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Prostate Cancer
Vaccines - Where Do We Stand? (July 2004)
The recipe for a
successful vaccine against prostate cancer is easy to state: identify
one, or preferably several, target proteins that are uniquely expressed
only on prostate cancer cells, program the dendritic cells in lymph
nodes to present small fragment replicas of those targets, raise up a
cadre of properly educated cytotoxic T cells and their associated helper
cells, dispatch the T cells to kill the targeted cancer cells, and keep
the T cell army re-supplied with new recruits sufficient to wage a long
battle. Unfortunately, the "devil is in the details" and accomplishing
this difficult feat is keeping many biotech companies working overtime.
Articles about cancer vaccines have become popular items in the lay
press and clinicians are bound to be asked about this somewhat
complicated subject.
An up to date
example of this developing science was reported in the June issue of the
Journal of Clinical Oncology by the Eastern Cooperative Oncology Group:
"Phase II Randomized Study of Vaccine Treatment of Advanced Prostate
Cancer...". Their results illustrate that progress in this area will be
soberingly slow, requiring sequential, small carefully made steps.
The study was
conducted on 65 men with rising PSA values above 2 ng/mL after primary
therapy (surgery or irradiation). The study focused on the evaluation of
the immune response to a PSA based vaccine, with a secondary interest in
PSA response. Probably the most interesting aspects of their work were:
1) the method of constructing the vaccine, and, 2) the biology
underlying the vaccine's mechanism of action. Vaccinia and fowlpox
viruses were genetically engineered to express a full-length
complementary copy of the human PSA gene. The vaccinia virus has an
acceptable safety record for local intra-dermal administration; and the
fowlpox virus, which was given by intramuscular injection, lacks the
ability to replicate in human tissue and has the additional favorable
characteristic of expressing its PSA antigen payload for long periods.
Four vaccinations at 6 week intervals were given.
The biologic
response to the administered vaccine is intriguing. The blood
mononuclear cells, precursors of the antigen presenting dendritic cells,
are "infected" by the viruses, and the viruses (now within the cytoplasm
of the cell) begin to manufacture PSA using the PSA gene as the
template. But PSA, instead of being secreted into the serum as occurs in
prostate cells, is digested into a multitude of small 10 amino acid
fragments, and these fragments are moved to the surface of the now
mature dendritic cell. Cradled within surface portion of the major
histocompatibility complexes, the protein fragments are "presented" to T
cells, thus sensitizing them to recognize the counterpart target PSA
fragments which appear on the surface of prostate cancer cells. The
consequence of this T cell recognition is a potential death blow to the
cancer cell.
Now the sobering
part from the study! No PSA responses nor clinical responses were
observed. However, the small but important step forward was the
observation that 46% of the patients demonstrated sensitization of their
T cells to PSA fragments, indicating a successful immune response to
vaccination. The subsequent planned trial will be a Phase III randomized
trial to further evaluate whether this PSA directed/viral vaccination
can exert control over a rising PSA, and in this trial the vaccine will
be combined with the immunologic stimulant, granulocyte-macrophage
colony stimulating factor (GM-CSF).
The Dendreon
Corporation currently has two prostate cancer vaccine trials underway.
The February 2004 PCa Commentary featured a discussion of these two
vaccine trials, both applicable for men post prostatectomy. PII is open
for men with a rising PSA post primary surgery; and protocol D9902B is
currently open for men with metastatic hormone refractory whose Gleason
sum is < 7. D9902B is the follow-up trial to the initial protocol
D9901 in which men with the full range of Gleason sums had been
eligible, and which showed, in its Gleason < 7 subset, a
significant difference in time to objective progression of 16 weeks for
vaccinated men versus 9 weeks for the control group. The Dendreon
vaccine employs an immunologic boost from GM-CSF, which is incorporated
into their prostatic acid phosphatase (PAP) based vaccine, "Provenge".
Unfortunately, the method of administration (leukophereses, ex vivo
incubation, and subsequent IV infusion X3 q 2 wks) for this product is
cumbersome, and my candid editorial opinion is that, if an effective
vaccine can be developed that can be administered by the intra-dermal,
subcutaneous, or intramuscular route, an injectable vaccine of this sort
will become the preferred method for widespread useage.
Cell Genesys
Corporation with its GVAC vaccine product has taken yet another approach
to the formulation of an anti-prostate cancer vaccine. Drs. Corman
(VMMC) and Higano (U of W) have been active participants in the 80 man
trial reported in abstract form at the June ASCO meeting. The study
group was comprised of men with metastatic hormone refractory disease.
The vaccine is comprised of cultured allogenic human prostate cancer
cell lines that have been irradiated and genetically modified to secrete
the human cytokine, granulocyte-macrophage stimulating factor (GM-CSF),
the potent stimulator of immune response. The vaccine is given by
injection. The mechanism underlying this type of vaccine is dependent
upon the ingestion of these cell by the subject's phagocytes. These
modified human prostate cells exhibit the fullest range of prostate
cancer cell antigens, and ultimately result in the dendritic cell
exhibiting a wide variety of protein fragments exhibited by the target
cancer cells. This is a different strategy than arbitrarily choosing
fragments of, for example, PSA, PMSA, or PAP for T cell sensitization.
The GVAC vaccinations were given twice monthly for 24 weeks. Results at
a median of 5.4 months were reported. Of 19 patients who received the
highest dose, 32% showed decline in PSA, and 82% of men in this group
developed an antibody response to at least one cell line. Activity
against bony metastases was evaluated by measuring a selected biologic
marker of osteoclast activity, which is proportional to the amount of
destruction of bone by metastatic cells. This marker was decreased in
62% of men. This Phase II study is now closed, and a follow-up Phase III
is planned to open in several months and will compare GVAC to a standard
chemotherapy treatment in HRPC men with bone metastases. This Phase III
protocol will be available locally in Seattle, and clinicians should
keep this option in mind for eligible patients.
Bottom Line:
Slow but steady progress is being made in developing an effective
vaccine against prostate cancer.
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