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processes during early exploration, and (3) considering novel, adaptive trial
designs to direct clinical development in a more optimal fashion.
“CANCER VACCINES”: KEY ELEMENTS AND CHALLENGES
“Cancer vaccines” or active immunotherapeutics encompass defined antigens,
analogues, or fragments, which are in fact molecular targeted agents. Immune cells
such as Th or Tc cells or antibodies elicited by the vaccine are aimed to recognize
specific molecules expressed by cancer cells or within the tumor environment. The
indirect mechanism of action (MOA) is a distinctive property of cancer vaccines
compared to other molecular targeted therapies. Particularly, while monoclonal
antibodies or tyrosine kinase inhibitors act directly on receptors and affect cell
viability or signal transduction pathways, vaccines relay on their capability to
induce immune mediators that in turn act on the target (Fig. 1). This has farreaching
implications in the R&D of such investigational agents and presents a set
of unique challenges that distinguish this class of drug candidates from all others.
In addition, there is no current benchmark in terms of approved cancer vaccine in
the United States, increasing the complexity, risk, and heterogeneity of the current
development strategies. The difficulty associated with establishing appropriate
preclinical models along with a relative complex MOA hinders their predictability.
By using preclinical models more often, it has been easier to predict whether a
vaccine induced immunity in humans, as opposed to whether an immune response
translated into clinical outcome. Unfortunately, this limitation along with the suboptimal
clinical efficacy of investigational cancer vaccines evaluated in the past
precluded the definition of reliable pharmacodynamic (PD) markers and surrogate
endpoints that are key to guide and accelerate the development process. Moreover,
the different safety profiles from that of more conventional classes of drugs and the
considerable heterogeneity in terms of technology platforms—from highly personalized,
cell based, to microbial vectors and synthetic, nonreplicating molecules—are
distinct features of investigational cancer vaccines posing significant challenges in
Figure 1 Challenges posed by development of cancer vaccines as largely related to the
indirect nature of their mechanism of action.