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

4 1 Search for Universal Tumor-Associated T Cell Epitopes
1.2
T Cell Epitopes as the Basis for Anti-Cancer Therapy
The potential clinical power of mobilizing T lymphocytes against human cancer has
been extensively reviewed elsewhere [1, 2]. T cell-directed cytokine therapy, for example,
has achieved remarkable clinical responses in certain patients. Results of donor
lymphocyte infusions for chronic myelogenous leukemia in relapse after stem cell
transplantation have been even more impressive, reliable and durable [3]. These clinical
experiments and other work in both animal and human models support the hypothesis
that T cells can under certain circumstances be triggered to induce meaningful
anti-tumor responses. Antigen-specific T cell responses are vital in each case,
and include the hallmark features of (i) peptide specificity and (ii) restriction to the
major histocompatibility complex (MHC). As protein antigens expressed by tumors
are degraded in the cytosol, peptides derived from these proteins are incorporated
into a peptide-binding groove of MHC molecules before these molecules become expressed
on the cell surface. Based on recognition by a clonally unique T cell receptor,
specific T cells ± if they exist in the repertoire ± recognize peptide in the context of
the peptide±MHC complex. In the case of CD8 + cytotoxic T lymphocytes (CTL), peptide
is generally recognized in the context of MHC class I. Tumor cells expressing
peptide±MHC complexes can trigger an effector T cell response, which for CD8 +
CTL may involve lysis of the target tumor cell. These peptide epitopes derive following
cytolplasmic proteosomal digestion of proteins which may or may not be cell surface
antigens. Indeed, most tumor antigens discovered to date are intracytoplasmic
self-antigens that are selectively expressed by tumor cells. The hypothesis that these
immunogenic peptide epitopes expressed by tumor cells can drive robust effector T
cell responses has become a major focus of clinical tumor immunology.
With tumor antigens in hand, how can they be used therapeutically? Two main approaches
± adoptive T immunotherapy and therapeutic vaccination ± have been envisioned
to exploit these findings for novel anti-cancer immunotherapy. In the first
strategy, tumor-specific T cells are expanded ex vivo and subsequently reinfused into
cancer patients. Antigen-specific adoptive T cell therapy for cytomegalovirus disease
and Epstein±Barr virus-related lymphoproliferative disorders that complicate allogeneic
bone marrow transplantation is safe and highly effective [4, 5]. Efforts are underway
to provide autologous antigen-specific T cell therapy for non-transplant cancer
patients [6, 7], although these strategies have been more difficult and hindered
by the need to generate sufficient numbers of patient-derived, tumor-specific T cells
that retain cytotoxic activity. In a second approach, patients are vaccinated against tumor-specific
or tumor-associated antigens in order to activate specific cellular and/or
humoral immunity against cancer. Most vaccination approaches have been shown to
be highly feasible and numerous trials ± which are not reviewed here ± are currently
underway. Many vaccine formulations have been tested, ranging from the use of single
antigens or parts of single antigens in peptide or nucleic acid form to the use of
tumor cells themselves as the substrate for tumor antigen inoculation. Early reports
in melanoma and hematologic malignancies suggest that antigen-specific vaccination
is safe and feasible [8±10]. Despite the enthusiasm generated by these early clin-