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Cancer Treatment: Preclinical & Clinical

Cancer Treatment: Preclinical & Clinical Abstract The first evidence that cannabinoids may have in vitro and in vivo antineoplastic activity against tumor cell lines and animal tumor models was published in the Journal of the National Cancer Institute nearly 50 years ago. Cannabinoids appear to induce apoptosis in rodent brain tumors by way of direct interaction with the cannabinoid receptor. They may inhibit angiogenesis and tumor cell invasiveness. Despite preclinical findings, attempts to translate the benefits from bench to bedside have been limited. This session provides a review of the basic science supporting the use of cannabinoids in gliomas, paired with the first randomized clinical trial of a cannabis-based therapy for glioblastoma multiforme. Another preclinical presentation reports the effects of cannabinoids on triple-negative breast cancer cell lines and how cannabidiol may affect tumors. The session’s second human trial raises concerns about the use of botanical cannabis in patients with advanced cancer receiving immunotherapy suggesting inferior outcomes. Funded by the National Institute on Drug Abuse and the American Cancer Society among others, investigators at the Medical College of Virginia/Virginia Commonwealth University investigated 4 cannabinoids for antineoplastic activity against 3 animal tumor models in vivo and 2 in vitro systems (1). They published their findings in the Journal of the National Cancer Institute in 1975, reporting that delta-9-tetrahydrocannabinol (THC), delta-8-tetrahydrocannabinol, and cannabinol were all active in vivo against Lewis lung carcinoma xenografts and in vitro. Of note, tumor growth rate in mice treated with cannabidiol (CBD) was significantly increased compared with controls in this early report. The investigators concluded that since cannabinoids readily cross the blood-brain barrier and are not as toxic as most of the cytotoxic agents used at the time, they are “an appealing group of drugs to study.” By the time these findings were published, cannabis had already been made a schedule I substance deemed to have a high potential for abuse and no accepted medical use, which served to inhibit the future investigations envisioned. After a significant gap in time, however, interest in exploring cannabinoids, particularly as agents that might be active against tumors of the central nervous system, has been reinvigorated. Elegant preclinical studies, largely emanating from the research of Guillermo Velasco et al. (2), have demonstrated the direct antitumor activity of cannabinoids against gliomas in vitro. In addition, cannabinoids have been shown to inhibit vascular endothelial growth factor and matrix mettalloproteinase-2, serving to decrease angiogenesis, invasiveness, and metastases. Despite this promising preclinical evidence, however, the 2017 report from the National Academies of Sciences, Engineering, and Medicine on The Health Effects of Cannabis and Cannabinoids concluded that “there is insufficient evidence to support or refute the conclusion that cannabinoids are an effective treatment for cancers, including glioma” (3). This was largely driven by the lack of controlled clinical trials supporting any benefit of cannabis, cannabis-based medicines, or individual cannabinoids in patients with malignant diagnoses. This session on “Cancer Treatment: Preclinical & Clinical” serves to help move the field from bench to bedside by presenting 2 basic science overviews and the findings of 2 clinical studies involving cancer patients. Guillermo Velasco from Madrid reviews much of his group’s work on investigating cannabinoids as anticancer agents, with a focus on gliomas generated in rodents. These findings served as the basis of the phase I clinical trial of nabiximols, a whole plant extract with a THC to CBD ratio of 1:1, in patients with recurrent glioblastoma multiforme presented by Chris Twelves from the University of Leeds (4). Investigations by Ramesh Ganju, from The Ohio State University, demonstrate that CBD has more positive antitumor potential than reported in the 1975 publication and elucidate the role of the immune system, particularly tumor-associated macrophages, in CBD’s effects. Finally, Gil Bar-Sela from Emek Medical Center and Technion/Israel Institute of Technology reviews his group’s findings from their observational study of outcomes in patients with advanced cancer receiving immunotherapy in those who do and do not use botanical cannabis (5). These findings, although not emanating from a randomized controlled trial that would have less potential for bias, certainly warrant further research on the use of cannabis during treatment with immunotherapy. Toward the Utilization of Cannabinoids as Anticancer Agents: Guillermo Velasco Cannabinoids as Therapeutic Agents in Oncology In addition to their well-established palliative benefits in patients with cancer, numerous preclinical studies have provided evidence that THC and other cannabinoids exhibit antitumor effects in a wide array of animal models of cancer and specifically in gliomas (1,6). Cannabinoids inhibit cancer progression through various mechanisms, the most common being the induction of cancer cell death by the stimulation of an endoplasmic reticulum stress-related, autophagy-mediated cell death pathway that leads to the induction of apoptosis (1,6). In addition, cannabinoids inhibit angiogenesis and block invasion in gliomas and inhibit metastases in other tumor types (1,6). It is worth noting that CBD, by acting independently of cannabinoid receptor types 1 and 2 (CB1 and CB2), produces antitumor effects in various tumor animal models, including gliomas (7). Cannabinoid-Based Anticancer Therapies in Glioblastoma Multiforme The first clinical investigation of the potential efficacy of cannabinoids as anticancer agents was a pilot phase I study in 9 patients with recurrent glioblastoma multiforme to whom THC was administered intracranially (8). Although no statistically significant conclusions can be extracted from a cohort of 9 patients, the results obtained in the study suggest that some patients may have benefited briefly from THC treatment in terms of reduced tumor volume on serial magnetic resonance imaging scans. Interestingly, analyses of samples obtained from 2 study patients before and after THC administration supported the notion that the molecular mechanism of cannabinoid antitumor action initially described in cellular and animal models is also activated in patients (8). The results of this first clinical study were encouraging but also pointed to the need for defining strategies to optimize the possible future use of cannabinoids as anticancer agents. The Velasco laboratory focused on 3 aspects: 1) improving knowledge about the mechanisms underlying the anticancer activity of cannabinoids, 2) identifying the factors that promote resistance to THC or cannabinoid anticancer activity, and 3) investigating the efficacy of cannabinoid-based combinational therapies. As described in further detail in other sections of this special issue, we identified the prominent role of TRIB3-dependent inhibition of the AKT–mTORC1 axis as a key step in THC-induced autophagy and cell death (9,10). Likewise, we found that THC triggered a modification on the sphingolipid composition of the endoplasmic reticulum that is transmitted to the autophagosomes (11). These changes, in turn, lead to the destabilization of autolysosomes thereby promoting the release of cathepsins and the subsequent activation of the apoptotic death of glioma cells (11). As discussed below, these observations may help the design of combination therapies based on adding cannabinoids to agents that can potentiate actions on these signaling pathways. Another strategy to optimize the utilization of cannabinoids as anticancer agents is based on the identification of the factors that determine sensitivity to treatment with these agents. Gene expression profile studies developed in cell lines and primary cultures of glioma cells demonstrated that increased expression of the neurotrophic factor midkine (MDK) (12), and the estimated glomerular filtration rate–ligand amphiregulin (13) could be biomarkers of resistance to THC and other anticancer agents (12). Likewise, we found that blockade of the MDK–anaplastic lymphoma kinase (ALK) axis could overcome this resistance by facilitating the activation of the autophagy-mediated cell death pathway (12,14). Moreover, MDK plays a prominent role in gliomas and specifically in glioma-initiating cells, a cell subpopulation that has been proposed to be responsible for the relapses that occur in most, if not all, patients with aggressive brain tumors. Blockade of the MDK–ALK axis, together with cannabinoids, efficiently targets this cell subpopulation (14) (see other unpublished observations as well), which could be a potentially interesting strategy acting on glioma-initiating cells to reduce or delay the incidence of relapse in patients with glioblastoma multiforme. These results constitute preclinical proof of the concept that biomarkers of resistance to cannabinoid anticancer activity can be identified, and it is possible to design therapies that can overcome this resistance. Subsequent research investigated whether the use of cannabinoids as anticancer agents could be optimized by assessing the efficacy of cannabinoid-based combination therapies. The administration of THC and temozolomide exerts strong antitumor action in glioma xenografts, an effect that also is evident in temozolomide-resistant tumors (15-17). THC to CBD combinations at a 1:1 ratio maintained the capacity to synergize with temozolomide and produce strong anticancer activity.15,16 Of note, these combinations resemble the composition of nabiximols (Sativex, GW Research Limited, Cambridge, United Kingdom), an oromucosal cannabis spray that has been used for therapeutic purposes. A similar effect was observed when THC and CBD were combined with radiotherapy in animal models of glioma (18). These results served as the basis for the development of a phase Ib trial aimed at evaluating the combination of nabiximols and temozolomide in patients with recurrent glioblastoma multiforme (NCT01812603 and NCT01812616). The results of the study have recently been published and are discussed in more detail below (4). Although the study was small, a statistically significant increase in the survival of the nabiximols and temozolomide arm at 1 and 2 years was observed (4). There is, therefore, a clear rationale for developing additional clinical studies. In this context, a new clinical study promoted and coordinated by the Spanish Group of Research in Neuro-Oncology (GEINO) is currently under preparation to investigate the effect of THC to CBD (1:1 ratio) plus temozolomide and radiation therapy in patients with recently diagnosed glioblastoma multiforme (GEINOCANN-NCT03529448). Although these studies have been performed mainly in patients with glioblastoma multiforme, it would be appropriate to follow a similar strategy in other cancer types in which preclinical data have yielded promising results. Identifying biomarkers of resistance and molecular alterations that could be associated with a better or worse response to cannabinoid treatments and designing the most appropriate cannabinoid-based combinational therapies for each tumor type and subtype are critical in defining the best strategy to incorporate cannabinoids into future cancer therapies. This research should facilitate the development of additional clinical studies that could help clarify if (and when) these compounds can be incorporated within the oncology toolkit. A Phase 1 b Randomized, Placebo-Controlled Trial of Nabiximols Cannabinoid Oromucosal Spray With Temozolomide in Patients With Recurrent Glioblastoma: Chris Twelves Glioblastoma multiforme is the most common malignant primary brain tumor in adults. Glioblastoma multiforme is incurable and has a 5-year survival rate of less than 6% (19). The current optimal therapy is debulking surgery, followed by local high-dose radiotherapy and temozolomide chemotherapy (20). The median overall survival is 14.6 months for those well enough to undergo treatment. Tumor recurrence usually occurs 6 to 9 months after treatment. After recurrence, the median overall survival is 1.0 to 10.8 months (21,22). Substantial advances have been made in the treatment of most cancer types; however, for patients with glioblastoma multiforme, this treatment with surgery, radiotherapy, and chemotherapy has remained the standard of care for the last 30 years. Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromising DNA repair is both a relatively favorable prognostic factor and predictive of a benefit from temozolomide (23). There is no current standard of care for patients with recurrent glioblastoma multiforme (24). Glioblastoma multiforme expresses CB1 and CB2 receptors, with high-grade tumors expressing high levels of CB2 (25). CBD and THC reduce glioma growth in preclinical models (26). The combination of THC and temozolomide, the standard chemotherapeutic agent used in treating glioblastoma multiforme, has substantial antitumoral activity in glioma xenografts, including those resistant to temozolomide (17). There is, therefore, a rationale for looking at cannabinoids in patients with glioblastoma multiforme. Notwithstanding these preclinical data, the only clinical data as yet come from the trial described earlier (8), which was a pilot study of instilling THC into the cavity where the brain tumor had been resected and recurred. This proved to be safe, with suggestions of brief reductions in tumor volume postoperatively. There was evidence of ex vivo biological activity in the form of reduced cell proliferation in 2 of the treated patients. Nabiximols oromucosal spray (Sativex) is a complex formulation containing THC and CBD, with additional cannabinoid and noncannabinoid components. Nabiximols is currently approved for symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis, who have not responded adequately to other antispasticity medications, in more than 25 countries, but not in the United States. A clinical trial to evaluate the safety and preliminary efficacy of nabiximols plus dose-intense temozolomide in patients with first recurrence of confirmed glioblastoma multiforme was designed (4). Patients older than age 18 years who had previously received radiotherapy and first-line temozolomide with a Karnofsky Performance Status of 60% or more were eligible for enrollment. The study was a 2-part phase 1 b trial at 10 sites (7 in the United Kingdom and 3 in Germany) conducted from January 2014 to August 2016. Doses of nabiximols (or placebo in the second part of the trial) were individualized. Participants started taking 1 spray per day of study medication on day 1. If tolerated, they escalated by 1 additional spray per day to a maximum of 12 sprays per day. If unacceptable side effects occurred, the study medication dose was reduced or stopped until resolved. The cap on the total number of sprays that patients could receive resulted in a maximum 30 mg CBD and 32.4 mg THC each day. The patients received the study medication while taking dose-intense temozolomide chemotherapy at 85 mg/m2 daily for 21 days, followed by a 7-day break for 13 cycles. The more intense temozolomide regimen is not universally used; however, it was selected to optimize chemotherapy in patients with relapsed glioblastoma multiforme. Patients could remain on treatment for a year or until they discontinued the trial. As this was an early phase clinical trial, tolerability was the primary endpoint as reflected by treatment-related serious adverse events. Secondary endpoints were preliminary evaluation of the efficacy of nabiximols (with dose-intense temozolomide) by progression-free survival at 6 months by magnetic resonance imaging (using response assessment in neuro-oncology criteria) and survival at 1 year; temozolomide pharmacokinetics were also studied. An additional, post hoc 2-year survival analysis was undertaken using the European Organisation for Research and Treatment of Cancer prognostic calculator. In part 1 of the trial, 6 patients in 2 cohorts received nabiximols as above. Once titration was completed and a stable personalized nabiximols dose was established, patients took a mean of 6 sprays per day. Three patients withdrew because of adverse events (1 each for lethargy, dizziness, and fatigue; nausea, diarrhea, and vomiting; and depressed mood). Following safety review team approval, in part 2, a total of 21 patients were randomized 1:1 to dose-intense temozolomide plus nabiximols (n = 12) or placebo (9); the 2 groups were similar in age and performance status. Patients in the nabiximols group received fewer sprays per day than those in the placebo group (mean 7.5 and 10, respectively); however, the mean dose of dose-intense temozolomide was almost identical (81.2 mg/m2 and 81.1 mg/m2, respectively), so co-administration of the cannabinoids did not impact negatively on the dose of chemotherapy. The major treatment-associated adverse effects included vomiting, dizziness, nausea, and fatigue, with more side effects noted in the cannabinoid recipients. Toxicity was, however, relatively modest compared with that of most chemotherapy. The study achieved its primary endpoint of showing that nabiximols was tolerable, and personalized dosing was feasible in this population without any new safety concerns. There was no evidence to suggest an effect of nabiximols on the pharmacokinetics of dose-intense temozolomide. With regard to efficacy, there was no difference in progression-free survival at 6 months (33% in both arms); however, there was a striking difference in overall survival at 12 months, which was 83% in the nabiximols arm compared with 44% in the placebo arm (nominal P = .04). It is important to emphasize that this was not designed as an efficacy study, nor was it powered for a survival endpoint. Because of the encouraging data, a post hoc analysis was performed of overall survival at 2 years, which was again higher in the nabiximols arm (50% and 22%; nominal P = .13). Overall, patients in both arms of the study had better outcomes than might be expected, perhaps because as clinical trial participants, they were not fully representative of patients in routine care. Nevertheless, in a second post hoc analysis, the survival of 10 of the 12 patients treated with nabiximols exceeded that predicted by the European Organisation for Research and Treatment of Cancer prognostic calculator, compared with just 3 of the 9 on the placebo arm. Again, this suggests a difference in efficacy between the 2 arms. This first systematic evaluation of a cannabis-based therapy in a randomized trial in patients with recurrent glioblastoma multiforme was, however, small so the possibility that this is a random finding due to bias remains; the absence of data on MGMT methylation is a significant limitation. An accompanying editorial, titled “Cannabinoids in Glioblastoma Multiforme—Hype or Hope?” described the findings as “intriguing” and advised that they be “interpreted with significant caution,” and acknowledged that “these interesting findings, backed up by a strong preclinical rationale, still warrant urgent exploration of the combination of temozolomide and nabiximols in a sufficiently powered larger study” (27). In conclusion, nabiximols spray was tolerated, and personalized dosing was feasible in this patient population. Although the observed survival differences should be interpreted with caution, they do justify further exploration in an adequately powered randomized controlled trial. A multicenter phase II trial is in development in the United Kingdom. Cannabinoid-Mediated Novel Signaling Mechanisms in Cancer: Current Status and Future Implications: Ramesh Ganju Cannabinoids can be divided into different groups, based on their source of origin, as endogenously produced cannabinoids (endocannabinoids), chemically produced synthetic cannabinoids, and plant-derived cannabinoids (phytocannabinoids) (28). The Ganju laboratory analyzed the effect of the synthetic cannabinoids, designated as JWH, and the phytocannabinoid (CBD) on breast and lung cancer (29,30). Of new cancer cases in women, 42% are breast and lung cancer, and in men, lung cancer accounts for about 13% of new cases. Metastases are the major cause of mortality in patients with these and other cancers. The effect of the synthetic cannabinoid JWH-133, which binds to CB2, on breast cancer in culture was first analyzed. Using breast cancer tissue microarrays, the CB2 receptor was shown to be expressed by breast cancer tissues. Using a publicly available dataset, patients whose cancers expressed higher levels of the CB2 receptor had better overall survival compared with those whose cancers expressed lower amounts of the CB2 receptor. We also analyzed the effect of the CB2 agonist JWH-133 on growth and metastasis of the triple-negative breast cancer (TNBC) cell line MDA-MB-231 in vivo. Among the different subtypes of breast cancers, TNBC represents approximately 20% of all cases and is associated with poorer prognosis and survival than other molecular subtypes because of early metastasis to other organs. In addition, unlike patients with other breast cancer phenotypes, those with TNBC lack clinically effective targeted therapies (31). JWH was shown to inhibit the growth and metastasis of TNBC cells. Furthermore, these effects were mediated through the CB2 receptor because the CB2 antagonist, SR144528, partially abrogated the effects of JWH on growth and metastasis (30). We also have observed that JWH-015 inhibits growth and spontaneous metastasis of the murine TNBC cell line MVT1 in a syngeneic mouse model (32). In addition, we have seen that CB2 receptor knockout mice injected with murine TNBC cells show more tumor growth and metastasis compared with wild-type mice. Furthermore, JWH-015 treatment inhibited growth and metastasis in wild-type mice but had no effect on CB2 receptor knockout mice. We also have shown that JWH-015 treatment inhibits the growth of a TNBC patient-derived xenograft model. Furthermore, we have shown that JWH treatment increases recruitment of CD8-positive T cells to tumors compared with vehicle-treated mice. We also have analyzed the effect of JWH-015 on various signaling pathways and have shown that CB2 agonist inhibits the functional effects of chemokine CXCL12 that binds to the chemokine receptor CXCR4 (33). CXCL12–CXCR4 signaling plays an important role in breast cancer metastasis. We have shown that JWH-015 inhibits CXCL12-induced migration, invasion, and wound healing of TNBC cells. CBD may comprise up to 40% of the Cannabis sativa plant and does not have psychotropic activity. A few clinical trials with CBD as a sole agent against a range of neurological disorders have been conducted. Notably, oral administration of CBD in doses up to 600-800 mg per day has been shown to be safe and well tolerated in clinical trials conducted in healthy subjects (34-36). We have analyzed the effect of CBD on the viability of human TNBC cells (SUM159 and MDA-MB-231) and mouse TNBC cells (4T1) and demonstrated that CBD significantly inhibits the viability of these cells (32). Furthermore, we have shown that CBD inhibits growth and metastasis of mouse TNBC cells 4 T-1 and MVT-1 in a syngeneic mouse model. We also analyzed the effect of CBD treatment on immune cell infiltration and found that CBD significantly inhibits the recruitment of F4/80 positive tumor-associated macrophages (TAMs) compared with vehicle control–treated mice. We further showed that CBD inhibits the recruitment of M2-TAMs (CD206 positive/F4/F80 positive cells). We analyzed the mechanism by which CBD inhibits the recruitment of TAMs into tumors and showed that CBD inhibits the production of cytokine GM-CSF and chemokine MIP-2 and CCL3. These chemokines have been shown to play an important role in regulating the recruitment of immune cells in the tumors. Recently, CBD has been shown to bind to transient receptor potential vanilloid type-2 (TRPV2). TRPV2 is a nonselective cation ion channel, involved in a variety of physiological and pathological processes. We analyzed the expression of TRPV2 in tumor samples from breast cancer patients and observed that TRPV2 was highly expressed in malignant and metastatic breast cancer compared with normal breast tissue. We also have analyzed protein expression in 120 TNBC patients’ samples by immunohistochemistry. Most of the TNBC patients’ tumors showed strong to moderate expression of TRPV2. TRPV2 also was highly expressed in human and mouse TNBC cell lines. Furthermore, we have shown that patients whose cancers expressed high levels of TRPV2 (or mRNA) had substantially better recurrence-free survival than those whose cancers expressed low TRPV2 (37). Patients with estrogen receptor–negative breast cancer who had higher TRPV2 expression and received chemotherapy treatment showed better recurrence-free survival than those who had lower expression of TRPV2. However, in patients with estrogen receptor–negative breast cancer who did not receive chemotherapy, no significant difference in recurrence-free survival was observed between those who had high or low TRPV2 expression. TRPV2 contains a pore-forming transmembrane loop that allows ions (Ca2+ and Mg2+) and xenobiotics to permeate biological membranes (38). We analyzed the effect of CBD on doxorubicin uptake in TNBC cells. We measured the uptake of doxorubicin by flow cytometry in the presence or absence of CBD. TNBC cells that were treated with CBD in combination with doxorubicin had higher drug uptake than cells treated with doxorubicin alone. In addition, TNBC cells treated with doxorubicin in the presence of CBD showed reduced viability, reduced colonies, and significantly higher apoptosis and apoptotic markers compared with those treated with doxorubicin or CBD alone. To further confirm that the effect is mediated by TRPV2, we used the TRPV2 pore blocker (tranilast) and showed that this abrogated the increase in doxorubicin caused by CBD treatment; it also reduced the expression levels of apoptotic markers. TRPV2 downregulation inhibited doxorubicin uptake and also abrogated the effect of doxorubicin and CBD on reducing the number of TNBC colonies. We have also shown higher uptake of doxorubicin and reduced viability after CBD treatment in cells overexpressing TRPV2 compared with empty vector-transfected cells (37). TRPV2 contains 6 transmembrane domains and a pore loop, which is involved in the uptake of ions. We have shown that cells overexpressing mutant TRPV2 that lacks pore loop show reduced doxorubicin uptake compared with vector control–expressing cells. We analyzed the effect of CBD on drug-resistant lung cancer cell lines and showed that CBD significantly inhibited colony and sphere formation of cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines. There was a significant inhibition of the cancer stem cells in NSCLC cells that were treated with CBD. In addition, we observed that CBD significantly inhibited the migration of the drug-resistant NSCLC. In conclusion, our studies indicate that CB2 is highly expressed in breast cancer, and its expression correlates with better prognosis in TNBC. The CB2 agonist JWH inhibits TNBC growth and metastasis in different mouse models, including the patient-derived xenograft mouse model. JWH also inhibits CXCL12-induced functional effects. We also have shown that CBD inhibits TNBC growth and metastasis, and CBD-treated tumors show reduced M2-TAMs. TRPV2 is highly expressed in breast cancer tissues, and its expression correlates with a better prognosis in TNBC, especially for those treated with chemotherapy. CBD increases doxorubicin uptake and apoptosis in TNBC by activating TRPV2. CBD inhibits the growth and migration of drug-resistant lung cancer cells. CBD could be used as a novel therapeutic strategy to enhance the efficacy of chemotherapeutic drugs and to enhance antitumor immune responses by decreasing immunosuppressive TAMs. Additional studies are needed to analyze the role of cannabinoids in the tumor microenvironment. Cannabis and Immunotherapy: Gil Bar-Sela Medical cannabis as a possible therapeutic intervention for cancer patients is highly visible these days (39). Nonetheless, only limited data from preliminary randomized clinical trials, focused mainly on feasibility of using cannabis for oncology symptoms, support its robust widespread use among oncology patients as a palliative treatment (40,41). Cannabis has predominantly been consumed for the treatment of cancer symptoms and therapy-related adverse events, such as nausea, anorexia, and cancer-related pain (39,40). Thus far, clear comprehension and full appreciation and awareness of its overall influence and effects on the immune system are not well understood. For example, the potent anti-inflammatory effects of medical cannabis in general and cannabinoids, in particular, have long been known, whereas the secondary effect of cannabis consumption on the immune system as a regulator of inflammation is frequently overlooked (42-44). Endocannabinoids are natural endogenous ligands of G protein–coupled receptors CB1 and CB2. This ubiquitous system, defined as the endocannabinoid system, is now recognized as regulating several physiological conditions and numerous diseases (45,46). Most recently, additional receptors have been identified as part of an extended endocannabinoid system (47,48), which is known to regulate immune responses in different cell types (49). Phytocannabinoids—the natural components of the cannabis plant—interact with the extended endocannabinoid system by activating and/or inhibiting different cannabinoid receptors and endocannabinoid transporters or affect the biosynthesis and degradation of endocannabinoid enzymes (46,50). Of late, endocannabinoids and phytocannabinoids have been shown to affect many immune cell functions, including control of cytokine secretion, induction of apoptosis, immune cell activation (both innate and adaptive system), promotion of chemotaxis, and modulation of pathogen clearance during infection (42,49,51). Because cannabis is now widely used by oncology patients, it is essential to better understand its effects on the immune system, especially those related to anticancer treatments, which are often disregarded by clinicians and patients using cannabinoids. Immune checkpoint inhibitors, targeting the molecules CTLA4, PD-1, and PD-L1, have changed the therapeutic landscape for patients with several advanced cancers (52,53). Our group’s first retrospective observational study demonstrated that medical cannabis consumption during immunotherapy could significantly reduce nivolumab response rates (54). A more extensive prospective observational study that evaluated the clinical outcome of cannabis use during immunotherapy in patients with numerous advanced malignancies was recently conducted (5). We clinically monitored 102 (68 immunotherapy and 34 immunotherapy plus cannabis) consecutive patients with advanced malignancies who initiated immunotherapy and compared cannabis users with nonusers. In parallel, we probed the levels of different endocannabinoids to test their possible effects on anticancer therapy and tumor progression (5). This study on the impact of cannabis consumption during immune checkpoint inhibitor immunotherapy cancer treatment showed that concurrent cannabis use might be associated with worsening of clinical outcomes. Cancer patients who used cannabis showed a significantly shorter time to tumor progression (TTP) (cannabis-users 3.4 months, 95% confidence interval [CI] = 1.8 to 6.0) vs 13.1 months (95% CI = 6.0 to noncalculable (NC)) for nonusers) and decreased overall survival (OS) compared with nonusers (cannabis users 6.4 months, 95% CI = 3.2 to 9.7, and 28.5 months, 95% CI = 15.6 to NC for non-users). The analysis was conducted with an adjustment for the line of treatment and showed significant estimated hazard ratios of 1.95 (95% CI = 1.17 to 3.26 for TTP and 2.18, 95% CI = 1.24 to 3.82 for OS; P = .011 and P = .007), respectively. Moreover, the use of cannabis was associated with reduced immune-related adverse events. In addition, we also analyzed a panel of serum endocannabinoids and endocannabinoid-like lipids, measuring their levels before and after immunotherapy in both the cannabis users and nonusers. Prior to immunotherapy, levels of serum endocannabinoids and endocannabinoid-like lipids showed no significant differences between the 2 groups, suggesting that the cannabis effect is most probably due to the phytocannabinoids. This study may have been biased as a significant difference was noted in that 46% of the cannabis nonusers were receiving immunotherapy as first-line treatment of their cancer compared with only 24% of the cannabis users (P = .03). The fact that three-quarters of those using cannabis were doing so in conjunction with second-line or greater immunotherapy obfuscates the contribution of the cannabis itself vs a more progressed state of disease to the inferior outcomes reported. Nevertheless, our findings collectively demonstrate that medical cannabis consumption has considerable immunomodulatory effects, and its use among cancer patients needs to be carefully considered because of its potential effects on the immune system, especially during immune checkpoint inhibitor treatment (5). Although we observed that cannabis consumption negatively impacts immune checkpoint inhibitor treatment effectiveness, the mechanism is unclear. Currently, the absence of mechanistic studies supporting the notion that cannabis exposure inhibits the reactivation of the immune response upon treatment with immune checkpoint inhibitors serves as no more than a warning that may not reflect the full effect of cannabinoids on the efficacy of this anticancer treatment. Because the inhibitory effect of cannabis on lymphocytes has been widely observed before (55-59), we are now clinically trying to map and characterize the “real-life” T-cell lymphocyte populations of cancer patients, comparing blood analysis of patients on active oncology treatment before initiation of cannabis and after 6 and 12 weeks of regular cannabis use. A better understanding of the impact of cannabis consumption in cancer patients will help in adjusting and optimizing cannabis use as a palliative cancer treatment and minimizing its potential risks for adverse effect on patients’ overall survival and time to TTP. Conclusions Since the 1975 Journal of the National Cancer Institute publication of “Antineoplastic Activity of Cannabinoids” (1), a tremendous amount of basic scientific investigation has been performed to elucidate the mechanisms and pathways by which cannabis-based medicines and cannabinoids may become valuable additions in the fight against cancer. Translating the elegant preclinical data into evidence of benefit to the patient is proving to be a complex endeavor. Hopefully, continued discoveries from the Velasco and Ganju laboratories will spawn clinical investigations that will someday yield significant evidence of a benefit of cannabis, cannabis-based medicines, or individual cannabis components, be they cannabinoids or terpenes, in patients with cancer. For now, we have a glimmer of hope from the small trial of nabiximols in patients with recurrent glioblastoma. Despite 8 of the 12 nabiximols recipients and 6 of the 9 placebo recipients progressing during the first 6 months of follow-up, survival at 12 and 24 months certainly favored the group receiving the cannabis-based medicine. Although caution must be used in interpreting the results from this small early phase clinical trial designed as a feasibility and tolerability study and not with survival as a primary endpoint, it does deserve kudos for being randomized and placebo controlled. Further research is warranted; indeed, additional studies are being launched. The observational study of the Israeli cohort of patients with advanced cancers receiving immunotherapy with immune checkpoint inhibitors has been practice changing already for many oncologists treating patients with these agents. The current inclination is to caution patients regarding the significant difference in progression-free and overall survival in patients who chose to use cannabis with their immunotherapy intervention and those who did not. A randomized controlled trial would be a challenge to conduct. As mentioned, the observational study presents a potential for bias that may have influenced the reported results. However, in the absence of what would certainly be a difficult randomized controlled study to conduct, clinicians should now apprise patients embarking on immunotherapy regimens of these findings so they may be aware of the potential risks. Hopefully, the future will see more of the preclinical observations of the anticancer effects of cannabis-based medicines translating into clinical benefit for cancer patients. Funding No funding was received in the creation of this manuscript. Notes Role of the funder: Not applicable. Disclosures: DIA: Scientific Advisor to AXIM, Cannformatics, Lumen, Maui Grown Therapies. GV: Past research grants from Schering Plough, GW Pharma Ltd and Cellmid Ltd and current grant from Neuron Consulting. Consultant for GW Pharma Ltd. RKG: Consultant to Guidepoint. CT, GBS: Nothing to disclose. Author contributions: GV, CT, RG, and GB-S presented at the conference and edited the transcription of their presentations. DA organized the manuscript, wrote the abstract, introduction, and conclusions and merged the speaker’s sessions into the final document. CT was also instrumental in editing the document. Acknowledgements: With gratitude to Jeffrey White, MD, for his role in co-chairing session 6 and organizing the meeting. Disclaimers: None . References 1 Munson AE , Harris LS, Friedman MA, et al. Antineoplastic activity of cannabinoids . J Natl Cancer Inst . 1975 ; 55 ( 3 ): 597 – 602 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Velasco G , Sanchez C, Guzman M. 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Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Cancer Treatment: Preclinical & Clinical

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Oxford University Press
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Copyright © 2021 Oxford University Press
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1052-6773
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10.1093/jncimonographs/lgab010
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Abstract

Abstract The first evidence that cannabinoids may have in vitro and in vivo antineoplastic activity against tumor cell lines and animal tumor models was published in the Journal of the National Cancer Institute nearly 50 years ago. Cannabinoids appear to induce apoptosis in rodent brain tumors by way of direct interaction with the cannabinoid receptor. They may inhibit angiogenesis and tumor cell invasiveness. Despite preclinical findings, attempts to translate the benefits from bench to bedside have been limited. This session provides a review of the basic science supporting the use of cannabinoids in gliomas, paired with the first randomized clinical trial of a cannabis-based therapy for glioblastoma multiforme. Another preclinical presentation reports the effects of cannabinoids on triple-negative breast cancer cell lines and how cannabidiol may affect tumors. The session’s second human trial raises concerns about the use of botanical cannabis in patients with advanced cancer receiving immunotherapy suggesting inferior outcomes. Funded by the National Institute on Drug Abuse and the American Cancer Society among others, investigators at the Medical College of Virginia/Virginia Commonwealth University investigated 4 cannabinoids for antineoplastic activity against 3 animal tumor models in vivo and 2 in vitro systems (1). They published their findings in the Journal of the National Cancer Institute in 1975, reporting that delta-9-tetrahydrocannabinol (THC), delta-8-tetrahydrocannabinol, and cannabinol were all active in vivo against Lewis lung carcinoma xenografts and in vitro. Of note, tumor growth rate in mice treated with cannabidiol (CBD) was significantly increased compared with controls in this early report. The investigators concluded that since cannabinoids readily cross the blood-brain barrier and are not as toxic as most of the cytotoxic agents used at the time, they are “an appealing group of drugs to study.” By the time these findings were published, cannabis had already been made a schedule I substance deemed to have a high potential for abuse and no accepted medical use, which served to inhibit the future investigations envisioned. After a significant gap in time, however, interest in exploring cannabinoids, particularly as agents that might be active against tumors of the central nervous system, has been reinvigorated. Elegant preclinical studies, largely emanating from the research of Guillermo Velasco et al. (2), have demonstrated the direct antitumor activity of cannabinoids against gliomas in vitro. In addition, cannabinoids have been shown to inhibit vascular endothelial growth factor and matrix mettalloproteinase-2, serving to decrease angiogenesis, invasiveness, and metastases. Despite this promising preclinical evidence, however, the 2017 report from the National Academies of Sciences, Engineering, and Medicine on The Health Effects of Cannabis and Cannabinoids concluded that “there is insufficient evidence to support or refute the conclusion that cannabinoids are an effective treatment for cancers, including glioma” (3). This was largely driven by the lack of controlled clinical trials supporting any benefit of cannabis, cannabis-based medicines, or individual cannabinoids in patients with malignant diagnoses. This session on “Cancer Treatment: Preclinical & Clinical” serves to help move the field from bench to bedside by presenting 2 basic science overviews and the findings of 2 clinical studies involving cancer patients. Guillermo Velasco from Madrid reviews much of his group’s work on investigating cannabinoids as anticancer agents, with a focus on gliomas generated in rodents. These findings served as the basis of the phase I clinical trial of nabiximols, a whole plant extract with a THC to CBD ratio of 1:1, in patients with recurrent glioblastoma multiforme presented by Chris Twelves from the University of Leeds (4). Investigations by Ramesh Ganju, from The Ohio State University, demonstrate that CBD has more positive antitumor potential than reported in the 1975 publication and elucidate the role of the immune system, particularly tumor-associated macrophages, in CBD’s effects. Finally, Gil Bar-Sela from Emek Medical Center and Technion/Israel Institute of Technology reviews his group’s findings from their observational study of outcomes in patients with advanced cancer receiving immunotherapy in those who do and do not use botanical cannabis (5). These findings, although not emanating from a randomized controlled trial that would have less potential for bias, certainly warrant further research on the use of cannabis during treatment with immunotherapy. Toward the Utilization of Cannabinoids as Anticancer Agents: Guillermo Velasco Cannabinoids as Therapeutic Agents in Oncology In addition to their well-established palliative benefits in patients with cancer, numerous preclinical studies have provided evidence that THC and other cannabinoids exhibit antitumor effects in a wide array of animal models of cancer and specifically in gliomas (1,6). Cannabinoids inhibit cancer progression through various mechanisms, the most common being the induction of cancer cell death by the stimulation of an endoplasmic reticulum stress-related, autophagy-mediated cell death pathway that leads to the induction of apoptosis (1,6). In addition, cannabinoids inhibit angiogenesis and block invasion in gliomas and inhibit metastases in other tumor types (1,6). It is worth noting that CBD, by acting independently of cannabinoid receptor types 1 and 2 (CB1 and CB2), produces antitumor effects in various tumor animal models, including gliomas (7). Cannabinoid-Based Anticancer Therapies in Glioblastoma Multiforme The first clinical investigation of the potential efficacy of cannabinoids as anticancer agents was a pilot phase I study in 9 patients with recurrent glioblastoma multiforme to whom THC was administered intracranially (8). Although no statistically significant conclusions can be extracted from a cohort of 9 patients, the results obtained in the study suggest that some patients may have benefited briefly from THC treatment in terms of reduced tumor volume on serial magnetic resonance imaging scans. Interestingly, analyses of samples obtained from 2 study patients before and after THC administration supported the notion that the molecular mechanism of cannabinoid antitumor action initially described in cellular and animal models is also activated in patients (8). The results of this first clinical study were encouraging but also pointed to the need for defining strategies to optimize the possible future use of cannabinoids as anticancer agents. The Velasco laboratory focused on 3 aspects: 1) improving knowledge about the mechanisms underlying the anticancer activity of cannabinoids, 2) identifying the factors that promote resistance to THC or cannabinoid anticancer activity, and 3) investigating the efficacy of cannabinoid-based combinational therapies. As described in further detail in other sections of this special issue, we identified the prominent role of TRIB3-dependent inhibition of the AKT–mTORC1 axis as a key step in THC-induced autophagy and cell death (9,10). Likewise, we found that THC triggered a modification on the sphingolipid composition of the endoplasmic reticulum that is transmitted to the autophagosomes (11). These changes, in turn, lead to the destabilization of autolysosomes thereby promoting the release of cathepsins and the subsequent activation of the apoptotic death of glioma cells (11). As discussed below, these observations may help the design of combination therapies based on adding cannabinoids to agents that can potentiate actions on these signaling pathways. Another strategy to optimize the utilization of cannabinoids as anticancer agents is based on the identification of the factors that determine sensitivity to treatment with these agents. Gene expression profile studies developed in cell lines and primary cultures of glioma cells demonstrated that increased expression of the neurotrophic factor midkine (MDK) (12), and the estimated glomerular filtration rate–ligand amphiregulin (13) could be biomarkers of resistance to THC and other anticancer agents (12). Likewise, we found that blockade of the MDK–anaplastic lymphoma kinase (ALK) axis could overcome this resistance by facilitating the activation of the autophagy-mediated cell death pathway (12,14). Moreover, MDK plays a prominent role in gliomas and specifically in glioma-initiating cells, a cell subpopulation that has been proposed to be responsible for the relapses that occur in most, if not all, patients with aggressive brain tumors. Blockade of the MDK–ALK axis, together with cannabinoids, efficiently targets this cell subpopulation (14) (see other unpublished observations as well), which could be a potentially interesting strategy acting on glioma-initiating cells to reduce or delay the incidence of relapse in patients with glioblastoma multiforme. These results constitute preclinical proof of the concept that biomarkers of resistance to cannabinoid anticancer activity can be identified, and it is possible to design therapies that can overcome this resistance. Subsequent research investigated whether the use of cannabinoids as anticancer agents could be optimized by assessing the efficacy of cannabinoid-based combination therapies. The administration of THC and temozolomide exerts strong antitumor action in glioma xenografts, an effect that also is evident in temozolomide-resistant tumors (15-17). THC to CBD combinations at a 1:1 ratio maintained the capacity to synergize with temozolomide and produce strong anticancer activity.15,16 Of note, these combinations resemble the composition of nabiximols (Sativex, GW Research Limited, Cambridge, United Kingdom), an oromucosal cannabis spray that has been used for therapeutic purposes. A similar effect was observed when THC and CBD were combined with radiotherapy in animal models of glioma (18). These results served as the basis for the development of a phase Ib trial aimed at evaluating the combination of nabiximols and temozolomide in patients with recurrent glioblastoma multiforme (NCT01812603 and NCT01812616). The results of the study have recently been published and are discussed in more detail below (4). Although the study was small, a statistically significant increase in the survival of the nabiximols and temozolomide arm at 1 and 2 years was observed (4). There is, therefore, a clear rationale for developing additional clinical studies. In this context, a new clinical study promoted and coordinated by the Spanish Group of Research in Neuro-Oncology (GEINO) is currently under preparation to investigate the effect of THC to CBD (1:1 ratio) plus temozolomide and radiation therapy in patients with recently diagnosed glioblastoma multiforme (GEINOCANN-NCT03529448). Although these studies have been performed mainly in patients with glioblastoma multiforme, it would be appropriate to follow a similar strategy in other cancer types in which preclinical data have yielded promising results. Identifying biomarkers of resistance and molecular alterations that could be associated with a better or worse response to cannabinoid treatments and designing the most appropriate cannabinoid-based combinational therapies for each tumor type and subtype are critical in defining the best strategy to incorporate cannabinoids into future cancer therapies. This research should facilitate the development of additional clinical studies that could help clarify if (and when) these compounds can be incorporated within the oncology toolkit. A Phase 1 b Randomized, Placebo-Controlled Trial of Nabiximols Cannabinoid Oromucosal Spray With Temozolomide in Patients With Recurrent Glioblastoma: Chris Twelves Glioblastoma multiforme is the most common malignant primary brain tumor in adults. Glioblastoma multiforme is incurable and has a 5-year survival rate of less than 6% (19). The current optimal therapy is debulking surgery, followed by local high-dose radiotherapy and temozolomide chemotherapy (20). The median overall survival is 14.6 months for those well enough to undergo treatment. Tumor recurrence usually occurs 6 to 9 months after treatment. After recurrence, the median overall survival is 1.0 to 10.8 months (21,22). Substantial advances have been made in the treatment of most cancer types; however, for patients with glioblastoma multiforme, this treatment with surgery, radiotherapy, and chemotherapy has remained the standard of care for the last 30 years. Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromising DNA repair is both a relatively favorable prognostic factor and predictive of a benefit from temozolomide (23). There is no current standard of care for patients with recurrent glioblastoma multiforme (24). Glioblastoma multiforme expresses CB1 and CB2 receptors, with high-grade tumors expressing high levels of CB2 (25). CBD and THC reduce glioma growth in preclinical models (26). The combination of THC and temozolomide, the standard chemotherapeutic agent used in treating glioblastoma multiforme, has substantial antitumoral activity in glioma xenografts, including those resistant to temozolomide (17). There is, therefore, a rationale for looking at cannabinoids in patients with glioblastoma multiforme. Notwithstanding these preclinical data, the only clinical data as yet come from the trial described earlier (8), which was a pilot study of instilling THC into the cavity where the brain tumor had been resected and recurred. This proved to be safe, with suggestions of brief reductions in tumor volume postoperatively. There was evidence of ex vivo biological activity in the form of reduced cell proliferation in 2 of the treated patients. Nabiximols oromucosal spray (Sativex) is a complex formulation containing THC and CBD, with additional cannabinoid and noncannabinoid components. Nabiximols is currently approved for symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis, who have not responded adequately to other antispasticity medications, in more than 25 countries, but not in the United States. A clinical trial to evaluate the safety and preliminary efficacy of nabiximols plus dose-intense temozolomide in patients with first recurrence of confirmed glioblastoma multiforme was designed (4). Patients older than age 18 years who had previously received radiotherapy and first-line temozolomide with a Karnofsky Performance Status of 60% or more were eligible for enrollment. The study was a 2-part phase 1 b trial at 10 sites (7 in the United Kingdom and 3 in Germany) conducted from January 2014 to August 2016. Doses of nabiximols (or placebo in the second part of the trial) were individualized. Participants started taking 1 spray per day of study medication on day 1. If tolerated, they escalated by 1 additional spray per day to a maximum of 12 sprays per day. If unacceptable side effects occurred, the study medication dose was reduced or stopped until resolved. The cap on the total number of sprays that patients could receive resulted in a maximum 30 mg CBD and 32.4 mg THC each day. The patients received the study medication while taking dose-intense temozolomide chemotherapy at 85 mg/m2 daily for 21 days, followed by a 7-day break for 13 cycles. The more intense temozolomide regimen is not universally used; however, it was selected to optimize chemotherapy in patients with relapsed glioblastoma multiforme. Patients could remain on treatment for a year or until they discontinued the trial. As this was an early phase clinical trial, tolerability was the primary endpoint as reflected by treatment-related serious adverse events. Secondary endpoints were preliminary evaluation of the efficacy of nabiximols (with dose-intense temozolomide) by progression-free survival at 6 months by magnetic resonance imaging (using response assessment in neuro-oncology criteria) and survival at 1 year; temozolomide pharmacokinetics were also studied. An additional, post hoc 2-year survival analysis was undertaken using the European Organisation for Research and Treatment of Cancer prognostic calculator. In part 1 of the trial, 6 patients in 2 cohorts received nabiximols as above. Once titration was completed and a stable personalized nabiximols dose was established, patients took a mean of 6 sprays per day. Three patients withdrew because of adverse events (1 each for lethargy, dizziness, and fatigue; nausea, diarrhea, and vomiting; and depressed mood). Following safety review team approval, in part 2, a total of 21 patients were randomized 1:1 to dose-intense temozolomide plus nabiximols (n = 12) or placebo (9); the 2 groups were similar in age and performance status. Patients in the nabiximols group received fewer sprays per day than those in the placebo group (mean 7.5 and 10, respectively); however, the mean dose of dose-intense temozolomide was almost identical (81.2 mg/m2 and 81.1 mg/m2, respectively), so co-administration of the cannabinoids did not impact negatively on the dose of chemotherapy. The major treatment-associated adverse effects included vomiting, dizziness, nausea, and fatigue, with more side effects noted in the cannabinoid recipients. Toxicity was, however, relatively modest compared with that of most chemotherapy. The study achieved its primary endpoint of showing that nabiximols was tolerable, and personalized dosing was feasible in this population without any new safety concerns. There was no evidence to suggest an effect of nabiximols on the pharmacokinetics of dose-intense temozolomide. With regard to efficacy, there was no difference in progression-free survival at 6 months (33% in both arms); however, there was a striking difference in overall survival at 12 months, which was 83% in the nabiximols arm compared with 44% in the placebo arm (nominal P = .04). It is important to emphasize that this was not designed as an efficacy study, nor was it powered for a survival endpoint. Because of the encouraging data, a post hoc analysis was performed of overall survival at 2 years, which was again higher in the nabiximols arm (50% and 22%; nominal P = .13). Overall, patients in both arms of the study had better outcomes than might be expected, perhaps because as clinical trial participants, they were not fully representative of patients in routine care. Nevertheless, in a second post hoc analysis, the survival of 10 of the 12 patients treated with nabiximols exceeded that predicted by the European Organisation for Research and Treatment of Cancer prognostic calculator, compared with just 3 of the 9 on the placebo arm. Again, this suggests a difference in efficacy between the 2 arms. This first systematic evaluation of a cannabis-based therapy in a randomized trial in patients with recurrent glioblastoma multiforme was, however, small so the possibility that this is a random finding due to bias remains; the absence of data on MGMT methylation is a significant limitation. An accompanying editorial, titled “Cannabinoids in Glioblastoma Multiforme—Hype or Hope?” described the findings as “intriguing” and advised that they be “interpreted with significant caution,” and acknowledged that “these interesting findings, backed up by a strong preclinical rationale, still warrant urgent exploration of the combination of temozolomide and nabiximols in a sufficiently powered larger study” (27). In conclusion, nabiximols spray was tolerated, and personalized dosing was feasible in this patient population. Although the observed survival differences should be interpreted with caution, they do justify further exploration in an adequately powered randomized controlled trial. A multicenter phase II trial is in development in the United Kingdom. Cannabinoid-Mediated Novel Signaling Mechanisms in Cancer: Current Status and Future Implications: Ramesh Ganju Cannabinoids can be divided into different groups, based on their source of origin, as endogenously produced cannabinoids (endocannabinoids), chemically produced synthetic cannabinoids, and plant-derived cannabinoids (phytocannabinoids) (28). The Ganju laboratory analyzed the effect of the synthetic cannabinoids, designated as JWH, and the phytocannabinoid (CBD) on breast and lung cancer (29,30). Of new cancer cases in women, 42% are breast and lung cancer, and in men, lung cancer accounts for about 13% of new cases. Metastases are the major cause of mortality in patients with these and other cancers. The effect of the synthetic cannabinoid JWH-133, which binds to CB2, on breast cancer in culture was first analyzed. Using breast cancer tissue microarrays, the CB2 receptor was shown to be expressed by breast cancer tissues. Using a publicly available dataset, patients whose cancers expressed higher levels of the CB2 receptor had better overall survival compared with those whose cancers expressed lower amounts of the CB2 receptor. We also analyzed the effect of the CB2 agonist JWH-133 on growth and metastasis of the triple-negative breast cancer (TNBC) cell line MDA-MB-231 in vivo. Among the different subtypes of breast cancers, TNBC represents approximately 20% of all cases and is associated with poorer prognosis and survival than other molecular subtypes because of early metastasis to other organs. In addition, unlike patients with other breast cancer phenotypes, those with TNBC lack clinically effective targeted therapies (31). JWH was shown to inhibit the growth and metastasis of TNBC cells. Furthermore, these effects were mediated through the CB2 receptor because the CB2 antagonist, SR144528, partially abrogated the effects of JWH on growth and metastasis (30). We also have observed that JWH-015 inhibits growth and spontaneous metastasis of the murine TNBC cell line MVT1 in a syngeneic mouse model (32). In addition, we have seen that CB2 receptor knockout mice injected with murine TNBC cells show more tumor growth and metastasis compared with wild-type mice. Furthermore, JWH-015 treatment inhibited growth and metastasis in wild-type mice but had no effect on CB2 receptor knockout mice. We also have shown that JWH-015 treatment inhibits the growth of a TNBC patient-derived xenograft model. Furthermore, we have shown that JWH treatment increases recruitment of CD8-positive T cells to tumors compared with vehicle-treated mice. We also have analyzed the effect of JWH-015 on various signaling pathways and have shown that CB2 agonist inhibits the functional effects of chemokine CXCL12 that binds to the chemokine receptor CXCR4 (33). CXCL12–CXCR4 signaling plays an important role in breast cancer metastasis. We have shown that JWH-015 inhibits CXCL12-induced migration, invasion, and wound healing of TNBC cells. CBD may comprise up to 40% of the Cannabis sativa plant and does not have psychotropic activity. A few clinical trials with CBD as a sole agent against a range of neurological disorders have been conducted. Notably, oral administration of CBD in doses up to 600-800 mg per day has been shown to be safe and well tolerated in clinical trials conducted in healthy subjects (34-36). We have analyzed the effect of CBD on the viability of human TNBC cells (SUM159 and MDA-MB-231) and mouse TNBC cells (4T1) and demonstrated that CBD significantly inhibits the viability of these cells (32). Furthermore, we have shown that CBD inhibits growth and metastasis of mouse TNBC cells 4 T-1 and MVT-1 in a syngeneic mouse model. We also analyzed the effect of CBD treatment on immune cell infiltration and found that CBD significantly inhibits the recruitment of F4/80 positive tumor-associated macrophages (TAMs) compared with vehicle control–treated mice. We further showed that CBD inhibits the recruitment of M2-TAMs (CD206 positive/F4/F80 positive cells). We analyzed the mechanism by which CBD inhibits the recruitment of TAMs into tumors and showed that CBD inhibits the production of cytokine GM-CSF and chemokine MIP-2 and CCL3. These chemokines have been shown to play an important role in regulating the recruitment of immune cells in the tumors. Recently, CBD has been shown to bind to transient receptor potential vanilloid type-2 (TRPV2). TRPV2 is a nonselective cation ion channel, involved in a variety of physiological and pathological processes. We analyzed the expression of TRPV2 in tumor samples from breast cancer patients and observed that TRPV2 was highly expressed in malignant and metastatic breast cancer compared with normal breast tissue. We also have analyzed protein expression in 120 TNBC patients’ samples by immunohistochemistry. Most of the TNBC patients’ tumors showed strong to moderate expression of TRPV2. TRPV2 also was highly expressed in human and mouse TNBC cell lines. Furthermore, we have shown that patients whose cancers expressed high levels of TRPV2 (or mRNA) had substantially better recurrence-free survival than those whose cancers expressed low TRPV2 (37). Patients with estrogen receptor–negative breast cancer who had higher TRPV2 expression and received chemotherapy treatment showed better recurrence-free survival than those who had lower expression of TRPV2. However, in patients with estrogen receptor–negative breast cancer who did not receive chemotherapy, no significant difference in recurrence-free survival was observed between those who had high or low TRPV2 expression. TRPV2 contains a pore-forming transmembrane loop that allows ions (Ca2+ and Mg2+) and xenobiotics to permeate biological membranes (38). We analyzed the effect of CBD on doxorubicin uptake in TNBC cells. We measured the uptake of doxorubicin by flow cytometry in the presence or absence of CBD. TNBC cells that were treated with CBD in combination with doxorubicin had higher drug uptake than cells treated with doxorubicin alone. In addition, TNBC cells treated with doxorubicin in the presence of CBD showed reduced viability, reduced colonies, and significantly higher apoptosis and apoptotic markers compared with those treated with doxorubicin or CBD alone. To further confirm that the effect is mediated by TRPV2, we used the TRPV2 pore blocker (tranilast) and showed that this abrogated the increase in doxorubicin caused by CBD treatment; it also reduced the expression levels of apoptotic markers. TRPV2 downregulation inhibited doxorubicin uptake and also abrogated the effect of doxorubicin and CBD on reducing the number of TNBC colonies. We have also shown higher uptake of doxorubicin and reduced viability after CBD treatment in cells overexpressing TRPV2 compared with empty vector-transfected cells (37). TRPV2 contains 6 transmembrane domains and a pore loop, which is involved in the uptake of ions. We have shown that cells overexpressing mutant TRPV2 that lacks pore loop show reduced doxorubicin uptake compared with vector control–expressing cells. We analyzed the effect of CBD on drug-resistant lung cancer cell lines and showed that CBD significantly inhibited colony and sphere formation of cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines. There was a significant inhibition of the cancer stem cells in NSCLC cells that were treated with CBD. In addition, we observed that CBD significantly inhibited the migration of the drug-resistant NSCLC. In conclusion, our studies indicate that CB2 is highly expressed in breast cancer, and its expression correlates with better prognosis in TNBC. The CB2 agonist JWH inhibits TNBC growth and metastasis in different mouse models, including the patient-derived xenograft mouse model. JWH also inhibits CXCL12-induced functional effects. We also have shown that CBD inhibits TNBC growth and metastasis, and CBD-treated tumors show reduced M2-TAMs. TRPV2 is highly expressed in breast cancer tissues, and its expression correlates with a better prognosis in TNBC, especially for those treated with chemotherapy. CBD increases doxorubicin uptake and apoptosis in TNBC by activating TRPV2. CBD inhibits the growth and migration of drug-resistant lung cancer cells. CBD could be used as a novel therapeutic strategy to enhance the efficacy of chemotherapeutic drugs and to enhance antitumor immune responses by decreasing immunosuppressive TAMs. Additional studies are needed to analyze the role of cannabinoids in the tumor microenvironment. Cannabis and Immunotherapy: Gil Bar-Sela Medical cannabis as a possible therapeutic intervention for cancer patients is highly visible these days (39). Nonetheless, only limited data from preliminary randomized clinical trials, focused mainly on feasibility of using cannabis for oncology symptoms, support its robust widespread use among oncology patients as a palliative treatment (40,41). Cannabis has predominantly been consumed for the treatment of cancer symptoms and therapy-related adverse events, such as nausea, anorexia, and cancer-related pain (39,40). Thus far, clear comprehension and full appreciation and awareness of its overall influence and effects on the immune system are not well understood. For example, the potent anti-inflammatory effects of medical cannabis in general and cannabinoids, in particular, have long been known, whereas the secondary effect of cannabis consumption on the immune system as a regulator of inflammation is frequently overlooked (42-44). Endocannabinoids are natural endogenous ligands of G protein–coupled receptors CB1 and CB2. This ubiquitous system, defined as the endocannabinoid system, is now recognized as regulating several physiological conditions and numerous diseases (45,46). Most recently, additional receptors have been identified as part of an extended endocannabinoid system (47,48), which is known to regulate immune responses in different cell types (49). Phytocannabinoids—the natural components of the cannabis plant—interact with the extended endocannabinoid system by activating and/or inhibiting different cannabinoid receptors and endocannabinoid transporters or affect the biosynthesis and degradation of endocannabinoid enzymes (46,50). Of late, endocannabinoids and phytocannabinoids have been shown to affect many immune cell functions, including control of cytokine secretion, induction of apoptosis, immune cell activation (both innate and adaptive system), promotion of chemotaxis, and modulation of pathogen clearance during infection (42,49,51). Because cannabis is now widely used by oncology patients, it is essential to better understand its effects on the immune system, especially those related to anticancer treatments, which are often disregarded by clinicians and patients using cannabinoids. Immune checkpoint inhibitors, targeting the molecules CTLA4, PD-1, and PD-L1, have changed the therapeutic landscape for patients with several advanced cancers (52,53). Our group’s first retrospective observational study demonstrated that medical cannabis consumption during immunotherapy could significantly reduce nivolumab response rates (54). A more extensive prospective observational study that evaluated the clinical outcome of cannabis use during immunotherapy in patients with numerous advanced malignancies was recently conducted (5). We clinically monitored 102 (68 immunotherapy and 34 immunotherapy plus cannabis) consecutive patients with advanced malignancies who initiated immunotherapy and compared cannabis users with nonusers. In parallel, we probed the levels of different endocannabinoids to test their possible effects on anticancer therapy and tumor progression (5). This study on the impact of cannabis consumption during immune checkpoint inhibitor immunotherapy cancer treatment showed that concurrent cannabis use might be associated with worsening of clinical outcomes. Cancer patients who used cannabis showed a significantly shorter time to tumor progression (TTP) (cannabis-users 3.4 months, 95% confidence interval [CI] = 1.8 to 6.0) vs 13.1 months (95% CI = 6.0 to noncalculable (NC)) for nonusers) and decreased overall survival (OS) compared with nonusers (cannabis users 6.4 months, 95% CI = 3.2 to 9.7, and 28.5 months, 95% CI = 15.6 to NC for non-users). The analysis was conducted with an adjustment for the line of treatment and showed significant estimated hazard ratios of 1.95 (95% CI = 1.17 to 3.26 for TTP and 2.18, 95% CI = 1.24 to 3.82 for OS; P = .011 and P = .007), respectively. Moreover, the use of cannabis was associated with reduced immune-related adverse events. In addition, we also analyzed a panel of serum endocannabinoids and endocannabinoid-like lipids, measuring their levels before and after immunotherapy in both the cannabis users and nonusers. Prior to immunotherapy, levels of serum endocannabinoids and endocannabinoid-like lipids showed no significant differences between the 2 groups, suggesting that the cannabis effect is most probably due to the phytocannabinoids. This study may have been biased as a significant difference was noted in that 46% of the cannabis nonusers were receiving immunotherapy as first-line treatment of their cancer compared with only 24% of the cannabis users (P = .03). The fact that three-quarters of those using cannabis were doing so in conjunction with second-line or greater immunotherapy obfuscates the contribution of the cannabis itself vs a more progressed state of disease to the inferior outcomes reported. Nevertheless, our findings collectively demonstrate that medical cannabis consumption has considerable immunomodulatory effects, and its use among cancer patients needs to be carefully considered because of its potential effects on the immune system, especially during immune checkpoint inhibitor treatment (5). Although we observed that cannabis consumption negatively impacts immune checkpoint inhibitor treatment effectiveness, the mechanism is unclear. Currently, the absence of mechanistic studies supporting the notion that cannabis exposure inhibits the reactivation of the immune response upon treatment with immune checkpoint inhibitors serves as no more than a warning that may not reflect the full effect of cannabinoids on the efficacy of this anticancer treatment. Because the inhibitory effect of cannabis on lymphocytes has been widely observed before (55-59), we are now clinically trying to map and characterize the “real-life” T-cell lymphocyte populations of cancer patients, comparing blood analysis of patients on active oncology treatment before initiation of cannabis and after 6 and 12 weeks of regular cannabis use. A better understanding of the impact of cannabis consumption in cancer patients will help in adjusting and optimizing cannabis use as a palliative cancer treatment and minimizing its potential risks for adverse effect on patients’ overall survival and time to TTP. Conclusions Since the 1975 Journal of the National Cancer Institute publication of “Antineoplastic Activity of Cannabinoids” (1), a tremendous amount of basic scientific investigation has been performed to elucidate the mechanisms and pathways by which cannabis-based medicines and cannabinoids may become valuable additions in the fight against cancer. Translating the elegant preclinical data into evidence of benefit to the patient is proving to be a complex endeavor. Hopefully, continued discoveries from the Velasco and Ganju laboratories will spawn clinical investigations that will someday yield significant evidence of a benefit of cannabis, cannabis-based medicines, or individual cannabis components, be they cannabinoids or terpenes, in patients with cancer. For now, we have a glimmer of hope from the small trial of nabiximols in patients with recurrent glioblastoma. Despite 8 of the 12 nabiximols recipients and 6 of the 9 placebo recipients progressing during the first 6 months of follow-up, survival at 12 and 24 months certainly favored the group receiving the cannabis-based medicine. Although caution must be used in interpreting the results from this small early phase clinical trial designed as a feasibility and tolerability study and not with survival as a primary endpoint, it does deserve kudos for being randomized and placebo controlled. Further research is warranted; indeed, additional studies are being launched. The observational study of the Israeli cohort of patients with advanced cancers receiving immunotherapy with immune checkpoint inhibitors has been practice changing already for many oncologists treating patients with these agents. The current inclination is to caution patients regarding the significant difference in progression-free and overall survival in patients who chose to use cannabis with their immunotherapy intervention and those who did not. A randomized controlled trial would be a challenge to conduct. As mentioned, the observational study presents a potential for bias that may have influenced the reported results. However, in the absence of what would certainly be a difficult randomized controlled study to conduct, clinicians should now apprise patients embarking on immunotherapy regimens of these findings so they may be aware of the potential risks. Hopefully, the future will see more of the preclinical observations of the anticancer effects of cannabis-based medicines translating into clinical benefit for cancer patients. Funding No funding was received in the creation of this manuscript. Notes Role of the funder: Not applicable. Disclosures: DIA: Scientific Advisor to AXIM, Cannformatics, Lumen, Maui Grown Therapies. GV: Past research grants from Schering Plough, GW Pharma Ltd and Cellmid Ltd and current grant from Neuron Consulting. Consultant for GW Pharma Ltd. RKG: Consultant to Guidepoint. CT, GBS: Nothing to disclose. Author contributions: GV, CT, RG, and GB-S presented at the conference and edited the transcription of their presentations. DA organized the manuscript, wrote the abstract, introduction, and conclusions and merged the speaker’s sessions into the final document. CT was also instrumental in editing the document. Acknowledgements: With gratitude to Jeffrey White, MD, for his role in co-chairing session 6 and organizing the meeting. Disclaimers: None . References 1 Munson AE , Harris LS, Friedman MA, et al. Antineoplastic activity of cannabinoids . J Natl Cancer Inst . 1975 ; 55 ( 3 ): 597 – 602 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Velasco G , Sanchez C, Guzman M. 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Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

JNCI Monographs – Oxford University Press

Published: Nov 28, 2021

Keywords: marijuana; neoplasms; triple-negative breast cancer; nabiximols

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