Cancer treatments that use a strategy called immune checkpoint blockade (ICB) have entered clinical practice in a big way, with six drugs now approved by the U.S. Food and Drug Administration (FDA) for a variety of cancers. These drugs release “brakes” on the immune system, boosting its ability to kill cancer cells. Specifically, they target the proteins PD-1 or CTLA-4, which are found on the immune system’s T cells, or the protein PD-L1 on tumor and other cells. Patients’ response rates, however, have been lower than hoped for in most cancers.
Much research and discussion has focused on analysis of particular features in tumors themselves that predict how they might respond to ICB. However, because ICB drugs act on immune system proteins, it is clear that each patient’s immune system is a major player in shaping response to treatment, and that certain tumor-independent features are at play. Here’s what we know about seven factors besides tumors themselves that may predict a patient’s response to ICB:
1. HLA: This stands for human leukocyte antigen and refers to a large set of proteins found on the surface of most cells in the body. HLAs play a major role in presenting fragments of “foreign” proteins to the immune system for recognition. The foreign proteins may be derived from infected cells or from cancers in which some proteins are mutant and could be recognized as foreign, potentially marking them for destruction by the immune system. Analysis of HLA subtypes has shown that the greater the variety of HLA proteins in a patient’s body, the better their response to ICB. Is there anything that a patient can do to increase their HLA diversity? Of course not—we are just born with certain sets of HLA subtypes.
2. Microbiome: It is well known that the repertoire of the bacteria occupying our guts is important in shaping our immune systems (as well as affecting our digestion, mood, and even mental status). In late 2017, I wrote about the effect of the gut microbiome on response to ICB. High diversity of gut bacteria and the presence of certain bacterial strains are associated with good response to ICB. Some researchers have reported that taking antibiotics before or during treatment with ICB drugs lowers their efficacy, but this may not be true for all antibiotics. Since then, newer studies have continued efforts to identify which of the many species of bacteria found in the gut support ICB efficacy.
A recent study showed that 11 species of bacteria isolated from the human gut together robustly boost immune system activity in the intestine by promoting generation of cytotoxic T cells—T cells that kill cancer cells or other cells that are infected or damaged. These 11 bacterial species, when transferred into mice, promote immune responses to infection with the bacterial pathogen Listeria, as well as tumor shrinkage in response to ICB. All 11 species represent very rare bacterial strains, meaning that their abundance in the gut is normally low.
Ongoing clinical trials are collecting data on the microbiome composition of patients treated with ICB. There are even trials in which fecal transplants from melanoma patients who had good responses to ICB are given to patients who failed to respond, in hope of promoting the efficacy of ICB. So far, the available preliminary results from these trials are encouraging! And at least one trial features a preparation of the “good” bacteria, SER-401, that will be given to melanoma patients along with an anti-PD-1 ICB drug. SER-401 is a collection of bacterial species based on those found in melanoma patients who responded well to ICB. …but are there other ways to promote a healthy microbiome?
3. Diet: Yes, a good diet is something you can do to support the gut microbiome. Recent research showed that a high-fiber diet is associated with the development of a diverse microbiome and better responses to ICB in melanoma patients. So, recommendations for patients receiving immunotherapy are: say no to processed meat and sugar, and say yes to more whole grains, fruits and vegetables. Not entirely surprising, right? It is reasonable to assume that these results will hold true for other ICB-treated cancers besides melanoma.
4. Probiotics: It is better to avoid commercially available probiotics—ingestible products containing live microbes. The same study that suggested a high-fiber diet is beneficial for ICB also looked at links between ICB responses and use of these ever-popular products. Patients who used probiotics had a lower rate of responses to ICB. As described here, the study was small and had its limitations, but its conclusions certainly make sense. Consider the finding that improvement of response to ICB is related to the presence of rare bacterial species, and it becomes clear that loading the gut with probiotics representing the most common and abundant bacteria may disadvantage the rare “good” bacterial species. So, if you are receiving ICB, do not rush to buy one of the many probiotics widely available in food markets or online.
5. Weight: It is well known that obesity is associated with a number of health conditions, including higher cancer risk. However, a recent study showed that obese patients (those with a BMI greater than 30) have a better response to ICB. Paradoxically, the abundance of the hunger-inhibiting hormone leptin in obese people may be associated with dysfunction of tumor-killing T cells. This dysfunction is driven by PD-1 accumulating on these T cells, blocking their tumor-killing activity. When anti-PD-1 ICB drugs are given to obese patients with these “PD-1-silenced” T cells, the treatment apparently tends to work well. However, this certainly does not mean that if you are receiving ICB drugs you should strive to increase your BMI.
6. Age: Last year a study was published documenting that in older melanoma patients (those older than 62), ICB may work better. This could be due to the higher presence of cells known as regulatory T cells in the tumors of younger patients. Regulatory T cells in general inhibit immune responses by cytotoxic T cells, so it could be that the tumor-killing activity of cytotoxic T cells is inhibited in younger patients with more regulatory T cells. There are no reliable data for the efficacy of ICB in older patients with other types of cancer. In clinical trials of ICB in non-small cell lung cancer (NSCLC), response rates of older versus younger patients were similar, but a small real-world study, showed hints that older patients do not do as well as younger ones. It is difficult to draw solid conclusions from these studies, but they raise some concerns about the efficacy of ICB in older NSCLC patients. Still, the rate of side effects with ICB was much lower compared to chemotherapy in all age groups.
7. Proton Pump Inhibitors (PPIs): PPIs are drugs often used to treat heartburn and other disorders associated with high levels of acid in the stomach. Commonly prescribed PPIs include the over-the-counter drugs omeprazole (Prilosec) and lansoprazole (Prevacid), the prescription drugs rabeprazole (Aciphex) and pantoprazole (Protonix), and some newer drugs. PPIs are generally considered to be very safe, but some disturbing news emerged recently from an analysis of responses to ICB in 140 melanoma patients treated in a randomized trial. Use of PPIs (initiated before ICB treatment and ongoing during the treatment) decreased objective response rates to ICB by almost half, and also reduced survival time. This finding was clear in a group of patients receiving the ICB drugs ipilimumab and nivolumab, but not ipilimumab alone. Apparently, patients receiving a PPI drug had significantly reduced levels of neutrophils (a type of immune system cell) in their blood. It appears that use of PPIs should be avoided in melanoma patients receiving anti-PD-1 drugs like nivolumab.
8. Cannabis: A small study of patients with various types of cancer detected potential adverse effects of cannabis on the efficacy of ICB, in particular for the ICB drug nivolumab (brand name Opdivo). Patients with melanoma, NSCLC, or clear cell renal cancer who used various forms of cannabis had a lower response rate (37.5 % in non-users versus 16% in users). This study was small and retrospective (i.e., it collected results from 140 patients treated in a real-world setting, rather than from a controlled study), but the findings are alarming, considering that cannabis in various forms is very popular among cancer patients.
The factors listed above that may influence the efficacy of ICB are various, and some are entirely out of patients’ control. However, it is prudent to maintain a high-fiber diet, avoid probiotics and PPI drugs, and perhaps refrain from using cannabis.