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

40 Levey
with some confidence. Caution is more appropriate when drawing conclusions
from the remaining nonrandomized studies that enrolled, in most cases, small
numbers of patients. What is encouraging, however, is the consistency of the
trend across multiple indications toward benefit in the setting of minimal disease
versus bulky disease.
RECENT TRENDS IN PRECLINICAL MODELING
The correlation between the successful preclinical application of personalized
cancer immunotherapy in early-stage disease and growing evidence for clinical
activity using these same approaches in early-stage cancer patients bodes well
forafieldthathasstruggledformanydecadestoemergefromamorass.As
cancer diagnostics continue to improve, one might predict an increase in the
number of patients whose cancer is detected earlier and who would thus be
amenable to personalized cancer immunotherapy. Evidence from recent clinical
studies suggests that many of these patients will experience a significant
improvement in recurrence free and overall survival by vaccination in the
postsurgical adjuvant setting. Yet is there a role for personalized immunotherapy
in patients whose disease is not detected early and who thus face a
poorer prognosis? The preclinical models suggest that active immunotherapy
alone will be insufficient to provide a meaningful impact on lifespan in this
setting. Instead, as is often the case in cancer care, personalized immunotherapy
will likely be used in combination with traditional cancer drugs
(chemotherapeutic agents) and with other immunomodulatory agents several
of which are still in experimental testing in humans. The remainder of this
chapter describes some of these trends with an emphasis on preclinical
experiments. In some cases, off-the-shelf (nonpersonalized) cancer vaccines
that have been tested in combination with other agents are discussed. There is
every reason to believe that personalized vaccines will also be useful in these
combination settings.
The challenge posed by the narrow window between tumor challenge and
death in preclinical models is even more pronounced in combination therapy
where at least two agents are intended to be administered, in many cases in a
staggered manner. In most combination studies, therefore, rodents with relatively
early-stage disease have been tested. This setting, then, does not in fact perfectly
mimic the advanced-stage setting in humans where drug combinations are
likely to be needed. Starting treatment with a cytotoxic agent when the tumor
burden in rodents is minimal may not mimic the extent of antigen release in the
form of apoptosis and secondary necrosis that is expected to occur in humans
with bulky disease administered the same drug. Nevertheless, the preclinical
models at least provide an opportunity to determine whether the combination
agent of interest is antagonistic, additive, or synergistic with immunotherapy.
Assuming an additive or synergistic effect is noted, the rationale for testing in
advanced-stage cancer patients will be strengthened.