CRx MAGAZINE

Winter 2020

A Revolution in Cancer Treatment

How One Company Is Combining Cannabis With Cell Encapsulation Technology to Fight Tumors in an Entirely New Way.

In recent years, cannabis-derived therapies have been growing in popularity in the world of cancer care. Clinicians and patients alike have been attracted to cannabis primarily for its palliative benefits, as cannabinoids have been shown to reduce the nausea and vomiting often associated with cancer treatment and provide effective relief for cancer-related pain.

But the benefits of cannabinoids in cancer are not just palliative. In addition to managing nausea and pain, cannabinoids have been shown to attack different types of cancers directly, arresting the growth and development of tumors and preventing the spread of cancerous cells to other parts of the body.

In light of this evidence, a handful of biotech companies are now seeking to harness the power of cannabinoids to develop new breakthrough cancer therapies. Among them is PharmaCyte Biotech, a California-based company that’s rethinking the treatment of solid-tumor cancers by combining the use of cannabinoids with its one-of-a-kind “Cell-in-a-Box” encapsulation technology.

“Our projection is that [this therapy] has the potential to treat many types of solid-tumor cancers”—including breast, lung, colon, and pancreatic cancers, says Mark L. Rabe, MD, cannabis program director at PharmaCyte Biotech. “Our initial strategy is to target brain cancer, but we know that these molecules work against other cancers as well. As long as there’s a solid tumor that Cell-in-a-Box can be implanted adjacent to, it would be a potential target.”

The Anticancer Impacts of Cannabis
Research in the United States on the use of cannabinoids to retard the growth of cancers goes back to the 1970s. In 1975, researchers at the Medical College of Virginia demonstrated that THC—one of the most prominent cannabinoids—has anticancer properties in lab mice. Their study, which was funded by the US government, found that THC slowed the growth of lung cancer cells in a dose-dependent manner and extended the mice’s lifespans by up to 36%.1 However, the study did not receive much attention at the time, and additional research was significantly hampered by US government policy relating to cannabis. In fact, in 1976, Gerald Ford announced a ban on all federal funding for research on the medical benefits of cannabis.2

In the 1990s, the US National Toxicology Program launched a two-year study of THC out of concern that cannabinoids could be carcinogens. The researchers in the study gave various dosages of THC via stomach tubes to rats and mice, but contrary to expectations, they found no evidence of a carcinogenic effect. In fact, THC appeared to have a protective effect against certain types of tumors. In the mice, the researchers noted a dose-related decrease in the risk of hepatic adenoma tumors and hepatocellular carcinoma. In the rats, they observed a dose-related decrease in benign tumors (polyps and adenomas) in various organs, including the testes, pancreas, and pituitary, uterine, and mammary glands. Among the mice, survival times were similar for dosed animals and controls, but dosed rats actually lived longer than did controls—again, contrary to expectations.3

In the three decades since the National Toxicology Program study, other research has demonstrated that cannabinoids inhibit the growth of other types of cancer as well, including glioma,4,5 tumors of the immune system (lymphoma),6 and skin tumors.7

Until the year 2000, research surrounding cannabis was still quite limited due to its classification as a Schedule 1 drug. Research was approved only if the intent was to show the harms of cannabis. But by the turn of the millennium, the conversation surrounding cannabis began to change substantially. The FDA began to grant more licenses to conduct cannabis research, and study of cannabis has since exploded.

It’s now known that cannabinoids inhibit the development and spread of cancer by several different mechanisms. In particular, cannabinoids are known to do the following:

Induce cell death. One of the key means by which cannabinoids inhibit the development of cancer is by promoting apoptosis.4,5,8,9 “Apoptosis is a mechanism the human body has to clear cells,” Rabe says. “Cells have a growth cycle where they’re born, they live a lifecycle, and then they die and are absorbed by the body and replaced by new cells. If there is an impairment in apoptosis and cells live longer, they are more likely to mutate and turn into cancer.”

In addition to promoting apoptosis, cannabinoids also promote autophagy, which is the orderly degradation and recycling of dysfunctional cell components, but which can also result in cell death. Cannabinoids have been shown to stimulate autophagy with several different types of cancer cells, including glioma cells, pancreatic and hepatic cancer cells, and melanoma cells.10

• Inhibit proliferation. In addition to directly promoting cell death, cannabinoids also slow the growth of cancer cells. CBD has been shown in in vitro studies to inhibit proliferation of colon cancer cells,11 and THC has been shown in in vivo studies of mice to slow proliferation of lung cancer.12 Both THC and CBD inhibit the growth of breast cancer cells,13,14 and in combination they also inhibit proliferation of human glioblastoma cells.15

In almost all types of cancer that have been tested, cannabinoids have been shown to either promote apoptosis, inhibit cell proliferation, or both.16

• Inhibit angiogenesis. Cannabinoids slow the growth and formation of blood vessels, preventing the development of blood supply to tumors. They accomplish this by blocking the activation of the vascular endothelial growth factor pathway in cancer cells.17 The antiangiogenic effects of cannabinoids have been shown with various types of cancer cells, including skin carcinomas,7 gliomas,5,17 and thyroid carcinomas.18

• Inhibit metastasis. Cannabinoids inhibit the migration and invasion of multiple types of cancer cells in culture, including glioma,19 lung,12,20,21 and cervical cancer cells.20 These effects are due in part to the action of cannabinoids on cannabinoid receptors CB1 and CB2. In addition, CBD has been shown to have significant antimetastatic effects in animal models through other mechanisms besides acting on cannabinoid receptors.13

Importantly, cannabinoids are selective in their impacts on tumor vs nontumor cells and they appear to inhibit cancerous cells without affecting their nontransformed counterparts.10

So far, research on the anticancer properties of cannabinoids is primarily limited to preclinical studies in petri dishes or in animal models. However, in 2006, researchers in Spain conducted a pilot trial of THC in human subjects, all of whom suffered from recurrent glioblastoma multiforme tumors. In the study, THC was administered directly into the brain tumors. Although the study included just nine subjects, the results were the first to indicate in humans that THC has possible antitumor activity when applied directly to a tumor.22

Targeting the Treatment to the Tumor
Although cannabinoids have clear anticancer properties, they may produce intoxicating and sedating effects. Some individuals have attempted to self-treat their cancer with cannabis by extracting the cannabinoids out of the cannabis plant and consuming them in extremely high quantities.

“The only problem with that is when you try to consume large quantities of cannabinoids, particularly THC, unwanted psychoactivity and tiredness can be prohibitive,” Rabe explains. “So our approach is to target the cannabinoids to the exact spot they’re needed and thereby increase their efficacy and decrease their side effects.”

The key to this strategy is PharmaCyte’s Cell-in-a-Box encapsulation technology. According to Rabe, Cell-in-a-Box is “a descriptive name to indicate that cells are put into a package.” That package is made of cellulose, which comes from cotton. The cellulose spheres are under a millimeter in diameter—about the size of a head of a pin—and can encapsulate many thousand living cells at a time. (While Cell-in-a-Box was invented and is owned by the biotech company Austrianova, PharmaCyte has exclusive worldwide licensing rights to the technology for use in fighting cancer as well as for other uses.)

“If you put a human cell in another human, you’re ordinarily going to get an immediate immune response,” says Gerald W. Crabtree, PhD, PharmaCyte’s chief operating officer. “The beauty of these capsules is that they prevent any immune system response to the cells. It’s like they’re inside a fortress, and there’s no response whatsoever. The capsules don’t irritate human tissue nearby where they’re placed.”

The encapsulated cells can live inside for months at a time. Living cells encapsulated in this way can also be frozen and stored for long periods of time, then thawed for later use.

Although the capsules can be filled with any kind of cell, in this case the intent is to fill them with cells that produce enzymes to convert inactive forms of cannabinoids (namely, THC and CBD) into their active forms. The idea is to implant the Cell-in-a-Box packages just upstream from solid tumors, then administer inactive forms of cannabinoids. In this way, the enzymes released by the encapsulated cells will activate the cannabinoids and unleash their cancer-fighting powers right at the site of the tumors.

“It’s almost like what we’re doing is putting a target right next to the tumor,” Crabtree explains.

An Early Proof of Concept
Although PharmaCyte is currently applying Cell-in-a-Box capsules for use with cannabinoids to treat solid-tumor cancers, the capsules themselves are generic packages that can contain virtually any kind of cell. PharmaCyte’s first use of the capsules was in combination with the chemotherapy agent ifosfamide, which is effective against pancreatic cancer, well known as one of the most lethal forms of cancer.

“Ifosfamide is a prodrug, meaning that in its initial form delivered to patients, it doesn’t do anything,” Rabe says. “But once introduced into the body, it is activated in the liver from its prodrug form into its active form. The only problem is that if you’re activating your chemotherapy in the liver, the active molecules are going to go everywhere—including to the pancreatic tumor, but also to the bladder, for example.”

This is a problem because the toxic side effects of ifosfamide make it prohibitive for use in oncology treatment. To remedy the situation, PharmaCyte’s innovation is to substitute something besides the liver to activate the drug and target the drug’s impact using Cell-in-a-Box. The company bioengineered a cell line that produces an enzyme that activates the drug. It then uses Cell-in-a-Box to place these enzyme-producing cells adjacent to tumors on the pancreas. As a result, ifosfamide can be administered in lower doses, producing a concentrated effect where the Cell-in-a-Box capsules are located.

In preliminary studies, this approach for administrating/activating ifosfamide has proven significantly more effective in treating pancreatic cancer than standard administration with activation by the liver. An early pilot study of the Cell-in-a-Box capsules used with ifosfamide in patients with advanced pancreatic cancer found that two of the 14 patients who received the treatment achieved partial remission by the end of study period and 11 had stable disease. One-year survival was 36%, three times that of the control group and twice that reported for the standard treatment (gemcitabine).23

PharmaCyte is currently on the cusp of starting a new trial of the same ifosfamide therapy for inoperable pancreatic cancer, but this time in a much larger Phase 2b clinical trial.

From Ifosfamide to Cannabis
Pharmacyte’s initial success with ifosfamide demonstrates that the concept of live-cell encapsulation is an effective method of targeting a drug to a specific site. But though the company is still investing heavily in developing the ifosfamide therapy, it has opted to pursue development of a cannabinoid-derived therapy at the same time as the ifosfamide therapy, on the grounds that cannabinoids have a wider application.

“Ifosfamide works best for pancreatic cancer,” Rabe says. “Cannabinoids, however, are effective against a broad range of cancers,” noting that they can be used for brain, breast, prostate, colon, lung, and skin cancers, in addition to pancreatic.

A particular appeal of cannabinoids is that they hold the potential to have an impact on tough-to-treat brain cancers. “A lot of other drugs are effective anticancer drugs, but they don’t cross the blood-brain barrier,” Crabtree says. “Cannabinoids do. How do you know this? Because if you inject THC in somebody, they’re going to get psychotropic effects.”

Besides the fact that cannabinoids can treat a greater variety of cancers than ifosfamide, cannabinoid therapy is also appealing simply because it is safer. “At high doses, ifosfamide would cause tissue damage, whereas cannabinoids only make you high,” Rabe says.

At the end of the day, however, the methodology behind the two therapies is exactly the same: place Cell-in-a-Box capsules at the site of a tumor so that a cancer prodrug can be activated there, with the only difference being the specific prodrug in question (ifosfamide vs a cannabinoid derivation).

As for the actual administration of the Cell-in-a-Box capsules, there are two different means of approach, according to Rabe. “One would be with invasive radiology with CT guidance, similar to a heart angiogram. A catheter is threaded into the vascular system and then guided with a CT scanner to get right to the site of a tumor,” he says.

Alternatively, in studies of dogs with breast cancer, the company has successfully injected the capsules with a needle and syringe at the site of the tumors. Once the cell capsules are in place, administration of the prodrug (whether ifosfamide or cannabinoids) can take place either orally or intravenously.

Next Steps
Thus far, PharmaCyte’s development of its cannabinoid therapy remains in the bench-science phase, according to Rabe. A key step the company recently completed was to engineer a cell line that could produce an enzyme to convert the inactive cannabinoids into their active form.

“In nature, the cannabinoid prodrugs exist in the plant, and they are converted into the active form nonenzymatically through the application of heat, either through evaporation or through a flame (as you might light cannabis to smoke it). We can’t rely on that. We want to control the activation through an enzyme that will do the conversion,” Rabe says.

There were two avenues available for finding an appropriate enzyme: The company could either locate an existing enzyme in nature that would accomplish the purpose or it could synthesize one from scratch. At this point, the synthetic route appears to be the most promising. In May 2019, PharmaCyte announced that it had successfully bioengineered a human cell line that would produce the necessary enzymes. The company is now testing that cell line’s effectiveness at converting cannabinoid prodrugs into their active forms.

If that identified cell line proves effective, the next step will be to propagate the cells and encapsulate them using the Cell-in-a-Box technology. At that point, the company can begin testing the combination of the encapsulated cells plus the cannabinoid-derived prodrug in animal models—a phase that Rabe says could conceivably begin within the next year. The company plans to focus its cannabis therapy on brain cancer initially, but anticipates that cannabis in combination with Cell-in-a-Box could ultimately be used to treat any solid-tumor cancer.

“My conclusion is this: I think cannabis or the constituents thereof hold significant promise as anticancer agents, particularly in combination with the Cell-in-a-Box encapsulation technology,” Crabtree says. Although he describes himself as skeptical when he first encountered the concept of using cannabis or cannabis constituents to treat cancer, Crabtree has completely changed his mind. “I really do have faith in this,” he says.

— Jamie Santa Cruz is a health and medical writer in the greater Denver area.

References

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2. Newton DE. Marijuana: A Reference Handbook. Santa Barbara, CA: ABC-CLIO; 2013:312.

3. Chan PC, Sills RC, Braun AG, Haseman JK, Bucher JR. Toxicity and carcinogenicity of delta 9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice. Fundam Appl Toxicol. 1996;30(1):109-117.

4. Sánchez C, de Ceballos ML, Gomez del Pulgar T, et al. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res. 2001;61(15):5784-5789.

5. Blázquez C, González-Feria L, Alvarez L, Haro A, Casanova ML, Guzmán M. Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res. 2004;64(16):5617-5623.

6. McKallip RJ, Lombard C, Fisher M, et al. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood. 2002;100(2):627-634.

7. Casanova ML, Blázquez C, Martínez-Palacio J, et al. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest. 2003;111(1):43-50.

8. Galve-Roperh I, Sanchez C, Cortes ML, Gómez del Pulgar T, Izquierdo M, Guzman M. Antitumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med. 2000;6:313-319.

9. Gomez del Pulgar T, Velasco G, Sanchez C, Haro A, Guzman M. De novo–synthesized ceramide is involved in cannabinoid-induced apoptosis. Biochem J. 2002;363:183-188.

10. Velasco G, Sánchez C, Guzmán M. Anticancer mechanisms of cannabinoids. Curr Oncol. 2016;23(2):S23-S32.

11. Aviello G, Romano B, Borrelli F, et al. Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. J Mol Med (Berl). 2012;90(8):925-934.

12. Preet A, Ganju RK, Groopman JE. Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene. 2008;27(3):339-346.

13. McAllister SD, Murase R, Christian RT, et al. Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat. 2011;129(1):37-47.

14. Caffarel MM, Moreno-Bueno G, Cerutti C, et al. JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008;27(37):5033-5044.

15. Marcu JP, Christian RT, Lau D, et al. Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol Cancer Ther. 2010;9(1):180-189.

16. Velasco G, Sanchez C, Guzman M. Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer. 2012;12:436-444.

17. Blazquez C, Casanova ML, Planas A, et al. Inhibition of tumor angiogenesis by cannabinoids. FASEB J. 2003;17:529-531.

18. Portella G, Laezza C, Laccetti P, De Petrocellis L, Di Marzo V, Bifulco M. Inhibitory effects of cannabinoid cb1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis. FASEB J. 2003;17(12):1771-1773.

19. Blazquez C, Salazar M, Carracedo A, et al. Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res. 2008;68:1945-1952.

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23. Löhr M, Kröger JC, Hoffmeyer A, et al. Safety, feasibility and clinical benefit of localized chemotherapy using microencapsulated cells for inoperable pancreatic cancer in a phase I/II trial. Cancer Ther. 2003;1(1):121-131.

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