The Shifting Landscape Toward Immunotherapies

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Immunotherapy Demystified: Investing in High Risk, High Reward Opportunities in Cancer Therapeutics

Research and development in cancer has made a seismic shift toward immunotherapies, like anticancer vaccines, and the resulting tremor can be felt in the hallways and laboratories of drug and biotechnology companies large and small. According to , an ebook released by the Parenteau BioConsultants and BioRankings Alliance, it is projected that by 2014, three of the top ten drugs will be anticancer immunotherapeutics. In addition, forecasters expect immunotherapeutics to dominate revenue streams in the coming decade.

“Market projections are notoriously prone to overexaggeration early on,” said Hal Siegel, PhD, chief scientific officer for Arizona-based ImmuneRegen BioSciences, a wholly owned subsidiary of IR BioSciences Holdings, Inc. “However, I think the promise in the field right now is pretty enticing, because the potential is so great.”

“It’s been a learning process. I think the agents we have available today are simply more potent and more effective than [those] we’ve had in the past. And, at least in terms of immunology, we’re really beginning to understand how cancers evade the immune system.”

—Howard Kaufman, MD Rush University Medical Center, Chicago

Why now?

Vaccines are an interesting story. They have been around for more than 200 years, thanks in part to English physician Edward Jenner. For his work in developing the smallpox vaccine in 1797, Jenner is considered the father of immunology. Much has been accomplished since then, evidenced by a plethora of immunizations. Of course, most of these vaccines are designed to prevent disease, whereas the bulk of vaccines being investigated in cancer are meant to stimulate immune responses in people who have a cancer diagnosis. Only recently has progress begun to inch forward where cancer vaccines are concerned.

“It’s been a learning process,” explained Howard Kaufman, MD, head of the cancer program at Rush University Medical Center in Chicago. “I think the agents we have available today are simply more potent and more effective than [those] we’ve had in the past. And, at least in terms of immunology, we’re really beginning to understand how cancers evade the immune system.” Kaufman said a better understanding of cancer’s suppressant mechanisms is changing the way researchers and immunologists are approaching vaccine development.

Andrew Parsa, MD, with the University of California San Francisco (UCSF) Brain Tumor Research Center, agrees. Researchers have learned that some types of cancer are extremely resistant to the immune system, Parsa said, and even within a single cancer type, certain subtypes exhibit more resistance to the immune system. “I think one of the goals over the next few years is to figure out who are the best patients for cancer vaccines,” Parsa said, “and which vaccine is best to give to a particular patient.”

The “need” factor

Randal Chase, PhD, president and CEO of Immunovaccine, Inc, a biotechnology company based in Halifax, Nova Scotia, Canada, believes the increased focus on anticancer immunotherapies and vaccines stems from an unmet need. When surgeons remove a primary tumor, or at least as much as they can see, they have no way to know whether metastasis has occurred, he explained. This is why patients are subjected to adjuvant radiation or chemotherapy, which Chase asserts can be brutal.

“The dilemma with chemotherapy is that not only is it brutal, it’s not completely effective,” Chase said. He explained that rogue cancer cells often survive unharmed by chemotherapy because they were not in a growth cycle. “The need still remains to be able to track down those rogue cancer cells wherever they are and kill them,” said Chase.

And that, Chase said, is where the immune system comes into play. “One of the smartest things would be to train the body’s immune system to look for cancer cells on a regular basis so that it can better defend itself.” He acknowledged that cancer vaccines have experienced some growing pains, not unlike most new technologies, such as monoclonal antibodies when they were first developed. “Those problems [with monoclonal antibodies] were worked out, and now some of the most important biotech products available are in fact monoclonal antibodies. I think we’re going to go through a similar phase with the development of cancer vaccines. And the good news is we’re starting to see evidence that it’s possible.”

Vaccine development

EMD Serono, Inc, an affiliate of Merck KGaA, Darmstadt, Germany, is a leader in the US biopharmaceutical arena. At present, the company’s therapeutic cancer vaccine Stimuvax (BLP25 Liposome Vaccine) is being investigated in two phase III trials: the START trial, which is evaluating patients with documented unresectable stage IIIA or IIIB non—small cell lung cancer; and the STRIDE trial for patients who have inoperable, locally advanced, recurrent or metastatic breast cancer. Jens Oliver Funk, MD, senior vice president and global head of therapeutic oncology for EMD Serono, said Stimuvax has already demonstrated positive results.

“What we see in ongoing work is the understanding of an augmented T-cell response—specific T cells that would lead to further anti-tumor immune effect,” Funk said. “That is important in the concept of a cancer vaccine, and that is so strikingly different from other therapies because the vaccines are not directly accelerating the effect on the tumor, but it’s rather a vaccineinduced immune effect by T cells that does something.” Funk said the success of Stimuvax has contributed to the overall optimism about immunotherapy vaccine development. “We are seeing the promise of a therapy that could have a very good internal effect in the patient, while at the same time being rather safe and inducing minimal toxicity,” he concluded.

Specificity without toxicity is key, said Parsa of UCSF, which is conducting a new phase II study involving vaccination for primary brain tumor glioblastoma multiforme. UCSF has received a SPORE grant from the National Institutes of Health and funding from patient advocacy groups to conduct the study. The vaccine, manufactured by Antigenics, a Massachusetts-based biotechnology firm, involves removing the tumor from the patient, then creating a custom vaccine modeled on the patient’s tumor—literally creating medicine from the tumor itself. This is similar to how Provenge—a dendritic vaccine by Dendreon—works, and it represents the epitome of personalized medicine.

Parsa cautioned that it is premature to draw significant conclusions about the Antigenics vaccine, but added, “All the data that we have currently is extremely favorable indicating that our survivalto- date for the patients that we’re treating is comparable to some of the other therapies that are being used as standard of care.” He described the effort as an important achievement nevertheless, “because it demonstrates that, so far, in a limited number of patients, we’re doing as well as some of the chemotherapy agents.”

Kaufman at Rush University is leading a nationwide phase III study of the OncoVEX vaccine in metastatic melanoma. OncoVEX is produced by BioVex, a privately held biotechnology company in Wolburn, Massachusetts. The vaccine replicates selectively in tumors, destroying cancer cells while stimulating a systemic immune response. Kaufman said the 26% response rate seen with OncoVEX in a phase II trial was greater than the 17% response rate for interleukin-2 and the 14% rate with interferon-alpha, two FDA-approved agents.

Kaufman said another advantage of the vaccine is that it can be administered in a physician’s office. “Presently, patients with advanced melanoma can get treated with multiple chemotherapies that can cause neuropathy, renal dysfunction, and often require hospitalization,” he said. “To be able to come into the doctor’s office, get a vaccine, and go home and get back to your life an hour later is fairly remarkable. Quality of life is very important.”

Boosters and platforms

Cancer vaccines are not being developed in a vacuum. Vaccine adjuvants and delivery platforms are necessary to combat this complicated disease effectively. Chase at Immunovaccine said a challenge with any vaccine is keeping the body from destroying it before it can trigger the designed immune response. He said the body recognizes the vaccine as foreign material once it has been injected and works to eliminate it. As a result, the vaccine is often removed over a period of days, sometimes even hours.

“That’s just too short a time for the immune system to see it, react to it, and to develop the appropriate immunological memory,” Chase said. This is why, according to Chase, most vaccines require a booster shot.

Immunovaccine’s “booster shot” is its DepoVax delivery technology. The technology, which has generated positive pre-clinical safety data, packages a therapeutic cancer vaccine antigen, an adjuvant, and a liposome into an oil that Chase said functions as a depot. “That depot lasts in the body not for hours or days, but for weeks and maybe months. That allows a prolonged presentation of those antigens, so the body gets lots of time to see them, to react to them, and to develop a strong response.” The company is also developing its own therapeutic vaccine, DPX-0907, and plans to initiate a phase I trial at five sites in late March 2010.

ImmuneRegen BioSciences recently entered into an agreement with the Fred Hutchinson Cancer Research Center in Seattle, Washington, to begin studies using Homspera, an adult stem cell active compound. ImmuneRegen said study results have shown Homspera can regenerate and strengthen the immune system and enhance wound healing. Siegel expressed enthusiasm over the opportunity to have Homspera evaluated in the area of melanoma. He said Homspera has shown promise in vivo and in active cellular therapy ex vivo to “extend immune responses, strengthen immune responses, and basically turn the immune system up a few notches and make it more effective at finding and destroying cancer cells.”

Successes inspire hopeKaufman said recent successes in cancer immunotherapy have lofted hopes. He noted that approved human papilloma vaccines have shown effectiveness in not only preventing but also treating cervical cancer, and Dendreon’s Provenge vaccine has been found to improve progression-free survival in men with advanced prostate cancer. Dendreon expects the FDA to approve Provenge mid-2010. Another success on the vaccine front is BioSante Pharmaceuticals’ GVAX, which recently received Orphan Drug designation from the FDA for advanced pancreatic cancer.

“If you carefully select the right patients or you have a very effective vaccine, you’re going to be able to have an impact on survival,” Kaufman said. “It goes back to understanding the suppressant mechanisms that patients experience at certain stages of their disease. That’s been a challenge to sort of figure out, but I think we’re getting better at it.”

A search at www.clinicaltrials.gov shows there are more than 500 open clinical trials for vaccine anticancer therapies in virtually every type of solid tumor and several hematologic malignancies. This represents a significant investment in a technology that has been under investigation for decades but has had limited success until recently. As successes pile up, pharmaceutical companies will not be the only beneficiaries. Patients will benefit from a shift toward treatments that promise increasing personalization of care and fewer adverse effects.