Download File - JOHN J. HADDAD, Ph.D.

56 Srinivasan
disease agents. Gardasil TM (Merck & Co., Inc., New Jersey, U.S.A.), the first
cancer vaccine approved by the FDA, is a prophylactic vaccine against cervical
cancer in young women (1). The vaccine is a quadrivalent virus–like particle
(VLP) vaccine and offers protection by generating neutralizing antibodies against
the human papillomavirus (HPV). This vaccine does not protect women who are
already infected with the papilloma virus and who may consequently develop
cervical cancer.
While traditionally the immune system has evolved to protect the host
from invading pathogens, it is also believed to be triggered when it perceives a
“danger” signal by the host’s self-tissue (2). In cancer, such signals may be
associated with the existence of tumor immunity as seen with clinical examples
of spontaneous regressions in melanoma, gastrointestinal, lung, and breast cancers
(3). In addition, histopathology of tumor sections has revealed infiltrating
lymphocytes around the tumor bed, and recent studies indicate that ovarian
cancer patients with such infiltrates in tumors have an improved prognosis
compared with similarly staged patients without lymphocytic infiltrates (4).
Therefore, the immune repertoire may contain autoreactive immune cells
capable of rejecting tumors, when activated appropriately. However, in spite of
clear animal model data demonstrating the potential therapeutic benefit of cancer
vaccines, with the exception of those for viral-mediated cancers, therapeutic
tumor vaccines have had only limited success in humans. More recent studies are
looking at enhancing tumor-specific responses using immune modulators in an
attempt to translate them to effective tumor protection.
Different types of cancer vaccines have induced tumor immunity and a
correlative antitumor response in syngeneic mouse tumor models, leading to
their efficacy testing in human. Most noteworthy examples of therapeutic cancer
vaccines that are in various stages of development are plasmid or viral-vector
DNA, dendritic cells (DCs) pulsed with peptide or RNA, allogeneic whole tumor
cells, allogeneic tumor-cell lysate, cytokine-transduced tumor cells, heat shock
proteins, and autologous T-cell therapy (5,6). Among the prophylactic vaccines,
the one that was recently approved is Gardasil TM for the prevention of cervical
cancer; precancerous genital lesions; and genital warts due to HPV) types 6, 11,
16, and 18 in young women (1).
Allogeneic tumor vaccines as potential form of a therapeutic vaccine were
tested in large randomized phase 3 trials. The two allogeneic tumor-cell vaccines
that were tested in phase 3 trials for melanoma were Melacine 1 (Corixa Corporation
Washington, U.S.A./GlaxoSmithKline, England, UK) and Canvaxin TM
(CancerVax Corporation, California, U.S.A./Micromet, Inc., Maryland, U.S.A.).
Both vaccines had showed efficacy in the early stages of clinical development.
However, pivotal trials did not indicate a clinical benefit and the trials were
discontinued. Phase 3 trials with GVAX 1 (Cell Genesys, California, U.S.A.)
are ongoing for the treatment of prostate cancer. In this chapter, we will discuss
the potential that some of the allogeneic tumor vaccines have offered and
the reasons for their failure in becoming a successful therapeutic agent. We will