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

Development of Novel Immunotherapeutics 167
Figure 11 Modeling the impact of biomarkers related to the mechanism of action, on the
development of investigational drugs with complex (indirect) mechanism of action, such
as cancer vaccines.
In face of the shear complexity of the MOA of all active immunotherapies
in development, we propose a different strategy to define target patient populations;
namely, by delineating ineligibility criteria based on thorough understanding
of the MOA (Fig. 11). For example, in order for a cancer vaccine to
have an impact on the tumor process, an immune response must be mounted—
for example, specific cytotoxic T cells (CTLs) that must migrate to the tumor site
overcome immune checkpoints within the tumor environment, recognize MHC
class I complexes, and trigger optimal effector mechanisms that result in altering
the viability of tumor cells. Even if we stay at this simplistic level, one realizes
that if any of the following criteria are not met, then the likelihood of a clinical
effect elicited by the vaccine therapy would be near zero due to the following
issues: (1) the patient’s immune system may be suppressed; (2) the patient does
not carry the right MHC allele in the case of epitope-based immunization; (3) the
patient’s tumor cells do not express MHC class I; (4) the patient’s tumor cells do
not express the target antigens; and/or (5) the patient’s tumor is a strongly
immune suppressive environment (no lymphocytes). Thus, parameters that
define the situations above become biomarkers that can be used to screen
patients eligible for the treatment; this approach to identify failure-linked biomarkers
is considerably easier than defining biomarkers that positively predict
clinical response during early development stages. Mathematically, use of
multiple failure-prediction biomarkers in support of this approach (patient
screening) would be as beneficial yet more easier compared to defining