A Potential MSS-CRC Immunotherapy from an AIDS Drug Start: the CCR5 Receptor Antagonist Maraviroc

Cobimetinib  + Atezolizumab  might have grabbed all the Microsatellite Stable-Colorectal Cancer (MSS-CRC) immunotherapy headlines in 2016 but quietly in the background was a second published/presented  Phase 1 Immunotherapy Clinical Trial with preliminary signs of activity in MSS-CRC patients.  I suspect it slipped under the medical radar earlier this year because its Phase 1 Clinical Trial results and related preclinical data were published in a (albeit very good!) scientific journal (Cancer Cell) rather than a medical journal.  The authors have recently been trying to address this by giving talks at major scientific/medical meetings such as the “Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival” conference in September.  Likewise, I am attempting to address this oversight of what I think are some pretty exciting preliminary clinical results with today’s blog!

Recycling in general is good for society & the planet Earth but have you ever heard of recycling drugs?  The official term for recycling drugs is “repurposing”.  It is an active area of research and an area of research I love for a number of reasons.  The major reason I love it is the potential major impacts on reducing the time to FDA-approval (and associated cost of the related drug development).  In a nutshell, it tests a drug which is FDA-approved for one disease against other diseases which preclinical scientific experiments indicate it may work.  This is a very cost and time efficient way to do drug development because aside from confirming efficacy in Clinical Trials for the new disease, in general most other aspects of clinical development have already been done when the drug was FDA-approved for its first use!

A CCR5 Receptor Antagonist AIDS Drug: Maraviroc

Maraviroc (brand-named Selzentry™, or Celsentri™ outside the U.S.) is an AIDS drug FDA approved in 2007.  It is a “CCR5 receptor antagonist” which works against AIDS because the CCR5 receptor is necessary for HIV to enter into its immune system host cells. The drug binds to the CCR5 receptor on immune cells, which then blocks the HIV protein gp120 from binding to the same receptor. By doing this, HIV viral particles are then unable to enter immune cells, blocking its AIDS disease line of attack.

maraviroc_graphical-abstract

Figure from Halama et al. Cancer Cell (2016) used with permission

Other Impacts of Maraviroc Blockage of the CCR5 Receptor: Potential MSS-CRC Immunotherapy

Blocking the CCR5 receptor on immune cells has impacts way beyond blocking HIV from infecting immune cells.  In cancer tumor immunology: Enter the macrophage.

Macrophages and MSS-CRC

One of the cell types in the innate immune system  is the macrophage.  Macrophages can either be tumor fighting (“M1-subtype”) or tumor helping (“M2-subtype”).  Discovering ways to control macrophages and switch which sub-type they are is an intense area of current research.

In CRC, macrophages within the tumor (“tumor-associated macrophages (TAMs)”) are often of the “tumor promoting” M2-subtype.  An area of active research has been to switch (or as scientists say, “repolarize”) these macrophages into M1-subtype tumor fighters.  As M1-subtype tumor fighters and members of the innate immune system, macrophages can either attack cancer cells directly or serve as intermediaries to facilitate attack by the adaptive immune system.

Scientists have discovered that one of the master switches for determining whether a macrophage is tumor promoting (M2-subtype) vs. tumor fighting (M1-subtype) is the “CCR5 receptor”. This research has been recently published in the journal Cancer Cell.  The exciting thing is that by blocking the CCR5 receptor with a CCR5 antagonist (e.g. Maraviroc), tumor promoting (M2-subtype) macrophages in CRC metastases can be switched (“repolarized”) into M1-subtype tumor fighters!

This not only can initiate direct innate immune system attack on tumors but it also has impacts on chemoresistance of these same tumors! Why is chemoresistance impacted?  Recent studies have shown that cytotoxic chemotherapies promote recruitment of tumor promoting macrophages into the tumor – and this is one immune system aspect of chemoresistance. Switching these macrophages into M1-subtype tumor fighters may get rid of this resistance mechanism and also attack the tumor with its own “defense”!

Now the Preliminary Clinical Data…

In a small exploratory clinical trial (NCT01736813, only 14 patients), patients received 300 mg twice daily the FDA-approved (for HIV treatment) commercially available drug Maraviroc.  All patients had MSS-CRC and were chemo resistant. The anti-CRC effects they saw in this small, preliminary patient population were encouraging:

  • Extensive tumor necrosis without harm to adjacent healthy tissue
  • Partial regression of lung metastases
  • Reductions in pro-tumor growth & chemo resistance signals within the tumors, as macrophages were switched to a tumor-fighting M1-subtype
  • Resensitization to various, previously failed standard of care chemotherapies used for CRC – producing tumor regressions
  • A well tolerated side effect profile with the most common side effect being elevation of liver enzymes

An example CT-scan image from trial is shown below (Figure 5C, Halama et al. Cancer Cell (2016), Figure used with permission).  This shows the total resolution of a MSS-CRC lung metastases (indicated with black arrow in the left image) of a patient receiving Maraviroc as monotherapy.

maraviroc_monotherapy_lung-activity

Following an initial treatment period of Maraviroc monotherapy, a number of patients on the trial began to receive previously failed chemotherapy in combination with Maraviroc (Table 4, Halama et al. Cancer Cell (2016), Table used with permission).  As shown, in the eight patients studied in this portion of the Clinical Trial, 3/8 patients showed a partial response of at least 30% tumor shrinkage and the remaining 5/8 patients all showed signs of clinical benefit.

maraviroc_combination-with-soc-chemo-table

All of this is quite exciting as far as preliminary data from a very small (14 patient!) Phase 1 trial can go.  A follow-up larger confirmatory Phase 2 trial, including study arms combining Maraviroc with either immunotherapy or chemotherapy drugs is slated to begin in Germany in January of 2017.

The specific repositioning aspect of this preliminary CRC data on Maraviroc has a number of interesting consequences however.  First of all, more than one company has done R&D on CCR5 receptor antagonists which leads to the possibility of relatively rapid large confirmatory US-clinical trials of CCR5 receptor antagonists – whether of Maraviroc or of a different CCR5 receptor antagonist – starting up.  Confirmatory trials, which if successful, could lead to a much faster than normal path to FDA approval for CRC use.

Secondly, Maraviroc is already FDA-approved (for anti-HIV use) and commercially available.  This opens up the possibility of off-label use while confirmatory studies are still in progress.  Oncologists can legally prescribe drugs off-label for their patients to use, if it is in their medical opinion that based upon clinical data (even if only preliminary) the drug could provide clinical benefit to their patients.  I anticipate that this is a medical discussion that will be happening between many CRC patients and their doctors based upon: the preliminary clinical data published in this Cancer Cell paper, the absence of a US clinical trial option (for now) and the known clinical safety profile of Maraviroc from its use in the AIDs patient population.

Where Do Things Stand Now?

This study was very small, only 14 (!) MSS-CRC patients – and small studies sometimes do not confirm in later larger clinical trials. But signs of clinical efficacy were seen in a significant proportion of the patients including objective responses.  It is also intriguing that the study showed that Maraviroc could be given both as a monotherapy as well combined with multiple types of standard of care chemotherapy for CRC – in both cases showing objective responses. 

The confirmatory Phase 2 trial will be starting soon in Germany (January, 2017).  The current Phase 1 trial data may only be preliminary but unfortunately the prognosis of many Stage IV MSS-CRC patients may not allow a lifespan long enough to wait for the German Phase 2 trial results to be known.

Looking at the commercial availability of Maraviroc and its preliminary clinical profile in MSS-CRC patients, it is likely that many stage IV CRC patients will be seeking the medical advice of their oncologists on its potential off-label use, especially as they begin to run out of standard of care treatment options.  In my own case, my standard of care options are dwindling and my life is on the line.  In that situation, it is an easy decision in my mind to ask for medical advice from my oncologist. The outcome of these medical advice discussions will be very patient specific – but I for one, know I will be having that discussion!

Of note: If you decide to ask your oncologist about Maraviroc, I strongly recommend bringing him/her a printout of the full scientific/trial paper I have hyperlinked in this post.  It contains much more information for them to use to make a medical judgement than I could fit into a blog post.  Buying it as a single paper PDF download is $30 – it would also be available free from any college or university library. 

Recycling is good for society, good for the planet, and in this case it may be good for MSS-CRC patients!

21 Comments on “A Potential MSS-CRC Immunotherapy from an AIDS Drug Start: the CCR5 Receptor Antagonist Maraviroc

  1. Thank you for doing such a wonderful job of explaining how this works. It is sometimes very difficult for the non-scientific reader to understand the complexity of how drugs work. I am quite certain that many patients will be having this conversation.

    Liked by 1 person

    • Thank you Jane – The only thing I recommend is that they print out the full scientific/clinical trial paper I hyperlinked when they speak to their oncologist – it contains a wealth of detailed information, much more than I could highlight in a blog. Hopefully it isn’t too expensive to buy a single paper – but if near a college, any college library will have access. In fact I don’t think I emphasized this enough in my blog entry, so I think I will go back and add in edit. A printout of primary literature is very important compared to the printout of a blog!

      Like

  2. After my dad was diagnosed with Stage IV colon cancer, we started to research treatment options. For a non scientific/medical mind it can be very challenging. Thank you very much for making complex studies and matters understandable and giving my dad hope. Living in Europe, I have read with interest about the trial in Germany. Thank you again for all you do. Wishing you all the best.

    Liked by 1 person

    • Thank you Helen for the nice note – my writing to fellow patients from my unique scientist-patient viewpoint is a labor of love. My best wishes for your Father. Take care, -Tom

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  3. Dear Tom, I believe this one will be especially well “fitting” with your clinical picture, since they emphasized the effect on lung mets. Statistically, again, you have much better chance with Maraviroc than anything else – 8 out of 14, 3 PR, 3 SD, 2 significant improvements – I consider this quite worthy a try (and no major side effects!) The only thing I did not like is the chemo follow up… I would prefer nothing or immunotherapy … Btw, what is going on with the trial you were accepted into? They said 8 weeks – is not it time yet? Good luck and big hug! Stella

    Liked by 1 person

    • Hi Stella!

      I have to admit, I am intrigued by this drug on a personal/patient level in addition to on a scientist level. I agree that it is looking pretty good statistically – with the caveat that with small patient numbers, statistics can do wacky things – it is seen quite often when Phase 1 trials are followed up with larger Phase 2 studies – but that being said, the current data is certainly a very good starting point!

      In terms of the chemo follow-up, keep in mind in the Phase 1 trial everything is very exploratory and you want to keep options open the best possible route forward for patients. In the Phase 2 trial there will be 3 separate arms specifically looking at the question you are posing – What is best? What is needed? So there will be 1.) Maraviroc only 2.) Maraviroc + PD1 inhibitor 3.) Maraviroc + standard of care chemo.

      Update on my trial – they emailed about 2 weeks ago confirming we were a go for mid-December and to be on the lookout for a communication towards the end of November with exact dates. So I am expecting to talk to them this week to hear specifics. I am VERY excited to get going on the trial!!!

      Hope all is well on all your various therapeutic strategies-

      Take care, -Tom

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  4. Dear Tom,
    Following our last discussion 2 weeks ago, I have contacted the medical teams of my mother here in Switzerland, Lausanne. After more than 3 days of discussion, phone meeting with German team, etc, it seems that the Trial is more marketing than anything else. The medical team refused to give my mother such a treatment and the German team agreed with them.

    We have insisted with all my effort to try but they told me this is more marketing than a treatment. What really surprised me was that seems the German medical team agreed to not treat my mother.
    My mother passed away couple of days ago and I still cry my blood and do not understand the medical team of CHUV who refused to treat my loved and unique Mother !

    I wish you all the best !

    Cheers
    Maz

    Like

  5. Hi Maz – I’m very sorry that your Mother passed away, my sincere condolences to you and your entire family.

    I have heard opposite feedback from others who have contacted the German research group & trial site but thanks for giving your viewpoint.

    Take care,
    Tom

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    • Hi Tom do you know if the German trial is up and running I couldn’t find anything on it but I am still a little “clunky” on researching these trials.

      Best,

      Tony

      Like

      • Hi Tony – My sources recently said it should be starting “any time now” – you can contact the Heidelberg Medical Center where it will be held and ask for an update directly from them. Sometimes there is a lag time before things show up/are updated in Clinicaltrials.gov -Tom

        Like

      • Hi Tom,

        How is working this Maraviroc on you? Any effects? Did you see any benefits yet?

        I am praying for you and really hope you will find your way and cure this cancer.

        Best Regards
        Maz

        Like

      • Hi Maz, I have experienced zero side effects. In terms of efficacy, since there is no comparator arm in my “n=1 trial”, it will be impossible to determine if any efficacy seen is specifically due to the maraviroc. I will get a readout on efficacy of the combo with a scan in April. -Tom

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  6. Dear Tom,

    So glad I found you in the internet ocean.

    My farther in-law has just been diagnosed of CRC, and it has spreaded into his liver with more than 10 spots. We are located in China, and all of the doctors/experts we went to here believed that it is too late for surgery, and the hope for Chemo is very minimum… Basically they are saying that he may only have months to live… I do not intend to buy those judgement. I am trying to find all the information I could related to CRC, and hopefully there will be some new drugs or new clinical trials out there that will significantly reverse his situation, and at least let him to stay with us longer. Therefore, it is so good for me to find you and your blog here, it is really really helpful.

    As you recommended, we will carry all of his reports from PET-CT, blood test, pathology to go to the doctor on Thursday, and to ask him if we could do MSI test and other possible immunotherapy, but I am just afraid they do not know much about the cutting edge techs in US or Europe…. At the same time, would you say that I should start to scramble some Maravirocs for him too?

    Hopefully there will be possible effective treatment out there for him, fingers crossed!

    Best of luck to you, and all of the CRC patients! Hope you could crack this thing soon!

    Rick

    Like

    • Hi Rick,

      I am glad you are getting MSI-testing, that is the single most important thing to do right now to guide therapeutic strategy!

      In terms of Maraviroc, I can not recommend specifically what you should do (since that would be medical advice and I am not a MD) – but I do recommend printing out the full paper and showing the Phase 1 trial data to show to the best MD you can find (in terms of being up to date on oncology experimental therapeutics) and get his/her medical opinion for your Father. At least in America, If the doctor prescribes it, Maraviroc is about 100x cheaper to buy than the average modern oncology drug.

      Take care,
      Tom

      Like

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  8. Tom, I must admit I was a little worried we would not being hearing from you for awhile. In retrospect, that was being a little selfish. The entire club depends on you and others for research and guidance. And we are waiting anxiously for your reports on your new trial. The very best of luck to you and make some history! Please God, cure our fabulous incurable scientist!

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