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4
Overcoming Cultural Challenges
to Collaborations
Many participants addressed a number of cultural challenges to col-
laborations, including
• ompetitiveness and unwillingness to share data and resources;
C
• endency to focus more on developing blockbuster drugs than
T
achieving breakthroughs;
• esistance to innovation; and
R
• ack of experience and resource investment by some pharmaceuti-
L
cal companies in immunotherapies used in combination therapies.
Suggestions from Various Workshop Participants on
Overcoming Cultural Challenges to Collaborations
• ore communication and transparency among collabo-
M
rating partners
• reater involvement of patients in determining how tissue
G
resources are shared and used
• safe harbor for industry to facilitate greater availability
A
of failed investigational compounds for research
• inancial incentives to encourage more collaboration
F
• estoring the research and development focus of phar-
R
maceutical companies
37
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38 COLLABORATIONS TO DEVELOP COMBINATION CANCER THERAPIES
COMPETITIVENESS
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 thera-
pies, 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. Com -
panies 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 perform-
ing 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 modali-
ties 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 ret-
rospective 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.
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39
OVERCOMING CULTURAL CHALLENGES TO COLLABORATIONS
SHARING RESOURCES
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 speci-
mens 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 col -
lected 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 Compre-
hensive Cancer Center and chief executive officer of the James Center
Hospital & Solve Research Institute, agreed and said, “It is still exceed -
ingly 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 sev -
eral 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
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40 COLLABORATIONS TO DEVELOP COMBINATION CANCER THERAPIES
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 -
TABLE 4-1 Rankings of Immunotherapy Agents with High Potential
for Use in Treating Cancer
Rank Agent Agent Category
1 IL-15 T cell growth factor
2 Anti-PD1 and/or anti-B7-H1 T cell checkpoint blockade inhibitor
(PD-1L)
3 IL-12 Vaccine adjuvant
4 Anti-CD40 and/or CD40L Antigen presenting cell stimulator
5 IL-7 T cell growth factor
6 CpG Vaccine adjuvant
7 1MT: 1-methyl tryptophan Enzyme inhibitor
8 Anti-CD137 (anti-4-1BB) T cell stimulator
Anti-TGF-β
9 Signaling inhibitor
10 Anti-IL-10 receptor or Anti-IL-10 Suppression inhibitor
11 Flt3L Dendritic cell growth factor/vaccine
adjuvant
12 Anti-glucocorticoid-induced TNF T cell stimulator
receptor (GITR)
13 CCL21 adenovirus T cell attracting chemokine
14 MPL Vaccine adjuvant
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- T cell checkpoint blockade inhibitor
3 (LAG-3)
SOURCES: Schlom presentation (June 14, 2011) and Cheever, 2008.
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41
OVERCOMING CULTURAL CHALLENGES TO COLLABORATIONS
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 respon -
sible 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 shar-
ing 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 actu -
ally 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].”
RESISTANCE TO INNOVATION
Participants cited another major impediment to progress in combina-
tion 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
1 See https://cabig.nci.nih.gov/caArray_GSKdata/ (accessed December 14, 2011).
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42 COLLABORATIONS TO DEVELOP COMBINATION CANCER THERAPIES
immunotherapeutics, which do not fit the typical drug development para-
digm, as they often involve cells rather than compounds, and show differ-
ent 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.
