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.
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.
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.
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!