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Could the Gut Microbiome Be One of the Missing Links in Cancer Immunotherapies?

“Our vision for Xpomet© Medicinale Festival is to connect all important key stake holders in next-generation healthcare and allow technologies to be translated within and from outside the healthcare field”

Xpomet© founder, Ulrich Pieper

Immunotherapy has become a revolution in the area of cancer treatment. Compared to traditional methods, such as invasive surgeries, radiation and chemotherapy, immunotherapy is more specific and less toxic to patients.

Immunotherapy treatments work by unleashing the immune system’s ability to fight cancer. These treatments can either activate or suppress certain branches of the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Together, they are offering a promising new avenue through which doctors can potentially improve outcomes for patients with advanced cancer.

The history of immunotherapy is rather long and a variety of strategies are in use now or are undergoing research and testing. To give just a few examples, one of the first remarkable immunotherapies was the CAR-T cell therapy, which stands for Chimeric Antigen Receptor-engineered T cell therapy, developed in 1989 by Gideon Gross and Zelig Eshhar at Weizmann Institute, Israel. CAR-T cell therapy uses T cells that have been genetically engineered to produce an artificial T-cell receptor which programs them to target an antigen that is present on the surface of tumours (1). For safety, CAR-T cells are engineered to be specific to an antigen expressed on a tumour that is not expressed on healthy cells, otherwise this kind of therapy would create havoc in the body. Instead, it is beautifully personalised and targeted.

The premise of CAR-T immunotherapy is to modify T cells to recognise cancer cells in order to more effectively target and destroy them. Scientists harvest T cells from patients, genetically alter them, then inject the resulting CAR-T cells into patients to attack their tumours. CAR-T cells can be derived either from T cells in a patient’s own blood or from the T cells of another healthy donor. There is great potential for this approach to improve patient-specific cancer therapy in a profound way, since CAR-modified T cells can be engineered to target virtually any tumour associated antigen.

According to a letter published in Nature Medicine last year (2), another promising development in this area is an immunotherapy approach that involves naturally-occurring tumour infiltrating lymphocytes (TILs) found at the site of an individual’s cancer. Lymphocytes, also called white blood cells, are a type of immune cells that are made in the bone marrow and are found in the blood and in lymph tissue. The two main subtypes of lymphocytes are B lymphocytes (which make antibodies) and T lymphocytes such as natural killer cells that are supposed to attack tumours as they develop and help control immune responses.

The aforementioned letter from Nature Medicine describes the case of a woman with advanced metastatic breast cancer who was given only a few months to live, after previously receiving several treatments (hormone therapies, chemotherapy) that did nothing to stop the cancer progression. But this dire prognosis was completely reversed when TILs were extracted from the patient’s tumour, grown outside of her body to boost their numbers and then injected back into the patient to tackle the cancer, leading to complete disappearance of all tumours and remission 22 months after treatment. Behind this new therapy are the scientists at the National Cancer Institute (NCI) and their spokesperson, Steven A. Rosenberg, M.D., Ph.D.

In contrast to CAR-T cell therapy, TILs-based immunotherapy develops the patient’s own lymphoblasts into treatments. These are natural T-cells, not genetically engineered. This is a very elegant solution and a highly personalised form of treatment: the T cells are “trained” to target the unique, patient-specific mutations found in an individual’s tumours, which are, more often than not, different from another person with the same type of cancer.

This type of immunotherapy has been already successfully applied to other ‘common epithelial cancers’, even at the metastatic stage: colorectal, bile duct and cervical. Other clinical trials are currently underway to target even notoriously hard-to-treat glioblastoma and pancreatic cancer, amongst others.

As promising as this may sound, especially considering the low levels of toxicity patients experience compared to conventional chemotherapies, cancers often develop resistance to these treatments, since metastases may have different mutations than the original tumour.

Why is that? One reason for cancer reoccurrence is theorised to be the state of the “biological terrain” and the tumour microenvironment. The study of the terrain is beginning to gain traction in mainstream cancer research. (3, 4) However, the concept is not new: traditional Chinese medicine (TCM) has viewed the terrain as essential for millennia. 

Thus, integrative oncologists with a focus on the “biological terrain” look at whether or not that biochemistry is balanced or disrupted and therefore inhospitable or hospitable to cancer. The terrain can be described as the internal environment of the human host which in turn influences the tumour microenvironment, which affects the progression or regression of the cancerous tumour. This happens due to the fact that cancer cells don’t exist in a vacuum and do not act alone. They enlist the body’s normal cells, molecules, and blood vessels in their efforts to survive, metastasise, and acquire drug resistance.

Going back to the importance of TILs, these have a secondary role as biomarker. According to Elizabeth M. Jaffee, M.D. from Johns Hopkins University in Baltimore, the presence of tumour-infiltrating immune cells and tumour mutational burden provides insights into whether a tumour is “hot” and likely immunotherapy-responsive, or “cold” and likely resistant to immunotherapy. Dr. Jaffe also talks about other signalling pathways in the tumour microenvironment (TME) that can shut down immune responses and how these might be able to be turned into biomarkers to guide treatment using newer immunotherapies. (5)

But most astonishingly of all, the emerging science of the gut microbiome (which refers to the trillions of bacteria, as well as viruses, fungi, archaea and protozoa that reside in our intestines and skin) shows the tremendous influence that these microbes have on how patients respond to immunotherapy treatment.

The microbiota, which is unique to each individual, can impact both positively and deleteriously on conventional chemotherapy and radiotherapy treatments due to the complex interplay that exists between the host’s microbiota and the host’s immune system, which are in constant communication at a number of anatomical barrier sites, including the skin, respiratory tract and, most importantly, the gut. Resulting from this cross-talk are multiple effects on how an individual’s immune system will respond to cancer treatments. (6)

To give just a few examples, Fusobacterium nucleatum, an anaerobic bacterium usually found in the oral cavity, is over-represented in the colons of patients with colorectal cancer. Cancers with high amounts of F. nucleatum are associated with a poor prognosis (7). On the other hand, a number of Gram-positive bacteria including Lactobacillus bestow anti-cancer qualities in the chemotherapy setting (8).

As a result, proactive strategies to beneficially modulate cancer patients’ microbiomes are now being explored in clinical trials. By manipulating the microbiome’s composition, there will be a possibility to modify susceptibility to illness as well as sensitivity to the therapeutic or toxic effects of various immunotherapy treatments, offering new clinical opportunities for precision medicine (9).

Cancer immunotherapy is undoubtedly a promising area of research that may contribute towards the eradication of this chronic disease in the near future. To fuel its advancement, better tools and technologies are needed that enable doctors and scientists to better understand the relationship between a tumour and the immune system, such as the “the cancer-on-a-chip” model developed by Dan (Dongeun) Huh, Ph.D., of the University of Pennsylvania, who in 2017 received a $1 million grant to develop a microchip-based research model that mimics human cancer and immune cell interactions, a technological innovation that has the potential to accelerate the development of effective immunotherapies across different types of cancer.  Furthermore, the importance of collaborations between nonprofit, academic, and biotechnology/pharmaceutical industry partners, couldn’t be overemphasised. To this effect, events like Xpomet/Medicinale could serve as a fertile ground in bringing all the key thinkers, researchers and biotech startups in this field together, connecting all important key stake holders in next-generation healthcare and allowing technologies to be translated within and from outside healthcare field.

We look forward to greeting you at our exciting forum at the upcoming Xpomet© Medicinale Festival to take place between 10–12 October 2019 in Berlin.

REFERENCES

(1)  Miliotou ANPapadopoulou LC   (2018) CAR T-cell Therapy: A New Era in Cancer Immunotherapy. Curr Pharm Biotechnol.;19(1):5-18

(2)  Zacharakis, N. et al (June 4, 2018). “Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer”. Nature Medicine volume 24, 724–730 

(3) Quail D, Joyce J. Microenvironmental regulation of tumor progression and metastasis. Nature Medicine, 2013 Dec 1;19(11), 1423–1437.

(4) Wang M, Zhao J et al. The role of the tumor microenvironment in tumorigenesis. Journal of Cancer 2017; 8(5):761-773.

(5) Chen, Gang & M. Jaffee, Elizabeth & Emens, Leisha. (2013). Immunotherapy and Cancer Therapeutics: A Rich Partnership. Cancer Immunotherapy: Immune Suppression and Tumor Growth: Second Edition. 415-432. 10.1016/B978-0-12-394296-8.00025-7 via ResearchGate

(6)  Science in Focus: The Microbiome and Cancer Therapy

Alexander, J.L. et al., Clinical Oncology , Volume 31 , Issue 1 , 1 – 4

(7) Mima K, Nishihara R, Qian ZR, Cao Y, Sukawa Y, Nowak JA, et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut 2016;65(12):1973e1980. [5] Yu T, Guo F, Yu Y, Sun T, Ma D, Han J, et al. Fusoba

(8)  Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013;342(6161):971e976.

(9)  Liu, K., & Lu, C. (2018). Gut microbes modulate host response to immune checkpoint inhibitor cancer immunotherapy. Translational cancer research7(Suppl 5), S608–S610. doi:10.21037/tcr.2018.05.37