Limiting protein intake may enhance response to immunotherapy

Restricting protein intake may improve responses to immunotherapy, according to study results published in Clinical Cancer Research.

Roberto Pili, MD, Robert Wallace Miller professor of oncology and professor of oncology and urology at Indiana University School of Medicine, and researcher at Indiana University Melvin and Bren Simon Cancer Center, and colleagues previously determined limiting protein in the diets of mice with breast cancer and prostate cancer slowed tumor growth.

In their most recent investigation, conducted in animal models of prostate cancer and renal cell carcinoma, Pili and colleagues determined that reducing protein intake among mice from 20% — the usual amount for humans — to 10% improved their responses to immunotherapy.

The protein restriction altered tumor-associated macrophage activity and enhanced tumoricidal capacity, significantly reducing tumor growth, according to researchers.

This research will serve as the foundation for a clinical trial at IU Simon Cancer Center for men with prostate cancer who are receiving immunotherapy. Pili will serve as principal investigator.

H emOnc Today spoke with Pili about the results of his team’s early research, how the first-in-human trial will be conducted, and the potential implications if preliminary findings are confirmed.

Question: Can you elaborate on the impact of protein restriction in animal models?

Answer: We saw a significant change in macrophages, which are a cell type involved in the innate immune system. Macrophages are very important for fighting infection in cancer. Good macrophages are called M1 phenotypes, and bad are called M2. In our most recent study, conducted in mouse models of prostate or kidney tumors, we saw good macrophages increase when we restricted protein in the diet and bad macrophages decrease. More importantly, when we restricted protein in the diet of the mice, we enhanced the effect of immunotherapy. We also saw an increase in T-cell infiltration and activation, and we saw some change in the microbiome, the bacteria in the gut.

Q: Did the results surprise you?

A: When we published the initial paper in 2013, I was in shock seeing the results of the protein restriction — specifically how just changing the amount of protein could have such a dramatic effect on these mice in terms of tumor growth. The study also dealt with source of protein, coming either from animal protein — like casein — or from soy, like plant-based protein. Plant-based protein definitely had a slowdown effect on tumor growth, whereas casein was almost accelerating tumor growth. That was an eye-opener, and that's why we pursued this current line of research.

Q: What are possible explanations for the results?

A: We believe that amino acids are important for regulating the growth of tumor cells and also the function of immune cells. We replicated the effect of protein restriction in different cells by restricting methionine, so changing just one essential amino acid showed a significant effect on macrophage function. I would say the No. 1 explanation is the availability of these essential amino acids because they can dramatically affect the tumor cells’ biology and, more interestingly, the biology of the immune cells. This could be a direct effect because the cells need amino acids and proteins to survive. The indirect effect may be through the microbiome. The diet can affect the bacteria in the gut and, by doing so, the bacteria in the gut can affect the immune system. It’s a very complex interaction, but it is quite fascinating.

Q: Can you provide an overview of the first-in-human trial set to open at IU Simon Cancer Center ?

A: This trial will include men with metastatic castration-resistant prostate cancer. These patients went through hormonal therapy, they had disease in their lymph nodes and bones. They are candidates for sipuleucel-T (Provenge, Dendreon), an FDA-approved vaccine therapy and, to date, the only immunotherapy approved for prostate cancer. We are going to divide 30 patients into two groups. Fifteen patients will be randomly assigned to receive the normal 20% protein content in their diets, and 15 patients will receive only 10%. The treatment phase will last about 6 weeks, during which time participants will receive meals prepared by a nutritionist. The goal is to see whether the dietary change may impact immune response. This is a pilot study, so we don’t expect it to be able to have efficacy data, but we are going to monitor the response to the PSA, and we’re going to monitor change in bone scans. We are going to look at whether it is feasible to provide these meals to patients for 7 weeks, and we are going to monitor the protein uptake. We have a blood test to measure how much protein these patients are consuming, and we also will look at immunological parameters.

Q: What are the potential benefits if protein reduction is proven to increase efficacy of immunotherapy?

A: This has really opened a new frontier for us to look more closely at the effect of diet. A lot of researchers believe patients with cancer need a high-protein diet in order to avoid muscle wasting. This is an important consideration, but we also want to start discussing the possibilities of new approaches to diet intervention. Things have to be tailored to the type of disease, stage of the disease and the type of therapy the patient is receiving. I think a healthy diet — not just to prevent cancer, but to help patients go through treatment —will become a standard of care in the future.

Q: What should doctors keep in mind when restricting protein intake for people with cancer ?

A: Right now, a dietary protein restriction should be done within a clinical trial because we still need to learn the feasibility and exactly how this may affect the immune system. Outside of a clinical trial, I would not necessarily recommend protein restriction at this point. What I would recommend is to limit the amount of animal protein and transition to a vegetative type of diet. I also would recommend reducing dairy consumption. We need to focus on how diet, nutrition and exercise can impact our patients with cancer while they are receiving therapy. – by Joe Gramigna

Reference :

Orillion A, et al. Clin Cancer Res. 2018;doi:10.1158/1078-0432.CCR-18-0980.

For more information:

Roberto Pili, MD, can be reached IU Simon Cancer Center, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202; email: rpili@iupui.edu.

Disclosures: Pili reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.