Vitamin D supplementation prior to starting immune checkpoint inhibitor therapy may significantly reduce the odds of developing colitis, according to a study conducted at Harvard Medical School. Although this was a retrospective chart review, the association was relatively strong in the multivariable analysis, with a 54% reduced risk (P = .03) compared with persons not taking vitamin D supplements, reported Kevin Tyan, BA, a second-year medical student at Harvard Medical School, at the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium.1
“We found that patients on vitamin D supplementation when they started their first checkpoint inhibitor had significantly reduced odds of developing checkpoint inhibitor–induced colitis, and we were able to verify this across two centers,” Mr. Tyan said. “This could point to a potential protective effect of vitamin D supplementation in immunotherapy.”
“These study findings could point to a potential protective effect of vitamin D supplementation in immunotherapy.”— Kevin Tyan, BA
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No Predictive Factors Yet Established
Colitis can be a serious adverse event associated with immunotherapy. Despite the concern, relatively few putative risk factors for its occurrence have been proposed. In particular, combinations of checkpoint inhibitors increase the risk more than single agents; monotherapy with drugs targeting cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) poses the next highest risk, followed by antibodies against programmed cell death protein 1 (PD-1). High levels of serum interleukin-17 and a microbiota enriched with Firmicutes and lacking in Bacteroides may also facilitate its development. Interestingly, preexisting inflammatory bowel disease (IBD) appears to be related—and this is the potential connection to vitamin D.
Vitamin D deficiency is well known to be prevalent in inflammatory bowel disease, seen in up to 40% of patients with IBD, and is an independent predictor for clinical relapse and disease severity. The hypothesis, therefore, is that vitamin D may play a role in checkpoint inhibitor–induced colitis as well. Vitamin D has immunomodulatory properties and has been shown to actively suppress autoimmune disorders, including colitis in mouse models, and helps to regulate gut health through vitamin D receptor signaling.
Mr. Tyan and his co-investigators examined potential risk factors for colitis in a retrospective cohort study of 246 patients with advanced melanoma treated with anti–PD-1 and anti–CTLA-4 regimens. The final analysis was based on 213 patients, 37 (17.4%) of whom experienced 38 cases of checkpoint inhibitor–induced colitis. Cases were grade 2 in 8 patients, grade 3 in 27 patients, and grade 4 in 3 patients.
Charts were reviewed for the presence of 37 unique variables as possible predictors for colitis. In the multivariable analysis, three factors were shown to be independent predictors for checkpoint inhibitor–induced colitis: class of immune checkpoint inhibitor, baseline neutrophil-to-lymphocyte ratio (≥ 5 vs < 5), and pretreatment vitamin D intake (yes vs no). Vitamin D supplementation was defined as administration of at least 400 IU.
The researchers sought to validate this finding in an independent cohort of 169 patients with melanoma treated with the same checkpoint inhibitors. In this group, there were 50 reports of immune-related colitis in 49 patients (29.9%), which included 13 cases of grade 1 toxicity, 22 grade 2 events, 15 grade 3 events, and no grade 4 events.
“We were able to validate checkpoint inhibitor class and vitamin D intake, but not neutrophil-to-lymphocyte ratio,” Mr. Tyan reported.
Consistent with previous studies, combination therapy was associated with a higher risk for colitis than single-agent anti–PD-1 therapy, and anti–CTLA-4 therapy was associated with a higher risk than anti–PD-1 treatment.
By dose, the researchers found no statistically significant difference between vitamin D doses less than or greater than 1,000 IU. They also found no association between vitamin D intake and durable tumor response to treatment.
Further Study Needed
Mr. Tyan acknowledged that the retrospective study had limitations, including uncertainty about the start date of supplementation, the possible effect of diet, and the subjective reporting of vitamin D—whether intake was truly daily. Investigators were also unable to measure baseline serum levels of vitamin D, which could have been a better proxy for physiologic levels (studies have shown an exponential dose response between vitamin D supplementation and physiologic serum levels).
“Also, we do not know whether some of our patients had a vitamin D deficiency to begin with, or whether they were supplementing for treatment of underlying diseases that may have confounded our analysis,” he added.
The researchers hope their hypothesis-generating findings can be further validated in prospective and correlative studies—which researchers are now conducting.
DISCLOSURE: Mr. Tyan owns stocks and patents and has a leadership role in Kinnos.
1. Tyan K, Grover S, Dougan M, et al: Association of vitamin D intake with decreased risk of immune checkpoint inhibitor-induced colitis. 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 89. Presented February 7, 2020.
“The investigators of the current study tested the hypothesis that vitamin D supplementation is associated with a reduced risk of checkpoint-induced colitis by rigorously assessing 37 variables in both discovery and validation cohorts,” said invited discussant Jarushka Naidoo, MBBCh, Assistant...