Dr. Marshall has done an excellent
job in his review of the
current status of the design,
development, and delivery of cancer
vaccines with emphasis on vaccines
for the treatment of gastrointestinal
cancers. He has clearly delineated both
the promise and potential limitations
of this actively emerging field of
investigation.
Historical Background
Important distinctions are made
upfront between "first-generation"
vaccines analyzed in previous and, in
some cases, recently completed clinical
trials, and the more sophisticated
vaccines and vaccine strategies that
are currently available for clinical
evaluation. The use of cancer vaccines
for the potential treatment of a
range of malignancies has now
reached new milestones in scientific
discovery. Areas of intense investigation
include the development and
characterization of (a) tumor-associated
antigens and tumor-specific antigens
that are overexpressed or selectively
expressed by malignant cells as
compared with normal adult tissues,
(b) novel vaccine delivery systems
for the induction of more efficient
host antitumor immune responses, and
(c) cytokines and other immunostimulants
to further augment immunogenic
properties of vaccine
preparations. The combination of gene
discovery with each of these areas
has accelerated the rate of both basic
mechanistic findings and potential
clinical applications.
Recent Innovations in
Vaccine Design and Delivery
There have been numerous recent
advances in our basic understanding
of immune mechanisms, tumor immunology,
and vaccinology. For example,
T-cell activation has now been
shown to be a complex phenomenon
involving the interaction of the major
histocompatibility complex (MHC)
and peptide, on the antigen-presenting
cell, with the T-cell receptor on
the T cell. Both CD8+ cytolytic Tcell
and CD4+ helper T-cell responses
are most likely essential to achieve
antitumor effects.[1,2]
For weak antigens such as tumorassociated
antigens, however, accessory
molecules are necessary for
efficient T-cell activation. These have
been termed "T-cell costimulatory
molecules." Preclinical studies have
demonstrated that when costimulatory
molecules are placed into a
syngeneic tumor cell that is weakly
immunogenic or nonimmunogenic
in a host, the transduced tumor cell
may become immunogenic to the
point that it elicits antitumor immunity.
Genes for costimulatory molecules
can be placed into vectors along
with tumor-antigen genes for use in
more conventional vaccines. This
strategy has also been shown to increase
the avidity, ie, potency of
T-cell responses.[3]
CEA-TRICOM Vaccines
Dr. Marshall has chronicled the
hypothesis-driven preclinical research
that has led to science-based clinical
trials in defining more effective vaccines
directed against the tumorassociated
carcinoembryonic antigen
(CEA). While CEA is expressed on
the vast majority of gastrointestinal
cancers, it is also expressed on
many other carcinoma types such
as lung, breast, and head and neck
cancers.
Early clinical trials demonstrated
that recombinant vaccinia viruses
expressing CEA as well as the replication-
defective avipox viruses expressing
CEA were safe and effective
in enhancing T-cell responses to
CEA in vaccinated patients with advanced
GI malignancies. A diversified
prime-and-boost strategy was
then used to enhance T-cell responses
and gave the first indication of enhanced
survival in a small cohort of
patients.[4]
The addition of one costimulatory
molecule (B7.1) to these vaccines, and
then the addition of a triad of costimulatory
molecules (B7.1, ICAM-1, and
LFA-3, designated TRICOM[5]), led
to the generation of enhanced T-cell
responses and evidence of increased
survival in patients with advanced
CEA-expressing carcinomas, especially
with the use of granulocyte macrophage
colony-stimulating factor
(GM-CSF [Leukine]) with vaccine.[6]
These studies have led to the initiation
of a multicenter randomized
phase III trial in patients with advanced
pancreatic cancer employing
recombinant vaccinia and avipox
vaccines containing five transgenes
(CEA, MUC-1, TRICOM).
Paradigm Shifts
The evaluation of cancer vaccines
in clinical trials may well necessitate
a new paradigm, as follows.
- Mode of Action- Cancer vaccines and cytotoxic drugs act quite differently in terms of mode of action. Cytotoxic drugs either kill or do not kill tumor cells. Lack of efficacy is due to either drug resistance by tumor cells, inadequate amounts of drug delivered to the tumor, and/or drug-induced toxicity in the host. Thus, if a patient's disease is progressing on a cytotoxic drug, that drug is immediately withdrawn. The use of a cancer vaccine involves a dynamic process in which the patient's own immune system is activated. To maximize the host immune response, however, one must not only give a primary vaccination but also multiple booster vaccinations. Multiple vaccinations are especially important due to the fact that factors may be given off by the tumor that will blunt the immune response. It is quite conceivable that a patient's disease will continue to progress following early vaccinations, only to see disease stabilization or a reduction in tumor burden following multiple vaccinations.[ 6] Thus, the paradigm of "drug withdrawal upon progression" should be revisited with the use of cancer vaccines.
- Phase I, II, III Paradigm- Clinical trials with a new drug are traditionally evaluated in patients with advanced cancers-often with a large tumor burden-who have failed prior cytotoxic therapies. Objective clinical responses are evaluated by Response Evaluation Criteria in Solid Tumors (RECIST), looking for a greater than 50% reduction in tumor volume. Since the generation of an immune response to a vaccine is a dynamic process in which T cells can be continually generated upon booster vaccines, a more appropriate end point for evaluation should be time to progression and, more importantly, survival. In addition, a more appropriate setting would be the evaluation of cancer vaccines earlier in the disease setting in patients with either a small tumor burden or a high probability of disease progression. This should particularly be considered in light of the relatively low level of toxicity seen in the use of cancer vaccines.
- Combination Therapies- One of the major advantages in the use of cancer vaccines is their reduced toxicity. One of the "conventional wisdom" paradigms that is now being reevaluated is that one cannot use cancer vaccines in combination with chemotherapy or radiation therapy. Preclinical studies, and now several clinical studies, have shown that patients can mount an immune response to cancer vaccine when given in combination with certain cytotoxic drugs,[7] hormones,[8] or local irradiation[ 9] of tumor. Indeed, recent preclinical studies have shown that when tumor cells are exposed to radiation[ 10] or certain chemotherapeutic agents at levels insufficient to kill tumor, the phenotype of tumor cells is actually modulated to make them more susceptible to T-cell-mediated killing.
