Could the Human Microbiome Hold the Key to Precision Cancer Immunotherapy?

The recent failure of Opdivo (nivolumab) to achieve its endpoint in a key lung cancer clinical trial was unexpected.¹ It’s one of several FDA-approved drugs known as immune checkpoint inhibitors. These biologic medications work by disrupting the interaction between programmed cell death 1 (PD-1) that is expressed on T cells and PD-1 ligand (PD-L1) that could be expressed by tumor cells.² PD-1/PDL-1 interaction has been established as a key mechanism by which tumor cells evade recognition by the immune system as it leads to suppression of activated CD8⁺ T cells.² Immune checkpoint inhibitors have been proven to be efficacious in recovering the immune system ability in recognizing and destroying tumor cells.³ However, not all patients respond to these drugs.⁴ Therefore, identifying response biomarkers remains an active research area. However, logically, patients’ tumors that overexpress PD-L1 would be expected to be respond to these drugs.³ A major variable that’s been implicated in Opdivo’s failure in meeting its endpoint in the latest lung cancer trial is that the patients were enrolled into the clinical trial with only at least 5% elevation in the expression level of PD-L1 relative to at least 50 elevation in the successful Keytruda (pembrolizumab) clinical trials. This was based on the observation that previous trials indicated that lung cancer patients with a low expression level of PD-L1 (>1) could also derive benefit from Opdivo treatment.⁵ Therefore, it remains possible that factors other than PD-L1 expression level have led to this disappointing result.

Preclinical mice studies have demonstrated that a certain type of intestinal commensal bacteria, Bifidobacterium, enhances response to anti—PD-1/PD-L1 therapy in mice.⁶ In these studies, administering the immunotherapy to the mice in combination with Bifidobacterium led to a better response relative to the immunotherapy alone.⁶ In light of these observations, several challenges and opportunities arise. First, could that specific type of commensal bacteria in the human gut play a significant key role in the response to immunotherapy? Finding an answer for this question would require the design of clinical trials that take into account not only the expression level of PD-L1, but also the analysis of the gut microbiome genome in order to identify bacteria that influence the response to anti—PD-1/PD-L1 therapy. Taking a peek into the future, could we design products that leverage our knowledge of the intestinal microbiome? The mice study by Sivan et al. demonstrated that oral administration of Bifidobacterium could be sufficient in boosting the response to immunotherapy. However, developing bacteria as a therapeutic product may have its own challenges. Therefore, it might worthwhile to identify the exact bacterial structural components and proteins that are essential for boosting the immune response. These molecules may offer a platform to develop well-characterized adjuvant therapeutics that could be co-administered with immune checkpoint inhibitors.

In summary, despite the recent failure of Opdivo in achieving its endpoint, cancer immunotherapy remains a major advance in the fight against cancer. Identifying response biomarkers beyond the germline and somatic tumor genome that involve characterizing the microbiome could open new frontiers in advancing cancer immunotherapy clinical applications.

References

1. Loftus P, Rockoff JD, Steele A. Bristol Myers: Opdivo failed to meet endpoint in key lung-cancer study. The Wall Street Journal website. wsj.com/articles/bristol-myers-opdivo-failed-to-meet-endpoint-in-key-lung-cancer-study-1470400926. Updated August 5, 2016. Accessed November 8, 2016.

2. Califano R, Kerr K, Morgan RD, et al. Immune checkpoint blockade: a new era for non—small-cell lung cancer. Curr Oncol Rep. 2016;18(9):59. doi: 10.1007/s11912-016-0544-7.

3. Edward B, Garon M.D, et al. Pembrolizumab for the treatment of non—small-cell Lung cancer. N Engl J Med. 2015;372:2018-2028. doi: 10.1056/NEJMoa1501824.

4. Sui X, Ma J, Han W, et al. The anticancer immune response of anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients. Oncotarget. 2015;6(23):19393—19404.

5. H. Borghaei et al. Nivolumab versus docetaxel in advanced nonsquamous non—small-cell lung cancer. N Engl J Med. 2015;373:1627-1639. doi: 10.1056/NEJMoa1507643.

6. Ayelet Sivan et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti—PD-L1 efficacy. Science. 2015;350(6264):1084-1089. doi: 10.1126/science.aac4255.