Download File - JOHN J. HADDAD, Ph.D.

156 Bot and Obrocea
outcome in general due to the fact that transplantable tumors are highly artificial.
Models involving spontaneously arising tumors were developed—yet the nature
of therapeutic targets in preclinical setting, with some exceptions, limited their
value in relation to exploration of humanized investigational drugs. Overall, it
was not yet possible to reproduce in a preclinical model the target expression
environment within a human tumor—one reason was the complexity and scarcity
of reliable information regarding the latter.
A distinct feature that has been notoriously difficult to reproduce in preclinical
setting has been the strict status of the immune system and immune
repertoire from patients treated with multiple standard therapies (such as radio
and/or chemotherapy). Since the MOA of active immunotherapies requires
immune competence, this represents a major parameter. In fact, attempts to
explore this question resulted in tantalizing observations consisting in additive or
even synergistic effects between select chemotherapies (cyclophosphamide,
paclitaxel, doxorubicin, cisplatin) and vaccination. Beyond the interesting scientific
explanation having to do with a T-cell repertoire conditioning or interference
with immune “breaks,” or the practical implications on designing
innovative combination approaches in clinic, a major criticism remains: The
effect of chemotherapies on immune system seems to be species specific so
thorough clinical exploration is needed to elucidate whether these observations
truly translate to man.
Finally, a major difference between preclinical and clinical setting—that
limits the translation of findings from the former to the latter—is the speciesspecific
recognition and response to “biological response modifiers” or adjuvants
in general. To be active, cancer vaccines rely on delivery of not only immunological
information such as epitopes but, at the same time, of motifs or
molecules that instruct the immune system to mount a response of a certain
magnitude and profile, most often by influencing the innate immunity. Most
recently, such molecules have been described as TLR ligands (CpG motifs
binding to TLR9; ds or ssRNA binding to TLR3, 7, and/or 8; LPS analogues
binding to TLR4; and even small molecules binding to TLR7 such as Imiquimode
1 ) that exert their function by activating receptor-positive DCs, NK cells,
or other cells of the immune system. Since receptor distribution on cell subsets,
the relative function of different subsets, and the fine specificity of receptors
vary from species to species, it is not unexpected that, for example, the TLR9
ligands CpG motifs have a different optimal structure in relation to an effective
innate immune stimulation in mouse and human. Therefore, preclinical modeling
may not be entirely predictive relative to immune-stimulating properties of
vaccine excipients.
Altogether, these issues suffice to raise a fundamental question that is
highly applicable to the preclinical modeling of active immunotherapies in
cancer, but to a lesser extent to other therapeutic strategies relying on more direct
mechanisms of action. Namely, one needs to acknowledge that preclinical
evaluation of an investigational drug, like a cancer vaccine aimed to treat a