I have already written a lot about experimental immunotherapies. Previous posts have ranged from the strong signs of clinical activity already seen by anti-PD1 checkpoint therapies in MSI-high Colorectal Cancer (CRC), to an overview of why the more common non-MSI CRC has been resistant to immunotherapy intervention, and finally a few of the non-anti-PD-1 immunotherapy strategies currently in clinical trials for CRC. Those efforts all follow the “standard model” of drug discovery – i.e. they are “off-the-shelf” medicines. Today I wanted to briefly discuss a cutting edge technology/treatment strategy that attempts to take immunotherapy a step forward from comparatively simple “one size fits many” medicines. An attempt to step forward into the almost Star Trekkian science fiction world of fully personalized immunotherapy. If that sounds futuristic, it is. In terms of experimental early clinical trials, in 2016, the future is now.

About Therapeutic Cancer Vaccines

IMG_0400In metastatic CRC, pieces of colon begin to grow uncontrollably in other parts of the body, but the untrained immune system often struggles to recognize that this is not normal. Tumors are technically noticeable by the immune system but they use all sorts of tricks to escape this detection. One strategy to teach the immune system that CRC tumors are hiding from it are “therapeutic cancer vaccines.” Like all vaccines (e.g. the well-known childhood infectious disease vaccines), therapeutic cancer vaccines attempt to teach the immune system that something foreign (in this case tumors) are not supposed to be in the body. To train the immune system to try to attack. Train it to try to destroy it. Unlike childhood vaccines, therapeutic cancer vaccines are intended to treat existing cancer, not just prevent it. The principles are the same, though – teach the immune system to recognize that something dangerous is invading the body! Targeting tumor “antigens,” (i.e. proteins potentially noticeable by the immune system) which are shared across multiple patients, have been researched and tested for quite a few years to try to train the immune system, and more often they are now being combined with recent immunotherapy intended to simultaneously activate the immune system. Many scientists believe that addressing both parts of the puzzle (training & activation) may generate the most effective immune response possible. This combination is like teaching the immune system how to drive (the vaccine) and then filling its car up with gas (the immunotherapy drug)! An example “shared-antigen” vaccine trial currently running for CRC is a brand new trial NCT02615574 at the University of Pittsburgh. This trial is based upon their earlier (and still enrolling) Phase 2 trial open to CRC patients with peritoneal surface tumors NCT02151448. In comparison to this shared-antigen vaccine technology, today I wanted to focus on an exciting new emerging strategy: personalized vaccines which many scientists hope will super-charge the treatment impacts of therapeutic cancer vaccines to entirely new levels!

Therapeutic Cancer Vaccines That are as Unique as Fingerprints

A dream of the cancer immunology field for years has been to make & test “personalized” therapeutic cancer vaccines. This is because the complete list of mutations contained within a cancer patient’s tumors (but not in the rest of their body) is as completely unique as the patient’s fingerprints. Patients may share some common mutations (e.g. KRAS G12D) but those examples are just a few possible mutated genes out of a usually much longer list. guide-in-the-fightEven though the goal was well known, there was a very practical problem:  how do you realistically identify not only the complete list of unique mutations in a patient’s tumor but also identify those that are recognized by their immune system? The second part of that question is important. Not all mutations are recognized by the immune system. Through very recent advances in science & engineering, personalized trials are now becoming reality! Personalized therapeutic cancer vaccines designed against preclinical animal models of CRC were recently published for the first time and they showed very significant activity in these models. The next goal is to test whether or not the animal model data successfully translates, with the hope that these personalized vaccines will show higher clinical activity compared to earlier generation (simpler) vaccines. There is still scientific research to be done, but with key bottlenecks steadily becoming addressed (e.g. high-speed genetic sequencing of tumors), fully personalized therapeutic cancer vaccines for CRC are now approaching the clinic, for example, this recently announced Phase 1 clinical trial at MD Anderson NCT02600949. I expect trials at additional cancer centers to soon follow. In addition to cancer centers, biotech and pharmaceutical companies are also starting to explore fully personalized therapies. Neon Therapeutics and Bristol-Myers Squibb (the maker of the PD-1 inhibitor nivolumab) will be the first, of what I believe will eventually be multiple, new biotech/big pharma personalized cancer vaccine combination therapies to enter early clinical trials. There are multiple more personalized therapy companies already in or planning to enter trials (e.g. BioNTech, Gritstone Oncology) as the technology and science expand into more and more tumor types, including presumably CRC.

An Alternative Personalized Therapy:  T-Cells

NCCRT-strongarmselfieAn alternative personalized immunotherapy technology and strategy, which is also rapidly progressing, is personalized immune T-Cell Therapy (e.g. NCT01174121). Recently, preliminary signs of clinical activity in a non-MSI CRC patient were presented at the CRI-CIMT-EATI-AACR Immunotherapy conference showing the possible potential for personalized immunotherapy against CRC. More info on this strategy is to come, once this data is published! The “one-two punch” of generating personalized immune system recognition of a patient’s cancer and activating the immune system (via a PD-1 inhibitor or other combination therapy) may be the trick needed to maximize the efficacy of immunotherapies against CRC, including non-MSI CRC. Each patient’s cancer is unique and personalized – why shouldn’t their treatment be too? Welcome to the future! Visit the Late-Stage MSS CRC Trial Finder  Tom-marsilje-stage-iv-colon-cancer-scientist-runningpicDr. Tom Marsilje is a >20-year oncology research scientist with “currently incurable” stage IV non-MSI 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 a 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 Bristol-Myers Squibb, the producers of nivolumab - a drug mentioned in this article, in the form of unrestricted educational grants. We maintain ultimate authority over website content and the content written in this article.

3 thoughts on “Personalized Immunotherapy: Therapeutic Cancer Vaccines

  1. Dear Dr. Marsilje,

    I just came across your article, and it is great!

    What are your thoughts on patients using their own tumors to make vaccines? Many doctors will not recommend this option to their patients, probably due to out-of-pocket expenses associated with it, but would recommend it to those closest to them. Preserving the live tumor, instead of putting it in wax or discarding it, is the key to what you called “fully personalized” medicine.

    We work with patients who want to leverage truly personalized medicine. One-size fits all drugs can be helpful, but we believe, like you, that fully personalized immunotherapies are the future.

    ~ Kris

  2. Dear Dr.Tom,

    Last year, my father got inspected to have metastatic colorectal tumor in liver at a hospital in Korea, he got surgery on his colon, but the tumors in liver was not resectable. I was very worried and googled to find the best way for him, and finally I found the JX-594 (Thymidine Kinase-Inactivated Vaccinia Virus Plus GM-CSF). I’m waiting the clinical trial to be started but will this therapy be effective on the type of non-K-RAS mutant type and non-MSI type?

    From South Korea,

    1. Dear Hungju – Thank you for your great question. We are unable to give direct medical advice but highly encourage you to speak with your father’s health care team about the specifics of the treatment. If you need more general information about treatment options and questions to ask please see our patient resource guide – https://fightcolorectalcancer.org/guideinthefight/

      If you have additional questions, please feel free to email us at answer@fightcrc.org

      -Patient Resources Team

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