The Microbiome Effect: Link Found Between Immunotherapy Success and Gut Flora

• Nice Insight

Pharmaceutical companies have turned their gaze to the microbiome in hopes of understanding the discrepancy between treatment effectiveness, specifically in highly promising cancer immunotherapies. Recent data has shed light on the link between the human microbiome and the effectiveness of immunotherapeutics. Although the microbiome’s role in modulating these therapies is still somewhat opaque, now would be an opportune time for pharmaceutical firms to consider strategic partnerships with companies that specialize in human microbiome research to make their immunotherapeutic stand out in a crowd that is already big and growing. Some estimates have cancer immunotherapeutic sales reaching USD $50b by the middle of next decade - up from $6b in 2016.¹

The Limitations of Highly Successful Immunotherapies

For some forms of cancer, immunotherapy has been FDA-approved and is very effective. For deadly, late-stage melanoma, combinational immunotherapy has a success rate of 88%. It should be noted that cancer immunotherapy, especially some forms of combination therapy, are very recently FDA-approved, and so the “tail of the curve” - i.e. the line on the graph of patients who survive - is only two years old. Visually, however, when this line is compared to the downward slope of no treatment or treatment with conventional methods, the difference is staggering.² Individual treatments include:

1. Immune System Checkpoint Inhibitors (ICIs), such as the popular monoclonal antibodies anti-PD-1/PD-L1 and anti-CTLA-4. Anti-CTLA-4 activates the immune system by sending more T-cells downstream to join the fight, whereas anti-PD-1/PD-L1 monoclonal antibodies uncloak the veil hiding cancer cells from T-cell elimination
2. Cellular and Gene Therapies, which modulate immune system responses by either sensitizing the antigen presenting cells (APCs) to recombinant proteins that resemble antigens on the surface of cancer cells, or by genetically modifying the T-cells to express chimeric antigen receptors (CAR T-cells) that are capable of identifying and killing cancer cells
3. Oncolytic Caccines are viruses that specifically target and kill cancer cells, which also releases antigens that are picked up by APCs to help activate more T-cells [2]; and
4. SMAC Mimetics, which are small molecules that modify apoptotic response (programmed cell death) in cancer cells.³

Combining cancer immunotherapies holds the most promise for increasing survival rates. When the two ICI therapies are combined, they are highly effective against some forms of cancer; such is the case for the deadly, late-term melanoma example of above. Its success comes from a CTLA-4/PD-1 combinational therapy. Also, many companies are combining oncolytic vaccines and ICIs, and recently SMAC Mimetics have shown synergistic effects with ICIs - neither alone had a profound effect on glioblastoma in mice (the most prevalent form of brain cancer) but combined they eradicated the tumors.³

Despite the high success rate of these treatments, researchers were immediately baffled by a subset of patients who did not respond - or responded negatively - to the treatment. This led researchers to probe the microbiome for answers.

Modulated by the Microbiome?

The human microbiome has been correlated with modulating immunology, neurology, and endocrinology. The scopes of its effects are so broad and complex that many consider it to be the “new organ,” but this is not entirely accurate. The human microbiome is so complex and far-reaching that “organ” might not be the right descriptor. A more appropriate definition of the microbiome is a genomic accessory cloud to the human genome.⁴ When dealing with disease states and the implementation of personalized approaches to managing a disease, the human microbiome is, in many ways, the third point to a triangle of individuation that also includes the genome and the epigenome.

Adverse drug reactions, which cost from $30B to $130B in the USA annually,⁵ have been attributed for years to genomic differences, polymorphisms in the genome that cause differential expression of some proteins, and thereby differential reactions to drugs. Gene polymorphisms causing fatal reactions to anesthetics has been well documented since the 1950s. Cytochrome P450 oxidase (CYP) variants - a series of proteins tasked with metabolizing toxic compounds in the body - are believed to modulate approximately 75% of the patientspecific reaction to drugs.⁴

Some aspects of the microbiome’s effect on drug compounds are well known. For example, some drug compounds rely on gut microbiota to increase bioavailability, especially those with low solubility and poor permeability. The extent, however, of how the transient flora of the microbiome affect treatment didn’t make its appearance until the advent of more personalized approaches to medicine - such as cellular, gene, and immunotherapies. It is perhaps the robustness of immunotherapy treatment that led to the questioning that sparked another gold rush into the microbiome for answers.

Preliminary Results

Although the research is preliminary, and at this stage mostly hypothesis-forming, several strong correlations have surfaced from current research into the interaction between microbiome flora and immunotherapy effectiveness.

Specifically, melanoma patients receiving anti-PD-1 drugs such as Keytruda (pembrolizumab) and Opdivo (nivolumab) had a more pronounced immune response - an increase in immune system cells within the tumors - if they had a more diverse gut flora, or if their microbiome contained a certain species of bacteria, such as Faecalibacterium. Non-responders had a lower microbial diversity in general and different gut flora makeup that had more bacteriodales, five families of environmental bacteria, than responders.⁶

Also, patients who received antibiotics - which are known to alter the microbiome drastically - in the month before immunotherapy treatment with a single ICI or a combination of two ICIs showed decreased responsiveness to treatment. In this group, the diseases progressed faster, and they showed a trend of decreased survival.⁷

Early studies, remarkably, seem to suggest a “pairing system” between a particular immunotherapeutic drug and a bacteria, i.e. “the presence of specific microbial species may determine patient response to a given drug treatment.”⁴ Furthermore, it seems that these relationships may be synergistic but different in nature. For example, “CTLA-4 may rely on bacteria–tumor cross-reactivity, whereas bacteria-induced antigen presentation is probably a key component of PD-L1 efficacy.”⁸ Researchers must better elucidate the microbiota’s mechanisms to comprehend its at times synergistic - and other times obstructive - effects.

Strategic Partnerships Needed

Of the over seven hundred respondents to the 2017 Nice Insight CDMO Outsourcing Survey, 34% noted oncology research as an area of focus. Of the same respondents, 42% indicated a monoclonal antibody (which encompasses some of the most popular forms of cancer treatment) as part of their pipeline, according to the survey. The 2017 Nice Insight CDMO Outsourcing Survey also demonstrated a downward trend in outsourcing biologics from the previous year, which suggests a comfort of in-house productions, and an opening for new exploratory partnerships.⁹

In total, 38% of respondents to the survey rely on an outsourcing partner for the preclinical phase of drug development. Given the preliminary data on the microbiome, finding a strategic partnership with a startup or a company with the capability for assessing and modulating the microbiome may prove fruitful in a highly competitive field of cancer immunotherapy.

Creating a strategic partnership may mean finding a company whose focus is microbiome research, such as Kallyope or The Janssen Human Microbiome Institute. A potential partner may focus on DNA microbiome sequencing to individual clients, and therefore has amassed a library of different microbiota floras, such as uBiome. Another route would be a partnership with a company that has shown the capacity for dynamic developmental solutions for biologics, such as with Catalent or BioVectra. An obvious choice for a partner may be a startup or an established company that attempts to modify the microbiome with pre- and probiotics, such as Ritter Pharmaceuticals, MicroBiome Therapeutics LLC, ViThera Pharmaceuticals, and Osel; or perhaps a company like Metabiomics Corporation, which attempts to modulate cancer microenvironments by directing an immune response to the cancer site using microbes.

In fact, such partnerships have already started to happen. For example, Evelo Biosciences has partnered with the Mayo Clinic to expand their library of cancer-associated bacteria by analyzing the microbiome of patient stool samples and comparing it to the tumor biopsies.¹⁰ In 2016, Evelo merged with Epiva, a startup that made its mark by developing therapeutics that exploit interactions between the microbiome and the immune system.

Because the microbiome is complex, transient and dynamic, a “cloud” of genetic material accessorizing the human genome (and epigenome), finding a solution at the level of therapeutic will no doubt take time and increased R&D, in this very exciting direction.

References

1. “Immunotherapy Drugs Market worth 201.52 Billion USD by 2021.” Markets and Markets. Jan. 2017
2. O’Donnell-Tormey, Jill. “Immunotherapy: Revolutionizing Cancer Treatment.” Focused Ultrasound Foundation. January 18, 2017. Webinar
3. Beug, Shawn T., Caroline E. Beauregard, Cristin Healy, Tarun Sanda, Martine St-Jean, et al. “Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma.” Nature Communications 8 (2017).
4. Kuntz, Thomas M., and Jack A. Gilbert. “Introducing the Microbiome into Precision Medicine.” Trends in Pharmacological Sciences 38, no. 1 (2017): 81-91.
5. Chan, Agnes L.f., Haw Yu Lee, Chi-Hou Ho, Thau-Ming Cham, and Shun Jin Lin. “Cost evaluation of adverse drug reactions in hospitalized patients in Taiwan: A prospective, descriptive, observational study.” Current Therapeutic Research 69, no. 2 (2008): 118-29.
6. Melao, Alice. “Gut Bacteria Tied to Cancer Immunotherapy Response in Melanoma.” Melanoma News Today. February 28, 2017. Web.
7. Mulcahy, Nick. “Antibiotics May Impair Cancer Immunotherapy.” Medscape. 13 Feb. 2017. Web.
8. Tsilimigras, Matthew C. B., Anthony Fodor, and Christian Jobin. “Carcinogenesis and therapeutics: the microbiota perspective.” Nature Microbiology. February 22, 2017.
9. The 2017 Nice Insight Contract Development and Manufacturing Survey.
10. Adams, Ben. “Evelo, Mayo Clinic team up to use bacteria for cancer immunotherapies.” FierceBiotech. August 02, 2016. Web.