Abstract
Simple SummaryCannabis is widely used by patients with cancer to help with cancer symptoms and treatment side effects. Though cannabis has immunomodulatory effects, and its consumption among cancer patients needs to be carefully considered due to its potential effects on the immune system. In this report, we provide the first indication of the impact of cannabis consumption during immune checkpoint inhibitors (ICI) immunotherapy cancer treatment and show it may be associated with worsening clinical outcomes. Cancer patients using cannabis showed a significant decrease in time to tumor progression (TTP) and decreased overall survival (OS) compared to nonusers. In contrast, the use of cannabis reduced immune-related adverse events (iAE). Thus, our report constitutes the first warning sign to the use of cannabis as a palliative treatment in advanced cancer patients starting immunotherapy and suggests that its consumption should be used with attentiveness. Furthermore, we show that the levels of endogenous serum eCB and eCB-like lipids are affected by immunotherapy and may potentially constitute monitoring targets to cancer immunotherapy treatment, which currently has poor clinical markers for predicting patient response rates.Cannabis or its derivatives are widely used by patients with cancer to help with cancer symptoms and treatment side effects. However, cannabis has potent immunomodulatory properties. To determine if cannabis consumption during immunotherapy affects therapy outcomes, we conducted a prospective observatory study including 102 (68 immunotherapy and 34 immunotherapy plus cannabis) consecutive patients with advanced cancers who initiated immunotherapy. Cannabis consumption correlated with a significant decrease in time to tumor progression and overall survival. On the other hand, the use of cannabis reduced therapy-related immune-related adverse events. We also tested the possibility that cannabis may affect the immune system or the tumor microenvironment through the alteration of the endocannabinoid system. We analyzed a panel of serum endocannabinoids (eCBs) and eCB-like lipids, measuring their levels before and after immunotherapy in both groups. Levels of serum eCBs and eCB-like lipids, before immunotherapy, showed no significant differences between cannabis users to nonusers. Nevertheless, the levels of four eCB and eCB-like compounds were associated with patients’ overall survival time. Collectively, cannabis consumption has considerable immunomodulatory effects, and its use among cancer patients needs to be carefully considered due to its potential effects on the immune system, especially during treatment with immunotherapy.
Highlights
To date, the U.S Drug Enforcement Administration (DEA) lists cannabis and its phytocannabinoids as Schedule I controlled substances that cannot be legally prescribed, possessed, or sold [1]
In view of the intrinsic limitations of this type of study, and in light of no other prior clinical indications to the subject, our results indicated that cannabis consumption should be carefully considered in patients with advanced malignancies treated with immunotherapy
Sample size calculation: We previously reported in a retrospective study that patients with advanced malignancies initiating immunotherapy treatment had a 14% combined rate of complete response (CR) and a 30% rate of partial response (PR) [28]
Summary
The U.S Drug Enforcement Administration (DEA) lists cannabis and its phytocannabinoids as Schedule I controlled substances that cannot be legally prescribed, possessed, or sold [1]. Despite the lack of robust evidence, the use of cannabis as a palliative treatment to relieve the side effects of drugs used in a range of medical conditions has been approved or is under consideration in many countries around the world and assumed to be safe [2]. The biological activity of cannabis is mediated by modulation of the endocannabinoid system (eCBS). This system comprises of two G-protein-coupled receptors (GPCR), cannabinoid receptors type 1 and 2 (CB1 and CB2, respectively), the two endocannabinoids (eCBs) N-arachidonoyl ethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes responsible for the biosynthesis and hydrolytic inactivation of these eCBs [9].
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