Turning a Cold CRC Tumor Hot: Part 1

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I wanted to spend my first scientific post on the hottest current topic in oncology research: immunotherapies. First of all: believe the hype.

I have been doing oncology research for more than 20 years. The recent emergence of immunotherapies acting against multiple advanced-stage cancer types (the long-strived for “Holy Grail” of oncology research) has truly caused a paradigm-shift. There is now immense research being done at all levels of private companies, cancer centers, research universities, research institutes and government labs to extend this first round of success into more patients and tumor types – and I firmly believe that these efforts will succeed!

Understanding Checkpoint Inhibitors

To understand immunotherapy, you need to understand “checkpoint inhibitors.” Hundreds of articles have been written about the truly paradigm-shifting “checkpoint inhibitors” such as the recently FDA-approved PD-1 and CTLA-4 inhibitors. At the very basic level, a checkpoint inhibitor is a treatment that helps the immune system see and go after cancer cells that are “pretending to be healthy” in order to avoid immune system detection. Clinical trials with checkpoint inhibitors are demonstrating great effect against multiple tumor types – including recently significant activity in a preliminary clinical trial of PD-1 inhibition in MMR-deficient (MSI) colorectal cancer (CRC). (Preliminary results were just released at ASCO 2015. They look exciting and a next phase trial (NCT02460198) is about to start.)

BUT… What about the rest our CRC community -- the approximately 80-85% who are not MMR deficient? Why have checkpoint inhibitors for the most part failed the majority of CRC patients in trials and how are immunotherapy researchers responding to this with newly designed therapies?

What makes a tumor “hot” and why are most CRC cases “cold”?

First, it’s important to understand the difference between “hot” and “cold” tumors in CRC.

Hot CRC Tumors

A tumor’s “hotness” is defined by how well it can be recognized by the immune system as dangerous and subsequently how well the immune system tries to attack it. For a number of cancers, a significant proportion of the tumors are considered to be “hot” – e.g. MSI-CRC, melanoma, renal cancer and lung cancer to name a few. These tumors tend to have a lot of mutations (“high mutational load”) which may give the immune system “more shots on goal” to recognize the tumor as dangerous. These tumors also tend to exist in neighborhoods (i.e. “tumor microenvironments”) that allow for successful immune system attacks after checkpoint inhibition.

Cold CRC Tumors

Non-MSI CRC tumors are a unique and different case. These are often referred to as “cold” tumors. In terms of the number of tumor genetic mutations, non-MSI CRC is one of the most highly mutated tumor types. In general non-MSI tumors do not respond to checkpoint inhibitors even though cancers with fewer genetic mutations, such as cancers of the stomach and head & neck, have shown responses.


It comes down to the tumor microenvironment (TME). Non-MSI tumors often exist in an environment that suppresses the immune system. So… simple checkpoint inhibition is not enough to remove the “Nothing to see here immune system, keep moving along!” shield (almost ”Romulanesque cloaking device”) surrounding the tumors.

Now that we’ve discussed “hot” and “cold” tumors, stay tuned for PART 2 of this series tomorrow where we will try to answer the question: What is being done by scientists to try to help those patients with “cold” tumors?

Dr. Tom Marsilje is a >20 year oncology research scientist with “currently incurable” stage IV colon cancer and also a Colon Club 2016 Colondar 2.0 model. 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.

One thought on “Turning a Cold CRC Tumor Hot: Part 1

  1. You say you are stage 4. I say you can get well without medical treatment! Get your body to do the job.

    In 1993-4 I recovered from stage 4 ovarian cancer with metastasis to the bowel, uterus, cervix and both lungs. The doctors had thrown their hands up and said nothing we can do. I had a spontaneous remission that time.

    Then in 2004 I had developed oesophageal cancer to the point where I could no longer swallow solid food. In a surprise turn of events I resolved some issues with people who were hassling me and I saw some immediate relief -the flu-like symptoms and the “sore throat that went a long way down” vanish immediately following the resolution and the lump cleared up in the month to six weeks afterwards. Another spontaneous remission but I saw some things.

    Later that year in Nov. I again developed ovarian cancer. This time I threw caution to the wind and used insight meditation (Vipassana) to investigate. What I discovered helped me effect deliberate spontaneous remission of the cancer (which I had seen metastasize to the bowel and was palpable). It took some weeks to clear away completely.

    5 more minor episodes of cancer 2006-2010 all of which I effected deliberate remission. And since then have been able to prevent the development of cancer. And I say that this has been possible yet I do have cancer stem cells in my body.

    Think like a scientist. The evidence is stark.
    1. The cancer cells don’t evade the immune system they are “hand and glove” with the immune system. The microenvironment involves many immune cells aiding the cancer cells.

    2. cancer cells from damage and genetic miscopying???? It is the same as saying you can take a sledge hammer to your car or introduce some viruses into your car’s controller computer and you have a teleport transporter! Cancer cells are deliberately created for a purpose.. a miguided purpose. They are a cell barrier trying to protect an area. Stem-cell mediated immunity erroneously ignited in the body. The “mutations” are deliberate changes in the genome. Cancer challenges the very foundations of biology for two reasons. One is that a belief causes the body to react in this way. Evidence that the body is not a machine but purpose-driven. The other challenge is that Darwinian evolutionary theory is wrong. There is intelligence behind life and not the sort that arises out of complexity and human brains.

    What you believe is significant enough to make you sick and make make you well again. From here and for several posts after it: https://kyrani99godnscience.wordpress.com/2013/08/25/what-causes-cancer-a-brief-account/

    And how about the beliefs? I am still in the process of making my cancer videos but this is important to know:


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