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Preclinical Models and Clinical Situation 33
Studies showing that large numbers of tumor-specific T cells isolated from a tumor
immune donor can induce tumor regression upon adoptive transfer to a tumorbearing
syngeneic recipient, highlight this kinetics problem, and offer a potential
solution, although a particularly daunting one in practice (3–5).
One might consider turning to more recently developed models of spontaneous
tumors in rodents where the latency period between the transforming
events and the lethal tumor-bearing state is relatively long and thus provides a
more realistic window for immune activation. Unfortunately, these models are
not amenable to treatment with personalized vaccines that are produced from
each individual host’s tumor for at least two reasons. The first is practical. One
must wait for a large enough primary tumor mass and/or metastases to develop
such that sufficient tissue can be harvested for vaccine production. This assumes
surgery can be performed on individual mice, that mice survive surgery on
potentially multiple anatomical sites, that the window for immune activation
after surgery and prior to death due to tumor recurrence will be wide enough, and
that surgery can be performed on sufficient numbers of individual mice to run
studies that stand up to statistical scrutiny. Second, the models where mice
develop spontaneous tumors driven by viral oncogenes like SV40 T antigen
under a tissue-specific promoter (e.g., RIP-TAg model) are complicated by the
expression of the dominant viral protein in the tumor itself. This expression
would likely mask or make irrelevant any immune response to individualized
antigens and does not reflect the antigen profile of most tumors in humans where
viral proteins are not a component of the proteome (6). This second issue may be
less of a concern with other transgenic models where mammalian oncogenes are
manipulated to drive transformation or where tumor suppressor genes are deleted
(7,8). However, the practical reasons related to surgery on individual mice apply
to these models as well. In conclusion, models of spontaneous tumor formation
are really only useful for testing off-the-shelf, shared antigen vaccines.
Various approaches to immunotherapy in preclinical models are discussed
below, and details of studies comparing the relative efficacy in the early-stage/
minimal residual disease setting versus more advanced setting are provided in
Table 1.
Tumor-Derived Heat Shock Protein-Peptide Complexes
Heat shock proteins (HSPs) are a group of proteins found in all cells in all life
forms. They function as chaperones, helping proteins fold while also transporting
them throughout the cell. In their chaperone function, they bind with a large
repertoire of proteins and peptides. Recent studies demonstrate an essential role
of HSPs (complexed with antigenic peptides) in the priming of immune response
by cells undergoing necrotic death (22).
Tumor-derived complexes of HSPs and their associated peptides have been
tested extensively in animal models of cancer. The published literature indicates
that HSPPCs are active against established disease in nine tumor models tested,