©TheCanadian Journal ofUrology™: International Supplement, April 2014
Prostatecancerasatargetfor immunotherapy
Training the host immune system to reject its own
developing tumor has been a long unrealizeddream.
A variety of strategies were attempted in the past to
stimulate an immune response in the prostate but
none proved successful.
11
Based on advances in our
understanding of the immune response, prostate
cancer has emerged as a good target for exploring
immunotherapy for a number of reasons. Mounting
evidence suggests that the prostate is predisposed
to inflammation, possibly owing to autoimmunity
or infection, thus, the host is capable of mounting an
immune response against prostate tissue.
12,13
That
prostate cancer may be in fact caused by chronic
inflammatorymediators adds further to the potential
of immunologic therapy of the disease. The slow
growth pattern of early prostate cancer also allows
time to develop an immune response. Further, the
prostate is a highly differentiated, gender-specific
organandprostateadenocarcinomaoffers avarietyof
suitable antigen targets for cancer immunotherapy.
14
Many genes within the prostate are transcriptionally
regulated by the androgen receptor and show highly
regulated expressionmostly restricted to the prostate
glandorprostate cancer tissue. Includedamong such
expressed genes are PSA, prostatic acid phosphatase
(PAP), prostate-specific membrane antigen (PSMA),
andprostate stem-cell antigen (PSCA).
Current leading immunotherapy strategies
inprostate cancer
Thereareanumberof investigational strategiesunder
development for the immunotherapyof prostate and
other cancersandarebeyond the scopeof thisarticle.
In addition to the approved autologous cellular
immunotherapy sipuleucel-T, thereare several viable
prostatecancer immunotherapyagents thatare in late
stage clinical trials and have been recently reviewed
byMadan and associates.
15
Therapeutic prostate cancer vaccines
Therapeutic cancer vaccines stimulate immune cells
that ultimately target tumor antigens and destroy
cancer cells and the toxicity of these approaches
appearsminimal.
Sipuleucel-T isanexampleofandex-vivoprocessed
vaccine for mCRPC. While there are significant
up front cost and logistic considerations with this
approach, it appears to result in an optimal immune
activation and the clinical application of this agent is
presented indetail later in this article.
Vector-based vaccines deliver an immune
stimulatory message in-vivo to immune cells. One
such vaccine, PSA-TRICOM, is currently inphase III
testing in mCRPC.
15
PSA-TRICOM consists of two
poxvirusesadministeredsequentiallywithouttheneed
for ex-vivo cellularprocessing. Thepoxviruses serve
as vehicles to transport targeting information to the
immune system and trigger an antitumor response.
In addition the large poxvirus genome makes them
well suited for the insertionof the genes for PSAand
3 T-cell costimulatory molecules that enhance the
response.
16
Vaccinia (used in rV-PSA-TRICOM) has a
well-established track record of safety in humans as
itwasused for the successful eradicationof smallpox
whenused as avaccine. Vacciniavirushas alsobeen
administered intravesically inpreliminary studies to
treatBCGrefractorybladdercancerwithnosignificant
toxicity.
17
Fowlpox (rF-PSA-TRICOM) serves as the
second virus used in this prostate cancer therapeutic
combination and is considered safe as it does not
replicate inhumans.
A non-patient specific allogeneic cellular
immunotherapy or whole-cell vaccine approach
has been used. GVAX is comprised of two prostate
carcinoma cell lines, PC-3 and LNCaP, genetically
modified to secrete GM-CSF and radiated before
injection. This approachprovidesmultiple potential
targets for the immune system. Phase III trials have
beendisappointingandadditionalwork isneeded to
optimize this approach.
18
Immune-checkpoint inhibitors
Immune-checkpoint inhibitors have a unique
mechanismofaction incancer. Thisnewlydeveloped
class of agents interfere with the immune system’s
autoregulatorymechanisms.
Anti-CTLA-4 antibodies such as ipilimumab,
currently FDA approved for metastatic melanoma,
and is currently inphase III testing in in a variety of
settings in mCRPC. Blockade of CTLA-4 signaling
with ipilimumab prolongs T-cell activation and
restores T-cell proliferation, which in turn amplifies
T-cell-mediated immunityand thepatient’scapacity to
mount an antitumor response. There is concernover
immune-relatedadverseevents (skin,gastrointestinal
tractaremost frequent)whichcanbe life threatening.
19
Programmed cell death protein 1 (PD-1) and its
ligand (PD-L1) are mediators of immune regulation
and are similar to the action of CTLA-4. Anti-PD-1/
PDL-1 antibodies are emerging as an alternative to
anti-CTLA-4 antibodies. Expression may correlate
with better activity of the ligand. It should also
be noted that it is not clear whether PD1 or PDL
50
Practical guide to immunotherapy incastration resistantprostatecancer: theuseof sipuleucel-T immunotherapy
