Nurse-Led Research Links Saturate Fatty Acids to Improved Immunotherapy Responses in NSCLC

Julie Malo, CCRP, a research nurse with the University of Montreal, discusses a nurse-directed initiative examining how the gut microbiome affects immune checkpoint blockade responses in patients with non–small cell lung cancer.

A saturated fatty acid diet, but not a high-fiber diet, may be linked to superior outcomes in patients with non–small cell lung cancer (NSCLC) receiving immunotherapy checkpoint blockade (ICB), according to Julie Malo, CCRP.1 However, the mechanisms between colon epithelial integrity and immune responses are not well understood and further strategies to use the microbiome as adjuvant therapy are warranted, she added.

Malo, who is a research nurse at the University of Montreal, presented findings from a nurse-led dietary intervention at the European Society of Medical Oncology Congress 2022. Immunotherapy is changing the treatment landscape across oncology, Malo said, adding that this treatment modality has had a particularly significant effect on the treatment of patients with melanoma and NSCLC.

“ICBs are now the standard therapy for a wide variety of [cancers] but are the backbone therapy for patients with NSCLC or melanoma,” she said. “We can see a significant improvement in the survival rate in patients treated with immunotherapy vs those treated with chemotherapy alone.”

For example, findings from Robert et al showed that treatment with nivolumab (Opdivo) prolonged the median survival of patients with melanoma compared with dacarbazine. At a follow-up of 18 months, the median overall survival (OS) with the immunotherapy (n = 210) was not reached compared with 10.8 months (95% CI, 9.3-12.1) with dacarbazine (n = 208). The hazard ratio was 0.42 (99.79% CI, 0.25-0.73; P < .001).2

Moreover, Reck et al demonstrated that pembrolizumab improved OS for patients with lung cancer. At a follow-up of 72 months, the median OS with immunotherapy was 26.3 months (95% CI, 13.3 to 40.4) vs 13.4 months (95% CI, 9.4-18.3) with chemotherapy. The number of events associated with pembrolizumab (n = 154) was 103 (66.9%) vs 123 (81.5%) with chemotherapy (n = 151; HR, 0.62; 95% CI, 0.48-0.81).3

“Despite these improvements in outcomes with ICB, resistance to these treatments is universal,” Malo explained. “Therefore, finding new strategies to increase ICB efficacy or [challenge] ICB resistance is an unmet clinical need.”

The Gut Microbiome

According to Malo, literature suggest that the microbiome plays a key role in the efficacy of immunotherapy treatments.3,4

The intestinal microbiome is the most populated of the different microbiomes in the human body, it is situated in the small intestine and the colon. Here, bacterial colonization occurs in a very gradual and specific way: the intestinal bacteria absorb oxygen and uses it to multiply and promote bacteria growth in anaerobic environment.6

Multiple factors affect the diversity of the microbiome, including where an individual was born, their current geographical location, and genetics. The microbiome increases its diversity through the first 3 to 5 years of an individual’s life, but, once established, remains relatively stable throughout adult life. Only major changes in lifestyle or diet, including the introduction of an antibiotic treatment, will upset the microbiome once it has been established. However, certain changes in the microbial composition can induce the production of toxics and create chronic inflammation. This process is called dysbiosis and it can affect the efficacy of ICB.4

Findings from Derosa et al showed that in a cohort of patients with NSCLC receiving ICB, the median OS among those who were receiving antibiotic therapy was 7.9 months, whereas, among those who were not receiving antibiotic therapy, the median OS was 24.6 months (HR, 4.4; 95% CI, 2.6-7.6; P < .01).

“In light of all this information, it is important to find ways to modulate the microbiome in order to use it as an adjuvant to ICB treatment,” Malo explained.

Nurse-Directed Initiative

Investigators sought to influence the gut microbiome in a noninvasive and natural way. To that end, a team of oncologists, oncology nurses, and nutritionists designed a questionnaire to ask patients about their different dietary habits, including their intake of fruits, vegetables, meat, and alcohol, as well as information about their geographical living environment. The questionnaire therefore offered a global view of their lifestyle habits.

The questionnaire was presented to patients (n = 105) with advanced NSCLC prior to their initiation of their ICB treatment. A 1-hour interview with a research nurse and a 47-question assessment captured information on the intake of 30 different nutrients. Examples of patient questions included if they ate 3 meals per day, if they fasted, if they consumed fresh or canned fruit, salad, vegetables, potatoes, chips, eggs or egg-based recipes, legumes, nuts and seeks, high-fiber breakfast cereals, whole wheat bread, other bread options, or rice.

“Our first finding was that our patients had a fairly homogeneous and relatively poor diet that was lacking variety,” Malo noted, adding that most patients reported that they do not eat bran cereal, oatmeal, or other grains, but almost all of them consume coffee.

Moreover, some foods were also associated with unexpected positive and negative responses.

“Protein drinks, white breaded fish, and other breads are associated with a negative response [whereas] other grains fruit, rice, beans, eggs and coffee are associated with a better clinical response,” Malo noted. “And unlike melanoma, where a study [conducted] by Spencer [et al] showed that a high fiber diet is associated with a better clinical response, a high fiber diet did not correlate with an improved PFS [progression-free survival] for our patients with NSCLC. It is important to note here that the median fiber intake of our patient was 14 g per day compared to 20 g.”

Moreover, after focusing on foods and clinical responses, investigators observed that a fatty acid diet correlated with a favorable outcome. According to Malo, the median PFS for patients on a low saturated fatty acid diet was 9.1 months compared with a median PFS of 17.4 months for a patient with a high saturated fatty acid diet.

Future Research

“With the emergence of the gut microbiome in the field of immune-oncology, providing evidence based dietary recommendation and educational tool for nurses is an important strategy to potentially increase ICB efficacy,” Malo said.

She concluded by noting that the mechanism between the bacteria of the gut and immune responses remain to be fully understood and that strategies designed to leverage the gut microbiome to enhance outcomes of adjuvant ICB therapy should be considered on a broader scale. Malo’s team is developing a new version of the food frequency questionnaire to better assess their patients intake of nutrients and the consequent effect on care.

References

  1. Malo J. Impact of diet on immune checkpoint blockade; nurse-directed dietary intervention. Poster presented at: European Society for Medical Oncology Congress 2022; September 9-13, 2022; Paris, France.
  2. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50. J Clin Oncol. 2021;39(21):2339-2349. doi:10.1200/JCO.21.00174
  3. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330. doi:10.1056/NEJMoa1412082
  4. Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol. 2018;29(6):1437-1444. doi:10.1093/annonc/mdy103
  5. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059
  6. Clarke G, Sandhu KV, Griffin BT, Dinan TG, Cryan JF, Hyland NP. Gut reactions: breaking down xenobiotic-microbiome interactions. Pharmacol Rev. 2019;71(2):198-224. doi:10.1124/pr.118.015768