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154 Bot and Obrocea
Another key aspect of the new paradigm is the implementation of a biomarker-guided
approach as early as possible during the development process in
order to optimize and expedite proof of concept evaluation in a manner that
increases the likelihood of success and reduces the size of clinical trials. The
concept of “stratified medicine” or “theranostic approach” implies, in essence,
definition and use of biomarkers as inclusion/exclusion criteria to direct the
evaluation of the investigational drug in patients that have highest likelihood of
clinical response.
Another aspect, resulting from the complexity of the MOA and insufficiency
of preclinical models, is the re-evaluation of the clinical response. While
in more conventional situations—such as those corresponding to investigational
drugs that influence tumoral cells directly—the predictable nature of in vitro and
preclinical modeling is established and accepted to a higher extent. In the case of
active immunotherapies, the value of preclinical evaluation may consist rather in
exploring the limits of the technology that will impact the design of clinical
studies, thus having a higher likelihood of being informative or meeting preset
success criteria.
Finally, in light of the early development stage of most cancer active
immunotherapeutics currently, it is key to leverage emerging proof of concept
data in clinic generated with more mature technology platforms into novel
approaches. More specifically, significant steps were undertaken in demonstrating
proof of concept in clinic with cell-based vaccines (e.g., autologous
dendritic cells (DCs) expressing target antigens or GM-CSF producing allogeneic
tumor cells), leading the way to late-stage development. While these
technology platforms have certain drawbacks, such as reliance on patient’s cells
or collection of poorly defined cellular antigens, information from clinic on their
performance is important for the development of newer “off-the-shelf” and
synthetic molecules, allowing a more expedite development process with
increased chances of success.
In the next paragraph, we focus on several factors outlined above (such as
the significance of preclinical and clinical exploration), the fundamental role of
biomarkers, and finally, exemplification with an investigational approach in
early clinical development.
REVISING THE ROLE OF PRECLINICAL STUDIES
Cancer immunotherapeutic approaches require quite cumbersome preclinical
modeling due to the inherent complexity of the MOA of therapeutic platforms
under development. Useful models—with capability to predict the PD profile of
an investigational drug—need to meet key criteria; nevertheless, due to intrinsic
differences of immune responsiveness and antigenic makeup between species
(Fig. 3), it has been very difficult if not impossible to envision a model equivalent
to, for example, the xenograft models used in preclinical pharmacology in
support of development of small molecules. One of the most illustrious examples