Three recent articles in Science discuss how the composition of the gut microbiome affects anti-PD-1 therapy for the treatment of melanoma, metastatic melanoma, and epithelial tumors, further bolstering the idea of gauging immunotherapeutic efficacy based on one’s microbiome composition.  We first reviewed this concept in Part VIII of The Emergent Microbiome Series and are revisiting it here.  Bolded patent documents are further summarized in the table at the end of this installment.

To recap, immune cells called T cells contain various checkpoint proteins that either activate or inhibit an immune response.  Immune checkpoint inhibitors are those proteins that act as the “off switch” to prevent T cells from initiating a constant immune signal.  By turning off these immune checkpoint inhibitors, an immune response can be initiated.

Immunotherapies essentially harness the body’s own immune system to fight disease.  The most well-known immune checkpoint inhibitors are the PD-1 receptor, the PD-1 receptor cognate ligand PD-L1, and CTLA-4.  Many of the drugs that target these proteins are monoclonal antibodies and include Keytruda® (pembrolizumab), Yervoy® (ipilimumab), and Opdivo® (nivolumab).  However, as mentioned in Part VIII, 60-80% of patients do not respond to these therapies.  Previous scientific and patent data suggest that clinicians can predict those patients who will best respond to immunotherapy based on his/her microbiome composition.  Furthermore, a patient’s microbiome can be altered in order to make immunotherapies more efficacious.

In the first Science article, melanoma patients with a “favorable gut microbiome” consisting of Faecalibacterium and Ruminococcaceae responded better to anti-PD-1 therapy than those patients without the above-mentioned bacteria.  In the second Science article, metastatic melanoma patients that responded to anti-PD-1 therapy had a more diverse microbiome, particularly with a higher abundance of intestinal Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium.  This work was performed by Thomas Gajewski from The University of Chicago, whom we mentioned in Part VIII of the Series.  He filed patent US9855302, which claims the methods of treating cancer with a combination of immune checkpoint inhibitor as well as a bacterial formulation containing Bifidobacterium.

In the third article, increased levels of intestinal A. muciniphila correlated with improved efficacy of anti-PD-1 therapy in patients with kidney and lung cancers.  This work was led by Laurence Zitvogel of Institut Gustave Roussy, whom we mentioned in Part VIII of the Series.  Zitvogel filed patent application EP3012270, which discloses a combination of a therapeutic targeting an immune checkpoint protein and an antibiotic.  Specifically, this refers to an anti-CTLA-4 antibody and an antibiotic from either the penicillin or vancomycin groups.  The antibiotic would act to modulate the gut microbiota and increase the efficacy of the CTLA-4 antibody.  The patent also claims a combination of a therapeutic targeting an immune checkpoint protein and a probiotic consisting of Bacteroides, which would also act to potentiate the efficacy of the CTLA-4 antibody.  Zitvogel also filed patent application US20160303172, which discloses methods to determine if a patient has gut dysbiosis and, furthermore, will benefit from cancer treatment.  The application also discloses the use of probiotics to improve the efficacy of cancer treatments.  Although the application specifically refers to chemotherapy, it also includes immunotherapies.  Interestingly, there were originally a total of 63 claims in the application but the first 48 claims were cancelled.  The remaining claims do not refer to methodologies for determining whether a patient has dysbiosis.  Furthermore, the claims disclose the administration of a probiotic as a method of directly treating cancer, not improving the efficacy of anticancer treatments.  Patent application US20170143780 from Zitvogel discloses a combination of an oncolytic virus and an immune checkpoint modulator.

Although the above-mentioned patents refer to combinations of immunotherapies and microbiome modulators, we wanted to also mention single agent microbiome modulators for treating various diseases, which was covered in Part IX of The Emergent Microbiome Series.  Patent application US20160220619 discloses methods of diagnosing and treating cancer via manipulation of the microbiome.  Specifically, this includes administration of a probiotic for the treatment of estrogen-related or estrogen-sensitive cancers.  Patent application US20170258854 claims the use of bacteria in the prevention or treatment of graft-versus-host disease.

It is important to note that many companies are pursuing modulation of the microbiome for therapeutic purposes, which is an area of significant financial, legal, and medical importance that we have reviewed here.  We are just scratching the surface of this exciting area of research.  The patent filings described above further suggest that intellectual property protection is a vital part of the research efforts in this burgeoning field.

 

Patent Number Inventor Assignee Title Issue or Publication Date
EP3012270 Laurence Zitvogel, Marie Vetizou Institut Gustave Roussy Products for modulating microbiota composition for improving the efficacy of a cancer treatment with an immune checkpoint blocker Apr 27, 2016
US20160220619 Delphine J. Lee, Caiyun Xuan Harbor-UCLA Medical Center Research and Education Institute Inc Methods of diagnosing and treating cancer by detecting and manipulating microbes in tumors Aug 4, 2016
US20160303172 Zitvogel et al. Institut Gustave Roussy Microbiota composition, as a marker of responsiveness to chemotherapy, and use of microbial modulators (pre-, pro- or synbiotics) for improving the efficacy of a cancer treatment Oct 20, 2016
US20170143780 Zitvogel et al. Institut Gustave-Roussy, Transgene Sa Combination of oncolytic virus with immune checkpoint modulators May 25, 2017
US20170258854 van den Brink et al. Memorial Sloan-Kettering Cancer Center Intestinal microbiota and gvhd Sept 14, 2017
US9855302 Gajewski et al. University of Chicago Treatment of cancer by manipulation of commensal microflora Jan 2, 2018

–David Puleo and Anthony D. Sabatelli, PhD, JD

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