“Cannabis or cannabis derivatives are widely used by patients with cancer to help with cancer symptoms and treatment side effects,” Gil Bar-Sela, MD, of the Emek Medical Center in Israel, and lead author of the study, said. “However, cannabis has potent immunomodulatory properties.”
Dr Bar-Sela concluded that “we provide here the first indication of the effect of cannabis consumption during ICI immunotherapy treatment and show it may be associated with worsening clinical outcomes when compared to non-users.”
“Cannabis or cannabis derivatives are widely used by patients with cancer to help with cancer symptoms and treatment side effects,” said Dr Bar-Sela.
Cannabis use was associated with shorter time to progression (TTP) and overall survival (OS) among patients with advanced cancer receiving treatment with immune checkpoint inhibitors (ICIs), according to an observational study reported at the European Society of Medical Oncology (ESMO) Virtual Congress 2020.
The overall clinical outcomes were estimated in terms of complete response (CR), partial response (PR), and stable disease (SD) as to the Response Evaluation Criteria in Solid Tumors RECIST 1.1 criteria. Cannabis-users showed a significantly lower percentage of clinical benefit (CR + PR + SD) outcomes: 39% vs. 59% over nonusers (p = 0.035). CR and SD indexes were larger over nonusers, although the differences were not statistically significant (CR: I-G = 20% and IC-G = 9%, p = 0.1329, SD: I-G = 20% and IC-G = 9%, p = 0.13), and PR indexes were equivalent between groups (I-G = 19% and IC-G = 21%, p = 0.86). Cannabis users were more likely to show symptoms of progressive disease, namely: n = 29 out of n = 34 (61%) patients in the IC-G group compared to n = 27 patients out of n = 68 (41%) in the I-G experienced progressive disease (p = 0.035).
* The numbers in these sections do not sum up to the total number of patients included in the study. Patients can be comprised in several subgroups simultaneously.
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 . More recently, additional receptors, biosynthesizing and degrading enzymes, and eCB-like lipids have been recognized as part of an extended eCBS [10,11,12,13] or an “endocannabinoidome” . The extended eCBS, among other things, regulates immune responses in different cell types, affecting cytokine secretion, the induction of apoptosis, and immune cell activation in innate and adaptive immune responses . The classical eCB, AEA, can produce a dose-dependent inhibition of mitogen-induced T and B human lymphocyte proliferations . On the other hand, 2-AG has both pro- and anti-inflammatory effects. eCB-like lipids like the N-acyl ethanolamides: N-palmitoyl ethanolamide (PEA), N-oleoyl ethanolamide (OEA), and N-stearoyl ethanolamide (SEA) have been shown to inhibit both T-cell responses directly . Phytocannabinoids, the natural constituents of cannabis, also interact with the extended eCBS by activating and/or inhibiting eCB and eCB-related receptors, enzymes, and transporters [10,17]. For example, via inhibition of the cellular reuptake of AEA by most neutral phytocannabinoids or cannabidiol (CBD) inhibition of the hydrolyzing enzyme, fatty acid amide hydrolase (FAAH), which, in turn, is responsible for the degradation of AEA and other N-acyl ethanolamides [18,19]. Since cannabis is now widely used in oncology patients, it is of great importance to understand the effects of cannabis on the immune system and its possible interaction with immunotherapy, which is designed to artificially stimulate the immune system and improve the immune system’s natural ability to fight the disease.
A series of χ 2 tests or Fisher’s exact tests (when the assumptions of the parametric χ 2 test were not met) and nonparametric Mann–Whitney U tests were conducted to analyze the differences between patients’ characteristics in both groups. Time to tumor progression (TTP) and overall survival (OS) was estimated using the Kaplan-Meier survival curve by group, and the log-rank test was computed to differentiate the survival curves between groups. Hazard ratios and the corresponding 95% CIs based on a Cox proportional hazards regression model were provided for multivariate analyses. We computed 2-tailed p-values, where p < 0.05 was considered a statistically significant result. Statistical analyses were performed using the SAS software package version 9.4 (SAS Institute, Cary, NC, USA).
Overall, our current study, with its limitations, demonstrates a statistically significant interaction between cannabis exposure before and during the ICI immunotherapy of advanced malignancies, their lymphocytes counts, and the detected immunotherapy success rates.