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Therapeutic and Prophylactic Cancer Vaccines 57
also examine the possible criteria that contributed to the success of Gardasil TM
and consider some of these ideas in the development of therapeutic cancer
vaccines.
ALLOGENEIC VACCINES
There is growing evidence that a variety of cancers can be clinically treated by
vaccines. This was seen in two randomized phase 3 studies where an autologous
tumor-cell-vaccine approach as an adjuvant for the treatment of colorectal
and renal cancers provided clinical benefit (7,8). Several vaccine strategies
(DC/peptide or RNA, protein or DNA) have employed a single-antigen approach
in which either an overexpressed or uniquely expressed tumor antigen or epitope
that is identified on tumor tissue is targeted. The limitation of this approach lies
in both the chosen antigen as well as the major histocompatibility complex
type of the patient (in the case of peptide immunization). Polyvalent tumor
vaccines that are allogeneic or autologous should, at least in theory, overcome
these limitations.
Tumor cells as polyvalent vaccines have been attractive as they are the
richest source of antigens. With a wide array of potential tumor antigens (some
or possibly most of them unknown), they could potentially activate and amplify
every facet of the immune system for both cellular and humoral antitumor
responses. These cell lines can be manipulated in vitro, such as addition of
cytokine genes to enhance potential antitumor effect (9). In addition (as with
whole tumor-cell vaccines), professional antigen-presenting cells (APCs) such as
DCs may phagocytize apoptotic tumor cells from the vaccine and effectively
cross-prime T cells with a host of immunogenic epitopes (10).
Added to its therapeutic appeal is the idea that allogeneic vaccines share
a manufacturing advantage. Allogeneic cell lines for use as whole cells, lysates,
or genetic manipulations can be initially difficult to establish in vitro and they
require antigenic consistency and proof of stability. However, once established,
this approach provides unlimited material for vaccination by overcoming
the requirement for tumor tissue and/or leukapheresis from the patient (as for
some autologous vaccines) and consequently the delay in preparation of vaccine.
They can be consistently manufactured in large lots that can be used to treat
multiple patients and be fully tested before release. Whole tumor cells, lysates,
and genetically modified tumors have been tried as allogeneic vaccines in
clinical trials.
Allogeneic Whole Tumor Cells
Some of the earliest attempts at inducing an antitumor response were in melanoma,
where intact allogeneic cell lines were used as a vaccine (11). Canvaxin TM
is a whole, multicell polyvalent vaccine consisting of a mixture of three sublethally
irradiated allogeneic melanoma lines that are of different HLA haplotypes