Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

ical trials, however, it is clear that most vaccination trials have achieved immunological
responses without significant clinical responses. To be sure, these are largely
phase Itrials designed to test safety not efficacy. The issues involved in the design of
cancer vaccine trials are complicated and particular to the field [11]. Successful approaches
in antigen-specific T cell immunotherapy will need to repair host immune
deficits in antigen presentation and T cell function, circumvent immunosuppressive
factors of the tumor, and possibly most importantly, optimize target antigens with regard
to clinical applicability and risk of immune escape.
1.3
Identification of Tumor-Associated Antigens
1.3 Identification of Tumor-Associated Antigens
Given the scarcity of clinically significant tumor-specific immune responses in cancer
patients, there had been reasonable doubt through the 1970s and 1980s that tumor-associated
antigens existed in human cancer outside of oncogenic viral proteins
or the immunoglobulin idiotype in B cell tumors. However, in landmark studies in
the early 1990s, Boon and colleagues and Rosenberg and colleagues molecularly dissected
the specificity of measurable T cell responses in melanoma patients [12, 13].
Tumor-associated antigens were rapidly characterized in several other malignancies
[12±14] and this initiated the hypothesis that most, if not all, tumors express antigens
that T cells can potentially attack [2].
The classical methods to identify tumor antigens have been extensively reviewed
elsewhere [1, 15, 16]. Tumor antigens have been identified by analyzing patients T
cell responses or by antibody-based techniques analyzing the humoral anti-tumor
immune response. Importantly, the phrase ªtumor-associated antigenº cannot be
used interchangeably with ªtumor rejection antigenº or ªtumor regression antigenº
[17]. Clearly, not all tumor antigens identified so far induce immune responses that
lead to tumor rejection. Of course, minimal clinical responses may relate as much to
an inferior mode of delivery or to a phase Idesign with limited power to detect efficacy
as it does to the antigen itself. There is no consensus as to whether cellular or
non-cellular modalities, active or passive immunization, or antigen-specific or tumor-specific
strategies are to be favored. Unfortunately, this area of research is still
primarily empirical, and the judgment of whether a particular antigen is useful or
not is a complex function of immunology, oncology, pharmacology and biostatistics.
As described by Gilboa, ªtumor rejection antigen is an operational term describing
how well an immune response elicited against a tumor antigen will impact on the
tumor growthº [17]. This depends not only on the nature of the tumor antigen but
also on the nature of the immune response to the tumor antigen. Variables such as
T cell avidity, tolerance and frequency play a major role for a tumor antigen to qualify
as a tumor rejection antigen. Potent tumor rejection antigens would elicit high avidity
T cell responses and recruit a high frequency of T cells with a high diversity in T
cell receptor usage. The establishment of immunological memory in the wake of
therapy is vital.
5