By David Puleo* and Anthony D. Sabatelli** --
Given that the majority of the human microbiome is found in the gut, it is not surprising that most microbiome-based therapeutic approaches have been used to treat gastrointestinal disorders, such as inflammatory bowel disease (IBD) and Clostridium difficile infections. However, growing evidence suggests that targeting the microbiome can have broader therapeutic implications, demonstrating the ever-evolving nature of the microbiome field. Specifically, microbiome modulators could be used to either enhance or suppress the immune response and would thus be considered immunotherapy. Part VIII of this Series reviewed how altering the microbiome could be used in combination with checkpoint blockade. As a continuation to Part VIII, this article will explore how microbiome modulators could be used as single agent immunotherapy to treat autoimmune disease, inflammatory disease, and cancer. Bolded patent documents are further summarized in the table at the end of this installment.
Microbiome-based Immunotherapy to Treat Cancer
Altering the microbiome to treat cancer is not a new idea. William Coley, a New York surgeon, administered streptococcal cultures to sarcoma patients. Later known as 'Coley's toxin', these cultures caused tumor regression. Similarly, an attenuated form of Mycobacterium bovis, bacillus Calmette-Guérin (BCG), is an FDA-approved immunotherapy for the treatment of bladder cancer and has also been used to treat melanoma. Originally developed as a vaccine against tuberculosis, BCG is delivered directly to the bladder and stimulates a local immune response at the site of the cancer. See patent application US20150071873 regarding a modified BCG therapy.
Several other patent documents reflect this effort to modulate the microbiome in order to elicit an anti-cancer immune response. PCT patent application publication WO2008099001 refers to the administration of bacteria that have been modified to contain a gene encoding a therapeutic that would act to diminish leukocytes, resulting in a reduction in solid tumor size. Patent US7981651 discloses Lactobacillus strains that would contain a gene encoding a protein with "oxalate degrading activity". A known component of kidney stones, oxalate has also been shown to induce production of reactive oxygen species as well as induce breast cancer. Interestingly, both methodologies from the above-mentioned WO2008099001 and US7981651 documents could prove effective in not only altering the microbiome composition in order to modify the immune response but could also allow for delivery of multiple tumor-targeted therapies. Also, both tumor therapies (gene products) can be produced using an inducer molecule, which would allow for exquisite control over dosing.
Patent US9320787 is directed to administration of attenuated or fully inactive Escherichia coli in order to treat colon cancer. The E. coli would be administered at a site distant from the tumor and induce monocyte activation. Patent application US20160228523 refers to the use of inactive gram-negative bacteria, such as Salmonella or Escherichia, in order to treat various types of cancers, including carcinomas, lymphomas, and sarcomas, and inhibit tumor growth and metastasis. The patent also discloses combination therapies with checkpoint inhibitors.
Patent application US20140348792 discloses the administration of a strain of the gram-positive bacterium Lactobacillus acidophilus that lacks a gene that is necessary for production of lipoteichoic acid (LTA), an essential component of the cell wall that elicits a pro-inflammatory response in the human body. Conditional knockout mice displaying pre-cancerous colonic polyps were treated with both wild-type and LTA-deficient L. acidophilus. Those mice treated with the latter displayed decreased colonic inflammation, indicating that the LTA-deficient L. acidophilus strain may have anti-inflammatory effects [Proc. Natl. Acad. Sci. USA 109, 10462–10467 (2012)]. The claims of the patent also recite the combination of the LTA-deficient L. acidophilus strain with a second probiotic bacterium in order to induce colon cancer regression.
Microbiome-based Immunotherapy to Treat Autoimmune and Inflammatory Diseases
Patent documents US20160193257, US9415079, US9421230, and US9433652 refer to the use of Clostridium spores to induce production of regulatory T cells (Treg) and were filed by Kenya Honda of RIKEN Center for Integrative Medical Sciences in Japan. Honda's work is featured in such high-profile journals as Cell, Nature, and Science. Particularly, he discovered that secretion of the chemical butyrate by Clostridia induces Treg production [Nature 504, 446–450 (2013)], which is the basis for the aforementioned patents. Honda is also co-founder of Vedanta Biosciences (PureTech Ventures). Of note, Vedanta is also co-founded by Ruslan Medzhitov, Professor of Immunobiology at Yale University. Vedanta claims to have both microbiome modulators that attenuate the immune system, e.g., which could be used to treat autoimmune disorders, as well as those which enhance immune response, e.g., which could be used to treat cancer. Vedanta's lead "compound", VE202, is a 17-strain Clostridia cocktail that induces Treg production and would be used to treat IBD as well as graft-versus-host disease. A similar patent application, WO2016102950, refers to the use of a Bacteroides strain for treatment of autoimmune and inflammatory disorders by modulating immune responses via increased Treg production.
The Future of Microbiome Research
Current research has established a link between the host patient microbiome composition and various disease states, such as psoriasis, asthma, and cardiovascular disease. However, the key question of association versus causation is still up for debate, i.e., whether changes in the microbiome are causative of disease or changes caused by disease influence the microbiome. Although this cause-and-effect relationship is still somewhat unclear, targeting the microbiome still has wide therapeutic implications. For this reason, the pharmaceutical industry is starting to take notice. Johnson & Johnson, Roche, and Pfizer, to name a few, are collaborating with smaller biotechs that have made the microbiome their niche. For example, the Johnson & Johnson-owned Janssen Pharmaceuticals is licensing Vedanta's proprietary technology with reported payments of up to $339 Million. The data generated out of such collaborations will undoubtedly contribute to better understanding of the microbiome as a whole and, furthermore, will aid in the ability to further manipulate the microbiome for therapeutic purposes.
* David Puleo is a Ph.D. Candidate in the Pharmacology Department at Yale University. Prior to attending Yale, David graduated from Boston College with a B.S. in Biochemistry, after which he worked for two years in the Center for Proteomic Chemistry at Novartis Institutes for BioMedical Research in Cambridge, MA.
** Dr. Sabatelli is a Partner with Dilworth IP
For additional information regarding this topic, please see:
• "The Emergent Microbiome: A Revolution for the Life Sciences -- Part VIII, The Microbiome and Immunotherapy I," October 31, 2016
• "The Emergent Microbiome: A Revolution for the Life Sciences -- Part VII, The Microbiology of the Built Environment," October 5, 2016
• "The Emergent Microbiome: A Revolution for the Life Sciences – Part V, Patents Relating to Obesity and Metabolic Disorders," February 28, 2016
• "The Emergent Microbiome: A Revolution for the Life Sciences – Part IV, Obesity and other Metabolic Disorders," February 18, 2016
• "Jackson Laboratory Hosts Microbiome Symposium Related to Cancer and Immunology," January 19, 2016
• "The Emergent Microbiome: A Revolution for the Life Sciences – Part III, Psychobiotics," October 13, 2015
• "The Emergent Microbiome: A Revolution for the Life Sciences – Part II, 2015 Patent Trends," August 11, 2015
• "The Emergent Microbiome: A Revolution for the Life Sciences – Part I, R&D Leaders," August 10, 2015