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Development of Novel Immunotherapeutics 163
efficacy and vaccine-induced immune response. Thus, in essence, the induction
of immune response would be aimed at eliciting central-memory (CM)
T cells with a capability to further expand to peripheral memory (PM) and
differentiate to peripheral effector (PE) cells, trafficking to the tumor site, and
exerting antitumor cell activity inasmuch as there are T cells endowed with
high functional avidity present. It is expected that host’s immune homeostatic
mechanisms together with tumor’s environment result in exhaustion, apoptosis,
and shrinkage of the self-tumor antigen–specific PE T-cell population.
The subsequent immunization steps would be aimed to reelicit expansion and
differentiation of PE cells from CM cells. Overall, repeat immunization would
ensure reinduction of CM cells and differentiation of PE cells present in the
system in an intermittent rather than continuous fashion. In addition, should
there be induction of anticognate tumor antigen–specific T cells that promote
a proinflammatory process, there is a possibility of “epitope spreading” that
is mirrored by activation, expansion, and differentiation of T cells specific
for other tumor antigens. Nevertheless, while the evidence in support of
this phenomenon is quite limited (4), epitope spreading would be able to
preempt—to a certain extent—immune escape mechanisms consisting in
antigen loss.
Despite the difficulties associated with the translation of observations from
preclinical models to clinic, preclinical exploration is still important to optimize
and advance complex active immunotherapeutic approaches to clinic. Exploration
of “idealized” models encompassing dominant antigens and powerful
methods of immunization in immune-competent organisms shed light on the
limits of active immunotherapy and pinpoint the nature of indications associated
with least chance of success in the clinic. Conversely, preclinical exploration
provides hints regarding the type of indications to be explored in clinic and the
end points to be evaluated (Fig. 9):
1. Minimal residual disease, postdebulking using surgery or other means that
do not induce a persisting immune suppression (“adjuvant” approach);
clinical end points may be overall survival, progression-free survival, and
time to relapse.
2. Limited but measurable disease (metastatic or isolated lesions), in a setting
that may or may not follow standard therapy that partially reduced the
tumor burden without inducing persisting immune suppression; clinical
end points may be progression-free survival, overall survival, tumor
regression, and/or time to progression (TTP).
3. Bulky disease (metastatic or isolated lesions), refractory to standard
therapy alone or rapidly relapsing, in a setting where immune competence
is preserved. In that case, while active immunotherapy alone is not
expected to impact disease progression, there is a potential that carefully
selected combination approaches result in clinical benefit (increased
response rate manifested through partial tumor regression, disease