Inner Strength

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By Deborah Komlos

Treating the suite of diseases collectively referred to as cancer has long been the domain of three primary approaches — surgery, radiation and chemotherapy. But such treatments are often very harsh, increasing the anxiety level of cancer patients who are typically already under physical and emotional stress. New cancer combatants in the works are calling upon a more natural yet strong source of therapeutic power: the body’s own immune system.

Immunotherapy involves helping the immune system recognize cancer cells as foreign. Active specific immunotherapies are those such as vaccines, which trigger the body’s immune system to fight disease. Passive immunotherapies are also an option, such as mono-clonal antibody therapy, which can involve — among other roles — antibodies binding to targets on tumour cells to prohibit proliferation. Some immunotherapeutics can be used on their own, but are often intended for use along with or after another treatment.

Extending the lifespan of individuals with cancer and giving them a good quality of life are key goals for cancer product development at Lorus Therapeutics Inc. (Toronto, ON), says Jim A. Wright, PhD, CEO.

“Most drugs that are used to treat cancer are cytotoxic, so when you treat people, they get sick,” Wright says. “Very few people — physicians, or scientists — nowadays talk about curing cancer.” At Lorus, the focus is on developing innovative treatments that “are effective, but they have low toxicity so we can manage cancer over the lifetime of a patient,” Wright says.

Lorus’s immunotherapeutic, Virulizin®, is a natural product originally derived from bovine bile and is now also being reproduced synthetically by the firm. Considered a biological response modifier and administered by intramuscular injection, Virulizin is currently in a Phase III clinical trial for advanced pancreatic cancer; in Mexico, it is approved for the treatment of malignant melanoma. The product has also shown promising activity in other cancers such as breast cancer, Kaposi’s sarcoma and cervical cancer, which Wright says is a big problem in North America and especially in developing countries.

“What Virulizin does is it kick-starts a biological pathway that fights cancer,” Wright says (Fig.1). The product activates the body’s macrophages — a type of white blood cell —which are attracted to the tumour site where anti-tumour molecules such as nitric oxide and cytokines are then released. The activated macrophages also release interleukins, Wright explains, which then attract to the tumour what are known as natural killer (NK) cells. The NK cells, in turn, release anti-tumour molecules to attack the tumour.

Wright mentions the importance of having a treatment option in addition to gemcitabine, the only drug currently approved for pancreatic cancer.

“People who get pancreatic cancer, less than two per cent of these people will survive a single year,” he says. All patients who receive gemcitabine will fail treatment within about six weeks, he adds. Virulizin presents the chance to test a new first-line treatment for this indication, Wright says, for which the clinical study is comparing treatment with gemcitabine to treatment with gemcitabine in combination with Virulizin. Also underway is testing of a second-line treatment for those who fail gemcitabine, comparing treatment with 5-fluorouracil (5-FU) to treatment with 5-FU in combination with Virulizin.

“Most chemotherapy treatments for cancer patients are combination because it gives probably the best opportunity for finding something that will be effective,” Wright says. “The trouble with most is that they’re cytotoxic, so when you add two together then you’re adding toxicity as well. But with Virulizin, you do not add toxicity, you only add the benefit of the drug.”

To the Target

As part of its immunotherapeutics portfolio, YM BioSciences Inc. (Mississauga, ON) is involving a monoclonal antibody approach. The firm’s intravenous product TheraCIM hR3 is a humanized monoclonal antibody that targets the epidermal growth factor receptor (EGFr). The product has already completed a Phase II clinical trial for head and neck cancer.

Compared to chemotherapy drugs, the immunotherapeutics being developed by YM BioSciences are biological in nature and are therefore inherently much safer, says Craig Binnie, PhD, director of Clinical Product Development.

Through its attraction to the EGFr, “(TheraCIM hR3) is targeting a specific marker on the surface of tumour cells and it doesn’t really target any other normal cell markers,” Binnie explains, adding that EGF receptor is expressed in some normal tissues. “But tumour cells over-express this marker at a much higher level than normal cells,” he says. “So this gives you the specificity so the drug actually targets the tumour. But it is intended to use this molecule in combination with radiation therapy — they’re very synergistic.

“What radiation does in head and neck cancers, it actually induces over-expression of EGF receptor, and then you follow it with the antibody and it mops these cells up,” Binnie says.

Another immunotherapeutic in YM BioSciences’ pipeline is Norelin™, a product comprising eight tandem copies of gonadotropin-releasing hormone (GnRH) at each end of an immunogenic bacterial toxin protein (Fig. 2). Delivered as a subcutaneous injection, the product has thus far completed a Phase I clinical trial in the treatment of hormone-dependent prostate cancer.

“All that does is it flags the GnRH to the immune system,” Binnie says of the Norelin molecule construction. “It presents it in a different context. The body would normally not produce antibodies to a self-protein. But what you’re doing by fusing it to a highly immunogenic protein, you flag it to the immune system as being something which is non-human.”

With a reduction of GnRH, the levels of testosterone in the body are driven down, Binnie explains, and it’s testosterone that drives the growth of prostate cancer in its early stages.

Binnie looks upon the current progress in immunotherapy research as the result of breakthroughs made in the 20 years since the birth of molecular biology. “People could actually clone genes and identify novel targets or targets that were only expressed in tumour cells versus normal cells and you needed the technology of molecular biology to identify those targets,” he says. The classic approach would be to then develop an antibody against the targets.

“So in the old days, in the ’80s, people would develop a mouse monoclonal antibody against the target,” Binnie says. But there were problems with immunogenicity, he says, because of the foreign origin of the protein.

“So what people have done and what we did, actually, is to make the antibody more human — humanization is the name — so that there is only a minimal amount of mouse amino acid sequences in there,” he says.

YM BioSciences’ monoclonal antibodies are 95 per cent humanized, Binnie says, adding that other firms, such as Abgenix Inc. (Fremont, CA), have produced antibodies that are truly human.

Powerful Cells

Victoria, B.C.-based Stressgen Biotechnologies Corp. has “one foot in cancer and one foot in chronic viral infections,” says Lee Mizzen, PhD, vice-president of Scientific Affairs. “What we’re focusing on is the sexually transmitted varieties of HPV (human papillomavirus), many of which can go on to become cancer.

“HPV is the most prevalent sexually transmitted viral disease; it’s ubiquitous,” Mizzen says. “Seventy per cent of sexually active adults have been or will be exposed to HPV.”

Stressgen’s lead immunotherapeutic, HspE7, is a fusion protein comprising a stress protein — also called a heat shock protein — and a protein antigen, against which the immune response is desired. Made via the firm’s proprietary CoVal™ technology, the product is injected subcutaneously like a vaccine. HspE7 recently received the Fast Track Product development program designation from the U.S. Food and Drug Administration for the treatment of patients with recurrent respiratory papillomatosis.

“It’s generally agreed that the best way to eradicate established disease such as virus-infected cells or cancerous cells is using CTLs (cytotoxic T lymphocytes),” Mizzen explains. “So we know the end result of Hsp-fusion protein vaccination is the induction of CTLs, at least in animal models, we notice.”

What induces CTLs are dendritic cells, Mizzen says, which are the most powerful regulators of immune responses.

“When you inject the Hsp fusion, the protein, it turns out that dendritic cells actually express on their surface a number of receptors that recognize Hsp. And so, you can imagine then, it’s like a homing device — the Hsp will find its way to the dendritic cell and lock onto the receptor on its surface,” Mizzen explains. The protein fusion is then engulfed by the dendritic cell, processed into peptides, and the antigen is then re-presented as small peptides by the class I pathway. Peptides presented by this pathway activate CD8+ T-cells, which then themselves become activated, proliferate and take on the CTL, or "killer T-cell," function.

“And so, many, many copies are made that are antigen-specific, off they go and systemically can search the body for any cells or tissues that contain that antigen,” Mizzen says of the CTLs. “So it’s a very specific way to eradicate diseased tissue while sparing normal tissue.”

Mizzen says most of the firm’s experimental evidence for HspE7 comes from studying dysplasias, which are pre-cancerous conditions. For instance, last year the firm completed a Phase III clinical trial for anal dysplasia.

Understanding Roles

With a current paucity in immunotherapeutics, Mizzen says the field of immunotherapy faces an important task.

“I think the challenge has been there since Day 1, and that is, your immune system is supposed to get rid of diseases in the first place. So why is it that you now have a disease and in fact, may have it for the rest of your life as a chronic infection or a cancer,” he says. “This is the central question: what is it about that disease that the immune system is not recognizing properly, and allowing it to be there in the first place. So I think it gets down to immuno-stimulation — how is it that we can re-educate the immune system to do the job it should have done in the first place.

“So even for us, despite the highly encouraging clinical data, we have to keep moving forward,” Mizzen says. “Each disease may have its own nuances and you only learn by clinical trials whether or not as you come into new diseases and new indications, whether the same platform technology works as well.”

Cheryl D. Helgason, PhD, senior scientist, department of Cancer Endocrinology at the B.C. Cancer Research Centre (Vancouver, BC) greatly praises the use of dendritic cells as a tool in cancer immunotherapy research.

“The research into dendritic cell biology is just expanding enormously . . . We’re realizing there are several different types of dendritic cells. Some of them actually play a role in making sure immune responses don’t get started,” Helgason says.

Helgason’s research in a mouse model of prostate cancer is looking at how dendritic cells might be involved in generating and activating a type of cell population called regulatory T-cells, which are believed to suppress the immune response. She’s also trying to understand the role of these cells and discover what specific molecules could be used to target them.

“They (regulatory T-cells) used to be called suppressor T-cells 20 years ago, when people first postulated that they existed,” she says. “It was in the context of autoimmune disease, actually, that people became excited about them because they could demonstrate that if they transferred T-cell populations without this suppressor activity, you could induce autoimmune disease.”

At the time, Helgason continues, the capability to purify and culture the cells was not there, and only in the last two to three years have people been able to more clearly demonstrate the existence and activity of these cells.

“So there’s a lot of interest in them in autoimmunity, in transplantation,” she says. “But people have just really started looking and saying, well, you know, in these cancer patients, this (regulatory T-cell) population is increasing. And so, in fact, these regulatory T-cells are probably playing some role in suppressing the immune response against the cancers that are progressing.”

Unfortunately, Helgason says, there currently are no specific antibodies against the regulatory T-cell population. Such antibodies could reduce tumour growth, she explains, and increase the immune response.

Helgason says the field of immuno-oncology in Canada is still quite young and there is much more to be learned.

“We know that with tumour progression, there are changes in the immune system. But people really don’t understand exactly what those changes are, what’s responsible for them, which makes it somewhat difficult to reverse them, change them,” she says. “I think that’s where we’re going to see at least some more growth in the next little while in the basic research level, is trying to identify better markers.”

Finding the markers is only one matter, she points out. “We don’t have a good way of assessing whether we are generating the kinds of immune response we need to generate,” Helgason says. “That’s probably the greatest challenge we have right now — what is an appropriate marker to use; is it presence of cytotoxic T-cells, is it antibodies? Do you in fact need both types of responses to see what you ultimately want to see, and that’s the reduction in tumour growth, and ideally, we’d like to get rid of the tumour.”

Helgason mentions that an emerging school of thought regarding cancer immunotherapy says that we should be thinking about vaccination, not treatment, which could see cancer vaccines being administered in much the same way that vaccinations are currently used for conditions such as chicken pox.

“The main thing is which people are actually at risk for developing which types of tumour and what would you vaccinate with. What are the appropriate antigens that are going to be expressed early on in these tumour cells,” Helgason says. “So that’s where genomics and proteomics are just going to revolutionize this field . . . You start looking at the proteins and genes expressed in the early tumour and it can give us all kinds of clues, mechanistically, about tumour growth itself. That could also be very helpful for developing vaccines.”