©TheCanadian Journal ofUrology™: International Supplement, April 2014
metastaticCRPC(mCRPC). Historically,chemotherapy
usingdocetaxelplusprednisonewas theonly therapy
to demonstrate a survival advantage in advanced
prostatecancer,making it the“goldstandard therapy”
in thisdisease state.
Thefirst of thesenewdrugsapproved formCRPC
was an autologous immunotherapy, sipuleucel-T.
4
Since that2010approval, therehavebeenotheragents
withdifferingmodesofaction thathavedemonstrated
increased survival in the setting of mCRPC. These
include thehormonal agents, abiraterone acetate and
enzalutamide, thechemotherapeuticagentcabazitaxel,
and bone targeting agents such as the radioactive
radium 223 dichloride.
3
These are reviewed in
detail elsewhere in this
Canadian Journal of Urology
supplement. Thisarticlewill focuson immunotherapy
in themanagement ofmCRPC.
Principles of cancer immunotherapy
Cancer is considered an immunosuppressive state
that requires an intervention to boost adaptive
immunity, including the antigen-specific defense
mechanism. One of the key characteristics of
cancer pathogenesis is the ability of the tumor cell
to avoid immune destruction.
5
Mounting evidence
has shown that a patient’s immune system can be
successfully trained to seek out and attack cancer
cellsbyexploitingsubtledifferencesbetweennormal
and cancer cells for use as immune recognition
targets.
6
Immunotherapeutic approaches to cancer
are varied and can be broadly divided into two
categories—passive or active.
Passive immunotherapy typically requires direct
delivery of cytokines, antibodies, and/or cells of the
immunesystem. Notablesuccesshasbeenachieved in
other tumorswithexogenously suppliedmonoclonal
antibodies, such as bevacizumab (specific forVEGF),
and trastuzumab (specific forHER2/neu) andothers
which targetantigensover-expressedon thesurfaceof
solid tumorswithanti-tumorefficacyand less toxicity
thanmostchemotherapies.
7
Unconjugatedmonoclonal
antibodies as monotherapy have little or no activity
on their own, and agents such as bevicuzimab and
trastzumab work best in combination. There also
may be the development of antibody dependent
cytotoxicty with these agents. PSMA antibodies
conjugated tootheragentsarealsounder investigation
as an immunotherapeutic strategy. Nevertheless,
the passive immunotherapeuticswhich target tumor
antigens must be chronically administered and are
not self-renewing nor do they appear to provide a
sustainable anti-tumor response. Urologic examples
include the use of alpha-interferon and IL-2 in the
management of renal cell carcinoma.
Incontrast,active immunotherapyoftenreferred to
as“vaccinetherapy” isdesignedtoelicitahost immune
responsethatspecificallytargetsthetumorcell through
a T-cell response cascade. Active immunotherapy
requires the targetantigen tobeprocessed inamanner
capableof inducingan immuneresponsethatgenerates
anti-tumor activity. T-cellsdonot respond to soluble
or nakedprotein antigens but rather require peptide
fragments from theantigen tobe“presented” to them
on the surface of antigen-presenting cells (APCs) via
human leukocyteantigen (HLA)molecules. Dendritic
cells, monocytes, macrophages, and Langerhan cells
are all APC that possess the requisitemachinery for
processing internalized intact protein into peptide
fragmentswhich can then stimulate a specific tumor
responsewithmemory capabilities.
While a variety of cells can function as APCs,
the pivotal steps in the induction of all active T-cell
immuneresponses include theuptakeandprocessing
of APCs with antigen and activating the APC to
expressco-stimulatorymoleculesand inducecytokine
production. APCsarepresent insubstantialquantities
in the peripheral blood, and various specialized
immune compartments in thebody and are theonly
cells endowed with the ability to stimulate naïve
CD4+T lymphocytes,whichcan initiatebothcellular
and humoral immune responses. While the main
function of APCs is to internalize and/or process
antigenandpresentantigenicpeptidesviaHLAclass
I and class IImolecules, they also express additional
co-stimulatorymoleculesrequired formaximalT-cell
stimulation. Some of these additional molecules
includemolecules CD80, CD86, or CD40, aswell as
intracellularadhesionmoleculessuchasCD54,which
are typicallyupregulated followingactivationof the
APC and serve asmarker ofAPC activation. These
co-stimulatory and adhesion molecules signaling
events result in T-cell proliferation and cytokine
production. Ultimately, the tumor cells are killed
through an apoptotic mechanism.
8,9
A common
urologicexampleofactive immunotherapy is theuse
of intravesical BCG for bladder cancer, recognizing
that the definitive BCG mechanism of action is
unclear.
A newer approach to immunotherapy involves
interferingwith the immune system’sautoregulatory
mechanisms, thereby enhancing T-cell activity and
potentiating antitumor effects using antibodies
targeting immunological checkpoint regulators such
asCTLA-4andPDL-1 thatdownregulate the immune
responsepathways.
10
49
GomellaETAL.
