Emerging Data Concerning Modifiable Host Factors and Immune Responses Fuel Discussion

Jennifer A. Ligibel, MD

Jennifer A. Ligibel, MD

There is a growing theory among researchers that modifiable host factors can influence immune responses to malignancies. Historically, tumor-intrinsic features and the immune microenvironment have been the focus of research to determine what factors induce response or cause resistance. The role the host plays and how it affects tumor biology and anti-tumor immunity and outcomes was the subject of this year’s Hot Topic Symposium during Society for Immunotherapy of Cancer’s 34th Annual Meeting & Pre-Conference Programs (SITC 2019).

In particular, this year’s symposium, co-chaired by Jennifer A. Ligibel, MD, director of the Leonard P. Zakim Center for Integrative Therapies and Healthy Living at the Dana-Farber Cancer Institute and Jennifer Mcquade, MD, MS, MA, assistant professor, Department of Medical Oncology at The University of Texas MD Anderson Cancer Center, focused on modifiable factors that can affect tumor response to treatment.

“It is amazing to think that we might be able to improve the effectiveness of treatment by altering factors in the host,” Ligibel, who is also an associate professor of medicine at Harvard Medical School, said in an interview before the symposium.

Those modifiable factors involve dietary fiber intake and the microbiome, obesity, and exercise, and have direct relevance to patients with cancer, said co-chair McQuade.

Jennifer Mcquade, MD, MS, MA

Jennifer Mcquade, MD, MS, MA

She pointed out that even in cases of melanoma, in which immunotherapy has the highest response rates, “the odds are still even as far as whether patients respond or don’t respond to treatment.” So patients often ask their physicians directly: “Is there something else that I can do that might augment response?”

Early Stages

Both Ligibel and McQuade noted that the research involving these modifiable factors are very preliminary. McQuade, who will be presenting on fiber and the microbiome, will emphasize that the current evidence suggests that patients with a diet high in fiber from fruits, vegetables, and whole grains have more of the bacteria in the gut microbiome that have been associated with response to immunotherapy. This makes biological sense given a known role of these bacteria in fiber digestion and prior work demonstrating that their downstream metabolites can influence immunity.

McQuade said the next steps in research involving diet and the microbiome will need to demonstrate causality. “We need to show that changing diet can change outcomes with immunotherapy,” she said. “Right now, we have plausible biology, we have epidemiological correlations, and we have emerging preclinical data. What’s next are interventional studies prospectively examining the ability of diet change to modulate the microbiome and immunity.”

Ligibel expects the Hot Topic session to focus primarily on observational studies in humans, as well as animal models, although she noted that data related to the microbiome and immune checkpoint inhibitors are a bit more advanced.

“This area of research is emerging,” Ligibel said. “There are certain patterns that are starting to become clear, but we’re in the early stages of understanding the relationship between host factors and treatment outcomes in patients who are being treated with immune checkpoint inhibitors.”

For patients undergoing treatment for melanoma with immune checkpoint inhibitors, as well as other malignancies, such as renal cell carcinoma and lung cancer, “there is a relationship between the gut microbiome and the response to immune checkpoint inhibitors,” Ligibel said. Research focused on the diversity of the gut microbiome and the dominating species in that environment have garnered increasing interest.^1,2,3

“Some research has suggested that diets that are higher in fiber are associated with patterns of gut microbiota that appear to have a greater likelihood of response,” said Ligibel.

Ligibel said that researchers have looked at animal models and found that taking a stool sample from a “human patient who is not responding to immunotherapy, and transplanting that sample into a mouse model reduces the likelihood that the mouse will respond to immunotherapy. Similarly, if you take a sample from a human who is responding and transplant that to a mouse, the mouse’s tumor will be more likely to respond.” One such study found that stool samples from patients who had responded to PD-1 blockade conferred a response to PD-1 blockade in mice who received the transplanted sample, whereas transplanted stool from patients who were resistant to PD-1 blockade therapy did not.^4,5

Other talks in the Hot Topic Session will focus on the relationship between body weight and response to immune checkpoint inhibitors and data from animal models indicating that exercise could enhance immune responses.

“In this situation, there’s some evidence, though it’s not consistent, that heavier patients are more likely to respond to immunotherapy agents,” Ligibel said. Some theories suggest that there is some suppression of immunity in patients who are heavier, she said. McQuade added that pre-clinical evidence will be presented showing that this immunosuppression may actually paradoxically render obese individuals more responsive to immune checkpoint inhibition which can target and overcome the immune dysfunction.

“Exercise has been demonstrated to have an effect on circulating immune markers. Data from animal models have also suggested that exercise may be able to enhance tumor immunity,” said Ligibel. For example, Koelwyn and co-workers suggested that exercise could serve as an adjunctive strategy to improve the immune system, which could favorably affect tumorigenesis.⁶

In conclusion, from a patient care perspective, “we need to consider the person that the tumor resides in,” said McQuade, “because that will affect tumor response as well. We’re going to hear about some provocative early data demonstrating that it might have an influence.”

Although the science is still emerging, Ligibel said, “This is clearly a new area of investigation, but I think this is an exciting new avenue within immuno-oncology.”

References

1. Roy S, Trinchieri G.Microbiota: a key orchestrator of cancer therapy.Nature Reviews Cancer.2017; 17:271—285.
2. Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti—PD-1 immunotherapy in melanoma patients.Science.2018;359(6371):97-103. doi: 10.1126/science.aan4236.
3. Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA- 4 blockade relies on the gut microbiota.Science.2015;350(6264):1079- 1084. doi: 10.1126/science.aad1329.
4. Biancheri P, Divekar D, Watson AJM. Could fecal transplantation become part of PD-1-based immunotherapy, due to effects of the intestinal micro- biome?Gastroenterology.2018;154(6):1845—1847.
5. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1—based immunotherapy against epithelial tumors.Science.2018;359(6371):91-97. doi: 10.1126/science.aan3706.
6. Koelwyn GJ, Wennerberg E, Demaria S, Jones LW. Exercise in regulation of inflammation-immune axis function in cancer initiation and progression.Oncology (Williston Park).2015;29(12):908-20, 922.