapies – What’s All the Fuss?

Immunotherapies have received an incredibly high amount of attention recently – with good cause! They are transforming treatment of multiple advanced major cancer types, e.g. melanoma and lung cancer, by using the immune system to fight the cancer. A general overview of immunotherapies and CRC was published by Fight Colorectal Cancer earlier this year. Today I’ll focus on a specific type of immunotherapy. Before we get started, for those who are not familiar with immunotherapy and its science (which admittedly has its entirely own different language!), remember we all start somewhere; you CAN understand this information! I and Fight Colorectal Cancer are here to help you in this process. This information is very important to know and there’s no way around the scientific terminology, but here’s advice how to tackle this information: read it all the way through to start, then-go back and review a bit more slowly, make a list of your questions and let’s tackle and review this together! Ready? OK, here we go… The immunotherapy drugs which are getting the most attention currently impact the “PD-1 Pathway”. Two types of drugs impact this pathway by blocking two sides of the same coin: “PD-1 inhibitors” and “PD-L1 inhibitors” (collectively I’ll call them “PD-(L)1 inhibitors” from now on). The PD-1 pathway exists to naturally “put the brakes” on the immune system to avoid autoimmune diseases. This is good! But… cancers have very successfully hijacked this system to use the PD-1 pathway for themselves – to deactivate the immune system and avoid attack – that is obviously very bad. DSCN8912At times, the immune system “can see” the tumor but it can’t attack it (no matter how much it wants to) because someone keeps pushing the brake pedal. PD-(L)1 inhibitors are drugs which block the tumors from doing this – in other words, they “release the brakes” on the immune system.

Shots on Goal

Scientists have theorized for years that the genetic mutations a tumor has will impact how likely it will be noticed by the immune system. There have been arguments about what is more important when you look at mutations: quantity (i.e. how many there are) vs. quality (i.e. how easily seen by the immune system). I personally view it as a “shots on goal” situation in-between those two arguments. I believe quantity matters indirectly because you may have a higher chance of a tumor having “high quality mutations” the more “shots on goal” you have.

Now… how does this relate to Colorectal Cancer (CRC)?

I’m going to use more scientific terms than I normally do because I firmly believe that it is very important for CRC patients to know these terms as immunotherapy science advances in clinical trials. I’m referring to “MSI status” (defined below) and associated terms. Your MSI status may significantly impact treatment discussions you have with your Doctor. It is a personal scientific goal of mine to make sure every CRC patient knows these terms and how their science relates to clinical trial immunotherapies. We talked above about “shots on goal”. Looking specifically at CRC, this idea trained the sights of scientists on “MSI-high” CRC because on average, MSI-high CRC tumors have a much higher number of mutations than the opposite case which is called “MSS” CRC. “MSI” stands for “Microsatellite Instable” and the opposite case “MSS” stands for “Microsatellite Stable”. MSI status is determined by tests which can be ordered by your doctor if they haven’t been done already. The terminology of these tests can be confusing – sometimes the tests refer to MSI tumors as being “Mismatch-Repair (MMR) protein deficient” In a previous column I discussed immunotherapy issues for MSS CRC – today I’ll focus on MSI-high CRC.

MSI-high CRC

Fight CRC RATSCRC tumors can be MSI-high either due to inherited Lynch Syndrome or alternatively it occurs in about 10-15% of cases of “sporadic” CRC. MSI-high tumors have been known for years to attract the attention of the immune system. Under a microscope, large numbers of immune system cells can often be seen in these tumors. The immune cells are just being blocked from fully doing their job. Scientifically, a high number of mutations (“shots on goal”) as well as often a high number of immune cells already present at the tumor site looked like a great situation to try PD-(L)1 inhibitors in clinical trials.

Preliminary Trial Results

The preliminary phase 2 clinical trial results of the PD-1 inhibitor immunotherapy pembrolizumab (Keytruda™) in MSI-high cancers were first released at ASCO-2015 with a full clinical trial publication appearing shortly thereafter in the New England Journal of Medicine. In the small trial, 9 out of 10 evaluable MSI-high CRC patients showed disease control (4 with at least 30% tumor shrinkage & 5 with stable disease of at least 3 months). Although the number of trial patients was small, the results were significant and matched perfectly the scientific hypothesis. Multiple PD-(L)1 inhibitor trials are currently in progress and open to MSI-high CRC patients – both in the case of monotherapies as well as various experimental drug combination cocktails. If you have MSI-high CRC, the Cancer Research Institute’s Immunotherapy Trial Finder is a great information resource to find these trials to discuss with you doctor. Results from in progress larger trials using PD-(L)1 inhibitors against MSI-high CRC are eagerly being anticipated. If the results of the small preliminary trial are confirmed, this would be the biggest scientific leap in the treatment for MSI-high CRC patients in decades! The American Gastroenterological Association (AGA) now recommends that all CRC patients be screened for the possibility of Lynch Syndrome which is overlap testing for MSI-status.  Although MSI-high is only a minority portion of CRC patients, I believe everyone knowing their MSI status is important because of the incredible potential for immunotherapies currently in clinical trials. For that reason, I hope all CRC patients now know what “MSI” is and plan on discussing MSI tests, the AGA’s new testing recommendations and finally the published results of the preliminary PD-1 inhibitor clinical trial with their doctor. Now that we have reviewed one of the most promising looking scientific advances in CRC immunotherapy, complete with descriptions of the PD-1 Pathway, preliminary clinical trial data of an experimental PD-1 inhibitor drug, MSI, MSS, MMR-protein deficiency, etc… I know it is a lot to absorb! What are your thoughts? What questions do you have? Let’s start a conversation! If you have a question about what you've read today, chat with us on our Patient Resources group on Facebook. Look for more information to come from Fight Colorectal Cancer and the new world of immunotherapies! Sign up so you don't miss a thing!   Tom-runningpicDr. Tom Marsilje is a >20 year oncology research scientist with “currently incurable” stage IV MSS colon cancer and is a Colon Club 2016 Colondar 2.0 model. He also writes a personal blog on life at the intersection of being both a cancer patient and researcher “Adventures in Living Terminally Optimistic” and posts updates to Twitter @CurrentIncurSci. As mentioned in his introductory post to this monthly column, he is a Ph.D. scientist and not an M.D. He exclusively gives his opinions on the “science” of experimental therapies – nothing written should be misinterpreted as implying medical advice. Disclosure: Fight Colorectal Cancer has received funding from companies in the form of unrestricted educational grants, including targeted therapy manufacturers Bristol Myers-Squibb and Lilly – the producers of Erbitux, Merck - the producer of Keytruda and Amgen – the producer of Vectibix. We maintain ultimate authority over website content and the content written in this article.

11 thoughts on “Releasing the PD-1 Brakes in MSI-high CRC Patients

  1. My wife has msi crc and has just started trail and is experiencing alot of pain in her abdomen where her lymph nodes ate enlarged. I noted it’s about 3 to 4 hrs after taking her meds. My question ,has this been a side effect with other people as well. Thank you and bless all of us going thru this

  2. Lets be sure to point out that the phase 2 study had 41% of the patients experience grade 3 or 4 side effects (severe or life threatening )

  3. I’m fine with scientific terminology, but what the heck are “shots on goal”? I don’t even know what sport that refers to. Help! Please use geek speak! ?

    1. Haha Sue – I do make it out of the lab on occasion but I’ll try to not overload posts with sports references in the future 🙂 In multiple sports, due to basic statistical probabilities, the chance of making a goal can be correlated to the number of shots attempted. So in tumor genetics, if you have a large number of mutations “possibly” recognized by the immune system… the larger that mutation number, statistically the higher the chance that at least one will be successfully recognized by the immune system, due to basic probability statistics. This translates into cancers such as MSI-high CRC, melanoma & smokers lung cancer which have among the highest response rates to immunotherapy, correlated to the fact that they also have among the highest average number of mutations. Hopefully that was geeky eough. 🙂 -Take care, Tom

  4. Dr. Tom,
    This is great information! Please keep it flowing. You give all us stage IV survivors hope! I just had my 3rd Resection last week and I love to read your columns…….Mike

  5. My husband is currently in a trial at MD Anderson, and is currently taking Nivolumab. He is MSI-high and was diagnosed with Stage 4 CRC two years ago with many liver mets. He started on the trial last June, and he is now NED. We are very happy and grateful for the drug and for all that made this possible. Thank you!

  6. I have slowly progressed up the stage ladder from Stage I to Stage IV over the last 8 + years. I understand the idea of corraling my mets using systemic chemo but it is really just a stop gap unless I get lucky. I tested negative for MSI. So this particular route is not available to me. I understand there have been very long term remissions and my onc. believe the success in survival will come from the immune system. This seems to be the thrust of the Duke tests that may be able to help us MSI negative patients. Do you have any further information on immune test that may be going on that would help the other side of the MSI picture?

    I know the Duke test is on brain cancer, but they are having success in a whole variety of solid mass tumors in mice, such as CRC. If their work with the brain tumors is approved does that mean there may be a fast track for the rest of their study?

    1. Research on MSS CRC immunotherapy is very active in many areas right now – we look forward to continuing to report on immunotherapy research as it advances!

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