1. Goodwin, Peter M.

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MILAN-Immunity stimulated by gut bacteria emerged as a key factor influencing the effectiveness of immune therapies for cancer in research reported at the 2019 European Society for Radiotherapy and Oncology (ESTRO) conference (Abstract SP-0333).

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"The immune system can potentially cure any cancer," said Marianna Nuti, PhD, from the University of Rome "La Sapienza" Department of Radiological, Oncological & Pathological Sciences. "The immune system can see antigens and the products released by the tumor cells. And [since] the novel therapies are immunotherapies, this has become a very important link."


She reported her new data showing that nivolumab seemed to influence microbiome composition during checkpoint inhibitor treatment for non-small cell lung cancer. The researchers concluded there was a "significant role of specific gut microbiota bacteria in influencing cancer development and response to immunotherapy" (J Clin Oncol 2018; doi:10.1200/JCO.2018.36.15_suppl.e15020).


According to Nuti, the implication was that patients with non-small cell lung cancer failing to respond to immune checkpoint inhibitor therapy with nivolumab had the potential to become responders if they received therapies that changed their microbiota.

Marianna Nuti, PhD. ... - Click to enlarge in new windowMarianna Nuti, PhD. Marianna Nuti, PhD

Examining the Microbiome

"Microbiome is important because it is linked to the immune system," Nuti told Oncology Times. And she said antibiotic therapy impacted cancer treatment because it changed the microbiome. "Therefore, we have to think when we treat our children, for example, with [unnecessary] antibiotics. Sometimes we are changing their microbiota and their capacity to respond to pathogens because they are linked to immunity. And [it's] the same with cancer and with other drugs."


Nuti described how her immunological research and the emerging understanding about the way gut bacteria stimulated immunity showed this could be harnessed for cancer treatment.


"The immune system is tailored [to] the kind of pathogens that we see during a lifetime, the kind of treatment, or the diet. Microbiota is in the middle of this and can change or modify or modulate immunity," she explained.


She believes it is necessary to understand how to keep T cells active by methods such as vaccination. They needed to be "primed" and ready to make use of therapies like immune checkpoint inhibition.


Further Research

Nuti was encouraged by research from France and the U.S. using transplants of microbiome into mice recipients with depleted microbiomes who were given tumor cells and then treated with immunotherapy.


"The mice that received microbiome from responder patients were able to respond to the therapy. So that means the microbiome impacted the capacity of the mice to reject the tumor challenge."


Her center made gut microbiome a clinical priority. "We've been working on microbiota as part of the immune monitoring we do routinely to our cancer patients undergoing immunotherapy," Nuti noted. Microbiota was regarded as just as important as other metrics, such as the numbers of responding lymphocytes and tumor genomics.


"At this point, microbiota is a biomarker of response. And we [understand] this better. But I think that in the future [we'll be] starting to see that responder patients can be selected from the beginning because they have a certain microbiota," she said.


Changing the Microbiome

Nuti was asked whether non-response to a therapy could be overcome by manipulating the microbiome, and if this could make checkpoint inhibitor treatments like anti-PD-L1 therapy more viable? She said it could.


Low intestinal microbial diversity had been found to be associated with severe immune-related adverse events and lack of response to neoadjuvant combination anti-PD1, anti-CTLA4 immunotherapy in research reported at the 2019 American Association for Cancer Research Annual Meeting. Along with a body of other research, this supported the use of microbiome manipulation in cancer treatment (Abstract 2822/8).


"We still have a lot of patients who do not respond to PD-L1 therapy and we need to work on those patients," said Nuti. Fecal microbiota transplants were being used to transfer immunity, but in the future, she noted there could be other methods.


"We can narrow down and maybe be more selective and find something more precise. Microbiome transplantation is a broad transplantation of several bacteria. Maybe we should decide which are the bacteria that we could use and select them.


"The large banks of different kinds of bacteria [help us] to see what kind of bacteria are missing in [a] patient. [So] maybe we can adjust that microbiota by diet, by probiotics, or by selecting bacteria, or bacteriophages, that can kill selected bacteria within the gut of that patient," she explained.


Health Care Collaboration

It's important for experts from different disciplines to work together to generate the optimum approach to harness the power of the microbiome in fighting cancer. "We need to work on that, because otherwise it's too complicated to give it to all patients. What I can say is that we know which are the good diets very well. We know what to avoid. We know already. The Mediterranean: olive oil, the fibers, not too much alcohol. Those good habits-we know them."


Although antibiotics could cause harm, Nuti said they were clearly beneficial when needed. But other drugs commonly prescribed as part of overall treatment packages should also be viewed with more caution because of their potential impact on the microbiome.


"Sometimes patients come in to the doctor and already have a list of drugs that they are taking-without much reason. And this can affect their microbiome and their immunity."


She recommended that more consideration be given to individualizing therapy on the basis of the patient's immunity and the factors that influence it. "Certain symptoms-that [seem] not so important-become important. For example, dietary habits or the way patients live and their performance status. We have to pin down exactly what are the most important features.


"[Microbiome] is one of our organs and it builds up during a lifetime. When we are born, we don't have the same microbiome as the one that we have when we are adults or when we are older," said Nuti. "It builds up with our life and our lifestyle."


Peter M. Goodwin is a contributing writer.