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

2
Outlining the Gap Between Preclinical
Models and Clinical Situation
INTRODUCTION
Daniel L. Levey
Antigenics Inc., New York, New York, U.S.A.
This chapter discusses preclinical models of cancer immunotherapy with emphasis
on autologous (i.e., personalized) approaches, and the value of these models in
predicting outcomes in human disease. No model is perfect, and transplantable
rodent tumor cell lines are particularly challenging tools because of their rapid
rate of growth from the moment of injection. In contrast, human cancers may be
latent due to slow growth over a period of many months to years before manifesting
themselves. It would thus seem unlikely that a rodent tumor cell line that
progresses from an inoculum to a lethal mass four weeks later can teach us
anything about the human disease. Nevertheless, because models of spontaneous
tumors are not amenable to autologous immunotherapy approaches comprising
each tumor’s unique constellation of mutated antigens, we currently must rely on
established cell lines that generally become selected for rapidly dividing clones.
Despite this challenging setting, the literature definitively shows that treatment
of rodents with minimal tumor burden (wherein treatment begins no later than
about 10 days post-tumor challenge or within a few days of surgical resection of
the primary tumor) with personalized cancer vaccines improves survival to a
significant degree. Such efficacy has been observed using several vaccine
approaches. Treatment of longer established disease is less effective with these
same approaches. Encouragingly, evidence has accumulated beyond just the
31