Many participants addressed a number of cultural challenges to collaborations, including
• Competitiveness and unwillingness to share data and resources;
• Tendency to focus more on developing blockbuster drugs than achieving breakthroughs;
• Resistance to innovation; and
• Lack of experience and resource investment by some pharmaceutical companies in immunotherapies used in combination therapies.
Suggestions from Various Workshop Participants on Overcoming Cultural Challenges to Collaborations
• More communication and transparency among collaborating partners
• Greater involvement of patients in determining how tissue resources are shared and used
• A safe harbor for industry to facilitate greater availability of failed investigational compounds for research
• Financial incentives to encourage more collaboration
• Restoring the research and development focus of pharmaceutical companies
Although companies are by nature competitive and that can impede collaboration, several participants mentioned the willingness of drug companies to collaborate in the development of combination cancer therapies, especially if they suspect their investigational agent would work better with another company’s drug and they did not have something comparable in their portfolio. “They would rather do it with two of their own drugs, because it makes life easy, but if it’s a really good idea, there is a lot of willingness to collaborate,” Dr. Engelman said, based on his experience working with several drug companies. Dr. Cantley concurred, adding, “The barriers are not that high if the data are really convincing. Where there’s compelling science, people will want to collaborate. Companies are very forward thinking about it.”
Dr. Lutzker said that even when a company already has a similar compound in development, if another company’s compound is performing better and would increase the likelihood of a successful combination, “we would go after that company to do a codevelopment plan. It just has to do with where you are in your own portfolio.” Dr. Canetta added that when he is asked by the press how his company’s competition is going with Roche, in regard to developing new melanoma drugs, he responds, “We are competing against melanoma, not Roche, and if there are modalities that make sense to put together, that’s what we will do.”
Dr. Blackman stressed the need for communication, collaboration, and transparency among companies developing cancer therapies. “We have to realize that we are all pretty much working on the same things, and the only way we will succeed is to list indications we would be willing to go to with our own internal combinations and maybe with the partner combination. At least in these early phases, we need to talk to each other, and make sure that we agree that we are either going to all go into the same space because we think there is some compelling biological reason and fundamental differences between the agents, or we are going to go in different directions to cover more ground and learn more as a field about where this combination may be active.” Dr. Lutzker noted that he has had a lot of discussions with companies in which they’ve made each other aware of what is in their drug development pipelines for combinations.
Dr. Blackman suggested that there be more collaborations between academia and industry in which academic institutions conduct the retrospective analyses of samples and data from previous trials and other studies to find biomarkers for patient selection so that the next clinical trials can be more successful and compounds are not shelved prematurely because a lack of patient selection made them perform poorly in clinical trials.
The discovery of such biomarkers often depends on the availability of annotated patient specimens from previous trials and other studies. Dr. Cantley stressed that more effort should be made to collect patient specimens during clinical trials, and to store and make these tissues available for future research on biomarkers. Dr. Perlmutter suggested that NCI’s Cooperative Groups, which conduct many of the government-funded clinical trials for cancer, be required to do more tissue banking and to share patient specimens collected. “Patients are getting quite impatient that they sometimes are asked to sign a consent that says ‘Let my tissue be used elsewhere,’ and the initial institution refuses to send it. Patients are now forming together to add text into their informed consents that says ‘you can only use my tissue if you will publish the analysis you do and openly share the tissue,’” she said.
Dr. Hohneker added that there is substantial variability in how IRBs interpret patient consent to grant the use of their specimens and data collected during the course of a study for the purposes of another research project. “We need very vocal patient representatives on IRBs that can bring in the fact that patients want the option [to share their specimens with other researchers] and that would help enable that data be available in the future,” he said. Once patient response biomarkers are discovered and validated, the next challenge is to have physicians routinely use them for their cancer patients and make them part of their standard of care, Dr. Engelman pointed out.
Several participants mentioned that it can be challenging to acquire failed compounds, biologics, and other investigational drugs for academic studies. “There are a number of drugs that pharma works with that are on target, but don’t survive the preclinical testing. These compounds would be very valuable to investigators working at the cell biology level. I would hope that they could be made available,” Dr. Stern said.
Dr. Michael Caligiuri, director of the Ohio State University Comprehensive Cancer Center and chief executive officer of the James Center Hospital & Solve Research Institute, agreed and said, “It is still exceedingly difficult for academia to get ahold of two or three investigational agents that come from two or three different companies, and lots of investigators are spending lots of money synthesizing compounds that already exist on company shelves.” His own institution has invested several hundred thousand dollars a year to synthesize these compounds, he said, and sponsored, along with other partners, a roundtable that resulted in a white paper on how to overcome the obstacles to sharing drugs for preclinical studies (OSU, 2011). Dr. Schlom showed a long list of potential immune stimulants housed by industry that other researchers have not
been able to access, and said that lack of access has held up the field (see Table 4-1).
Dr. Flaherty agreed, saying that access to drugs should be the number one priority. “Until we figure out a way to improve that, then the other things, such as the need for surrogate endpoints, aren’t really as critical,” he said.
Recently, NCI has procured or synthesized several hundred molecules with anticancer potential (see Appendix A). Dr. Doroshow said NCI can supply these compounds to NCI intramural scientists and to its contrac-
|1||IL-15||T cell growth factor|
|2||Anti-PD1 and/or anti-B7-H1 (PD-1L)||T cell checkpoint blockade inhibitor|
|4||Anti-CD40 and/or CD40L||Antigen presenting cell stimulator|
|5||IL-7||T cell growth factor|
|7||1MT: 1-methyl tryptophan||Enzyme inhibitor|
|8||Anti-CD137 (anti-4-1BB)||T cell stimulator|
|10||Anti-IL-10 receptor or Anti-IL-10||Suppression inhibitor|
|11||Flt3L||Dendritic cell growth factor/vaccine adjuvant|
|12||Anti-glucocorticoid-induced TNF receptor (GITR)||T cell stimulator|
|13||CCL21 adenovirus||T cell attracting chemokine|
|15||PolyI:C and/or PolyICLC||Vaccine adjuvant|
|16||Anti-OX40||T cell stimulator|
|17||Anti-B7-H4||T cell checkpoint blockade inhibitor|
|18||Resiquimod and/or 852A||Vaccine adjuvant|
|19||LIGHT and/or LIGHT vector||T cell stimulator|
|20||Antilymphocyte activation gene-3 (LAG-3)||T cell checkpoint blockade inhibitor|
tors, but not to extramural investigators. A program is being established to allow investigators to submit requests for in vitro studies of the effects of specific combinations of these investigational agents (Mayfield, 2011).
Industry representatives expressed a varied response to the request to share investigational drugs. Dr. Lonberg responded that the supply of study drugs is not limitless, and that the scarce supplies of these drugs forces even large companies to prioritize the studies in which they are used. Dr. Bachman pointed out that GSK puts their failed compounds in places such as Sigma Chemical Company, where others can easily access them. “We try to freely give those out. It’s just a request that is sent.” He added that GSK is also making available to all academics the epigenetic toolbox it has created to study epigenetic effects in studies of cancer drugs. GSK also publishes in the public domain1 its genomic and other data on cell lines or compounds that are not relevant to the intellectual property (IP) of one of its molecules, including test results for a number of inhibitors on nearly 300 cell lines.
Dr. Caligiuri suggested the development of a safe harbor for industry where risk is mitigated and the compounds are distributed in a responsible fashion with meaningful collection and sharing of the data. Dr. Bachman noted that he is willing to share his industry’s compounds with researchers in academic institutions, but the intellectual property (IP) language of those institutions contradicts that of the industry’s, and the lawyers are often unable to work out an agreement authorizing the sharing of the compounds. “Everyone is risk averse,” Dr. Caligiuri explained. “Unfortunately, attorneys are hired to protect universities and they miss the big picture.”
Dr. Cantley noted that his organization uses financial incentives to foster collaborations. “If you just pay a bunch of people’s salaries and ask them to work together, you’ll get them to work together, but if you actually hold above them a million and a half dollars and say, ‘if you do that, we’ll give you the money,’ there’s a reward for actually getting them to do what we need them to do,” he said, and noted the investigators are only paid for patients as they enroll them, “so there’s some money up front to get people playing [together].”
Participants cited another major impediment to progress in combination therapies: the drug industry’s reluctance to embrace innovation and its tendency to want to run business as usual. For example, Drs. Schlom and Flaherty said this attitude is especially impeding progress in cancer
immunotherapeutics, which do not fit the typical drug development paradigm, as they often involve cells rather than compounds, and show different functionalities depending on their dose and how they are combined. Many potential immune stimulants have failed standard preclinical tests run by pharmaceutical companies because singly they are not effective at the maximum tolerated dose, but there is abundant evidence that when these “failed” compounds are used with tumor vaccines at lower doses, they enhance the vaccine’s efficacy, Dr. Schlom pointed out. “But it’s alien to them—immunotherapy is still something that most pharmaceutical companies don’t want to deal with right now,” he said.
Dr. Flaherty added that “what has held back progress in this area is that individual sponsors wanted to see that they are in sight of the finish line, in terms of having an approvable drug, either as a single agent or in combination with an archival therapy—something that’s stable and static and not a moving target. But we can’t wait for each of those agents to find their home as single agents. All of these immunologics were stalled because they didn’t have single agent activity and therefore a finish line in sight.” He stressed that this thinking goes contrary to the notion of what he called “codependent targets”—targets that will only demonstrate real benefits in combination with other therapies.
Dr. Hohneker pointed out that the manufacturing and development of the biologics used in immunotherapy is not a core competency of every pharmaceutical company. Immunotherapies require a major investment of resources that some companies have not yet made, and are not willing to make until there is more proof of concept demonstrated in this area. Dr. Munos noted that the “play it safe” attitude of most pharmaceutical companies has taken industry away from making breakthroughs. “We’ve encoded so-called ‘best practices’ into standard operating procedures, hoping that this would replicate past successes, instead of finding new breakthroughs,” he said. Dr. Munos noted that the drug industry has shifted its resources away from early discovery research into late clinical trials, and suggested “bringing back the passion for R&D [research and development]. There’s hardly been a breakthrough in history that was not underpinned by a lot of passion. We need to bring that back and focus on breakthroughs, not blockbusters.” He suggested such research could be financially supported using the resources currently being spent to test compounds that are of limited clinical relevance and likely to give an incremental benefit at most.