Journal of the National Cancer Institute Advance Access originally published online on October 30, 2007
JNCI Journal of the National Cancer Institute 2007 99(21):1570-1573; doi:10.1093/jnci/djm219
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© Oxford University Press 2007.
NEWS |
Business Barriers Slowing the Pace of Cancer Immunotherapy Research and Development
No cancer vaccines and only a handful of antitumor immunotherapies have gained regulatory approval, despite several decades of effort. Experts think that increased knowledge about the immune system and better agents are starting to change this.
However, regulatory and intellectual property issues currently hinder development of such therapies, they say, and will continue to cause problems unless researchers have better access to agents that are still under investigation. Two recent government-sponsored meetings highlighted these concerns, and some scientific leaders are even calling for the U.S. Congress to step in.
Testing agents together in combinations, as immune-system therapies often require, is a particular problem. Companies fear that their drug applications will be slowed down if they let outside researchers use their investigational drugs in any trial that might link the agent with side effects. But that approach often leaves agents to languish for years—agents that researchers say could be successfully attacking cancers as part of a two-drug combination.
The problems result from two separate but intertwined issues. First, the immune system has multiple levels of control that need to be overridden before a cancer drug can effectively attack its target, so combination therapies are often needed to generate enough antitumor activity for regulatory approval. "If you think of a car moving forward as quickly as possible, there are three components to it: ignition key, accelerator, and brakes. A vaccine is like the ignition key, but to get maximal movement of the car, you need to press on the accelerator and disable the parking brake," said Drew M. Pardoll, M.D., Ph.D., codirector of the cancer immunology and hematopoiesis program at the Johns Hopkins University School of Medicine.
Second, because few immunotherapeutic drugs are currently approved for use, investigators need to combine the investigational agent that they are studying with another experimental agent. And often the two agents are owned by different companies with different goals. The most straightforward path to regulatory approval is to use a drug alone or to combine it with other drugs that have already been approved. That way, any previously unseen toxic effects are probably from the new agent or an interaction between the new agent and the existing one. In either case, the toxic effects largely become the problem of the people developing the new agent rather than of the owners of the already approved agents.
If researchers are testing a combination of two experimental agents—whether in a cancer vaccine or to turn off the immune system parking brake and step on the gas—and there is unexpected toxicity, the development of both agents can be seriously delayed or stopped. At least, that is the argument that companies make when asked why they will not allow academic researchers or other groups access to their investigational agents.
"You could have your phase III program put on hold by the [U.S. Food and Drug Administration]. And if you’re the person who let the adjuvant be used in someone else's trial, you could get fired," said Arthur Krieg, M.D., the chief scientific officer at Coley Pharmaceutical Group in Worcester, Mass. "So the usual response is you just say no." (Coley is one of the few companies that have traditionally let academics use its vaccine adjuvant.)
The result is that researchers, particularly those at academic institutions or small biotechnology firms, have no access to the most promising agents. The owners of those agents often will not release them—even if a strategy has strong biological rationale and preclinical data to back it up. By contrast, if such agents were already approved, then interested researchers could simply purchase them off the shelf and use them as they saw fit.
However, academic researchers aren’t the only ones who lose out, said Daniel Speiser, M.D., Ph.D., an associate member of the division of clinical oncoimmunology at the Ludwig Institute of Cancer Research in Lausanne, Switzerland. "The companies miss chances and lose time. The public should be more aware that we are losing opportunities," he said. "In part, we are doing work that is less useful because we cannot do the more useful work."
Raising the Issues
Martin (Mac) Cheever, M.D., director of solid tumor research at the Fred Hutchinson Cancer Research Center in Seattle, helped organize a conference sponsored by the FDA and the National Cancer Institute in February to talk about these issues. "One of my goals in hosting the conference was to make people recognize that it is a problem," Cheever said.
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When academics write grant applications, they lay out the project in the most optimistic way, describing why they think their strategy will work. "They don’t say, ‘It would work better if we had different adjuvants, but we can’t get ahold of them,’" he said. Similarly, NCI funds the best grants that researchers submit. "They don’t say, ‘This is the best cancer vaccine grant we got, but it would be much better if it had different adjuvants, and therefore we won’t fund it.’
"So in a sense [NCI is] not seeing the problem. They are funding the best science presented to them, but it is not the best science possible," said Cheever, who is a veteran of both academic and industry cancer vaccine efforts.
The FDA–NCI meeting covered a variety of topics related to the development of immunotherapeutics and vaccines for cancer, but several speakers followed Cheever's lead and raised concerns about regulatory and intellectual property problems. For example, Pardoll and Jeffrey Schlom, Ph.D., head of the immunotherapeutics group in the laboratory of tumor immunology and biology at NCI, pressed the FDA representatives about whether adverse events detected when a combination of drugs are used would really affect regulatory approval for either agent alone.
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Although the agency officials did not say that they would ignore such data, they said that they would handle it on a case-by-case basis. "My personal view is that the FDA is not the issue at all," Schlom said. "But the companies perceive it this way. If you have vaccine A and want to use it with adjuvant B, both companies A and B will say, ‘We don’t want to use it in combination because if there is any toxicity the FDA will deep-six our product.’ When you talk to the FDA, they say, ‘No, no, no, we look at everything as a whole and make a decision.’ But companies don’t want to take a chance. They hide behind it."
In an interview, Raj Puri, M.D., Ph.D., director of the division of cellular and gene therapies in the Center for Biologics Evaluation and Research at the FDA, reiterated that they would evaluate combinations and adjuvant–antigen vaccine mixtures on a case-by-case basis. Puri declined, however, to say that they would review combination and single-agent safety data separately or that problems with such combinations would not affect the approval of an agent with a strong history.
Identifying Key Agents
In addition to trying to raise awareness about the problem, Cheever has been gathering data to identify exactly which investigational immunotherapeutic agents researchers want most. He solicited input from members of six academic societies—the American Association for Cancer Research, the American Association of Immunologists, the American Society of Clinical Oncology, the American Society of Hematology, the Cancer Vaccine Consortium, and the International Society of Biological Therapy—asking researchers to submit the agents that they need access to on an NCI Web site. He compiled that information and came up with the top 30 agents that researchers most want to use. These agents were the subject of a smaller NCI-sponsored meeting held in July.
The goal of that meeting was to prioritize the list (see box) and come up with a plan for improving access to at least some of the agents. For example, some of the drugs could be produced by NCI's RAID (rapid access to intervention development) program, which is aimed at manufacturing investigational agents. Cheever and the RAID staff are finalizing the list, which they hope to release in October. There are no guarantees, though, that the RAID program will have the resources to make the agents or that NCI leadership will see the project as high priority.
When asked if the government can get around patent rights by manufacturing an agent and distributing it for free, Cheever pointed to a safe harbor clause in the federal Food, Drug, and Cosmetic Act. The law states that testing a drug to generate data for an FDA submission will not be considered patent infringement.
But Pardoll isn’t so sure that the government's producing the drugs is going to work. "The agents that have come out of it, I think, are really great agents. And if five, just five of them, could be accelerated in terms of their availability, that would be the most important nonscientific advance forward in our field in the last 20 years. And Mac Cheever should get the Nobel Peace Prize," he said. "But there is a huge amount of skepticism. It is one thing to prioritize, and another to get corporate buy-in to release these compounds, and another to get the resources to produce these compounds. I’ll be amazed if it happens."
Adjuvants
Many experts pointed out that these intellectual property issues and the regulatory complications of combining two investigational agents affect many areas of drug development. But the complexity of the immune system makes it worse for immunotherapeutics. No area is worse off than vaccine development.
Effective vaccines must contain an antigen (e.g., a recombinant protein, foreign substance, or fragments of tumor cells), which stimulates an immune response against the desired target, and an adjuvant, which amplifies and sustains the response. By tradition and policy, the FDA does not approve any adjuvants as standalone products. Rather, the FDA considers the antigen–adjuvant mixture used in a vaccine to be one product and grants approval for the single entity. That means that adjuvants—even ones that have been used in several different successful and widely used vaccines—are not available for sale or readily available as off-the-shelf products for clinical trial testing. (The only exception, alum, was grandfathered in when the FDA took on the role of approving new agents in 1938.)
Thus, any researcher working on a cancer vaccine has one hand tied behind his or her back, according to Cheever. Most oncology drug development occurs after an agent is first approved, when researchers can test it in a variety of diseases and drug combinations.
"The problem with these adjuvants is that if they are not approved as standalone agents, we are never going to find out how to use them. We don’t know which adjuvants, dose, route, timing, or combination [to use with an antigen], and we are never going to know that unless you can get your hands on the adjuvants to do the experiments," Cheever said.
And cancer vaccine developers need potent adjuvants. Vaccines that prevent infectious diseases, such as influenza, rely on antibody production, which happens when B cells are activated. By contrast, vaccines that attack tumors require activation of T cells. T cells are part of the innate immune system, which is the body's first line of defense against foreign invaders but does not naturally amplify its response with repeated exposures the way that B cells and the adaptive immune response do. Stimulating that response is therefore trickier.
"So we are talking about T-cell vaccine adjuvants, which are more difficult to find than good B-cell vaccine adjuvants," Speiser said. In the last decade or so, strong T-cell adjuvants have been developed, but "nothing is readily available because all of these agents are the intellectual property of some company that have their own development plans. We do not have the freedom to try—even if there are good ideas with sound rationales—because of these protections."
For example, his group had been working with a strong T-cell adjuvant, called CpG 7909, and had promising results in early phase clinical trials. However, Coley Pharmaceuticals, which initially developed CpG 7909, later licensed development of the adjuvant for cancer therapy to Pfizer. Pfizer has thus far declined to let Speiser and other academics continue their research.
Meanwhile, the FDA says that it cannot approve adjuvants as standalone agents because they have no therapeutic value on their own. Adjuvants are typically given at low doses relative to what would be used if the same drug were being tested as a therapeutic agent. Therefore, the only way that academic researchers can access these agents is if a company uses the compound as a single agent and gets regulatory approval. The growth factor granulocyte–macrophage colony-stimulating factor is a case in point. The drug was approved for use to stimulate white blood cell proliferation. Cancer vaccine researchers now use it at much lower doses as an adjuvant.
Besides Cheever's initiative, one possible way around this problem would be to get Congress to provide protection from lawsuits for damages caused when a third party uses the originating company's adjuvant. There is precedent for such action, with Congress protecting infectious vaccine developers to spur vaccine production and development.
Protection from potential lawsuits could encourage companies to allow others access to drugs that they are not interested in developing themselves. But such protection wouldn’t help with companies’ worrying about side effects from a combination halting a single agent's development. That situation is likely to improve only if the companies feel more confident that the FDA will separate the issues, even though there is no such guarantee.
"My personal view is that this is something the director of NIH and the director of NCI should take up with Congress as an issue," Schlom said. "If there is a congressional hearing and you have the president of certain biotech and pharmaceutical companies brought before a committee, and the chair says, ‘You have a drug that has shown some evidence of clinical utility already and you won’t release it for others to do a trial,’ this would put the force of government muscle—and public pressure—on the companies."
Whether the government will intervene remains unclear. But Cheever does think that the renewed efforts to examine this problem are important. About the list of high-priority agents, he said, "if nothing else, it is a report card. If we have a list of agents that we think will work in cancer and we go through the same exercise 2 years from now and come back with the exact same list, then you know the systems have failed. The institutions have failed."
Examples May Illuminate the Mounting Cancer Vaccine Development Problem
As scientists’ understanding of cancer biology and the immune system improves, business-related barriers to immunotherapy and cancer vaccine development become more apparent. The history of two agents, an anti–CTLA-4 antibody and the GVAX prostate cancer vaccine, illustrates the problems, said Drew M. Pardoll, M.D., Ph.D., codirector of the cancer immunology and hematopoiesis program at the Johns Hopkins University School of Medicine. The two agents are owned by different companies—the antibody by Mederex Inc., and their partner Bristol Myers Squibb, and the vaccine by Cell Genesys—and they each show some limited therapeutic value alone. But as early as 1999, James Allison, Ph.D., at Memorial Sloan-Kettering Cancer Center in New York, showed that combining the two agents could eradicate some tumors in animal models.
"Starting almost a decade ago, both reagents became available for use in humans, and a number of us tried to get Mederex and Cell Genesys to get together to do a combined clinical trial," Pardoll said. "Lo and behold, last year at ASCO, in May 2006, already 6–8 years after the animal experiments had been done and after the actual human reagents were available, data were available on six patients."
As predicted by the preclinical experiments, the combination appeared to have better power. Experience suggests that less than 10% of patients respond to either agent alone. "Even more impressive is that at least two patients have had durable responses of a year or beyond, which you don’t see with anything in advanced hormone-refractory prostate cancer," Pardoll said.
There were side effects, however, that led the regulatory agency to halt the trial temporarily. "It is over a year later now, almost a decade now [from Allison's first report on the combination], and the trial has reopened, but I don’t know if they’ve enrolled a seventh patient," Pardoll said.
The companies, in the meantime, have focused on developing their drugs as single agents and are hesitant to test the combination further in case more side effects appear—and derail their phase III monotherapy trials. And they aren’t letting anyone else use the agents in combinations, either.
"I can tell you that the scientists and clinical development leaders would love to do this, but the lawyers and the business development people will tell you about the concerns they have that adverse events or whatnot from these combination trials could harm the registration for these agents as a single agent," Pardoll said.
So the potentially valuable combination waits, and immunotherapy limps along with a considerable handicap.
| Priority Agents for Cancer Therapy Experts gathered in mid-July to prioritize a list of 20 investigational agents that cancer researchers want to be able to use in their research. The compounds were selected from a total of 124 submitted by members of six academic societies. The criteria for ranking included the agent's potential value in cancer therapy, its perceived need by multiple investigators, a lack of broad access currently, and whether the agent was likely to become commercially available soon. The top agents in order of priority: IL-15 (interleukin 15) Anti-PD1 and/or anti–B7-H1 (PD1 ligand) IL-12 Anti-CD40 and/or CD40 ligand IL-7 CpG 1-methyl tryptophan Anti-CD137 (anti–4-1BB) Anti–TGF-beta Anti–IL-10 receptor or anti–IL-10 Flt3 ligand Anti-GITR CCL21 Adv MPL Poly I:C and/or poly ICLC Anti-OX40 Anti–B7-H4 Resiquimod and/or 852A LIGHT and/or LIGHT vector Anti–LAG-3
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