©TheCanadian Journal ofUrology™: International Supplement, April 2014
expression in the tumor or lymphocyte is necessary
forananti-tumorresponse. The theoreticaladvantage
of targeting thePD-1axis is lesspotential toxicityand
are in early stage testing inprostate cancer.
20
Principles of active cellular immunotherapy
One active immunotherapy approach involvesAPCs
that are isolated ex-vivo through leukapheresis and
“loaded” with the antigen of choice. This is the
principle of sipuleucel-T therapy.
21
Ex-vivo isolation
ofAPC’s through leukapheresis and antigen loading
provides access to a large number of APCs (10
8
to
10
9
cells). This active cellular immunotherapy offers
advantages over passive immunotherapies since the
targetproteinof interestdoesnothave toberestricted
to thecellsurface. Rather, the targetantigenneedsonly
be presented asHLAmolecules on cells of the target
tissue recognizable by theAPC-stimulatedT-cells. A
samplingof all theproteinsproducedbya tumor cell
arepresentedaspeptide-MHCIclass(HLAmolecules),
which are delivered to the cell surface and are
recognizedbyT-cell receptorsofCD8+T lymphocytes.
In favorofautologousactivecellular immunotherapy,
the ability to access a large number of APCs via the
apheresis source has been possible for more than a
decade, suggesting thatefficient targetingofantigen to
theseAPCswouldmake theharnessingof the immune
system to eradicate tumors tenable. In addition to
sipuleucel-T prostate cancer immunotherapy other
dendritic cell based therapies are being investigated
inmanyother tumor typesusingdifferent in-vivoand
ex-vivo activation strategies.
22
An evolving concept in tumor immunology is
knownas“antigenspreading” thathasbeenobserved
inthe immunotherapyofprostatecancer.
23
Thisenables
the immune system toadapt to tumormutations and
broadens the anti-tumor response. The activated
T-cell tumor kill is initiallydirected against a specific
antigen; thereleaseofadditional tumorantigens from
the lysed cell activates new tumor targeting tumor
associated antigens broadening (“spreading”) the
anti-tumor immuneresponse. Lastly, theconcept that
immunotherapyworksbestwith lower tumorburdens
cannot beunderestimated.
24
Development of sipuleucel-T
Sipuleucel-T represents the first “personalized”
immunotherapy for the treatment of cancer using
a patient’s own immune cells to overcome the
self-tolerance hurdle for the treatment of tumors.
It is also important to stress that sipuleucel-T is
not a gene therapy, since APCs are loaded with a
purified recombinant protein and are not genetically
manipulated or transfected with any form of viral
or recombinant DNA or RNA. The loading of the
recombinant protein is performed ex vivo where
the optimal concentration of immunogen can be
controlled.
PAP was chosen as the target antigen for the
prostate cancer treatment because it is expressed
at detectable levels in more than 95% of prostate
adenocarcinomas and is highly specific to prostate
tissue.
25,26
PAPwas also reported to be an effective
targetantigen inexperimentalmodels.
27
The receptor
forGM-CSF is expressedbroadlyonbloodandbone-
marrow derived APCs.
28
Engagement of the GM-
CSF receptor by ligand results in the upregulation
of the expression of a variety of molecules byAPCs,
including HLA class II, co-stimulatory molecules
noted previously (CD80, CD86, or CD40), adhesion
molecules (such as CD54), and a variety of secreted
cytokines. Intrinsic to its design, PA2024 (the name
of the recombinant fusion protein consisting of GM-
CSF and PAP), can bind to the GM-CSF receptor,
leading to APC activation, increased expression of
adhesionandco-stimulatorymolecules,andprolonged
APC survival in culture. APC activation results in
increasedantigenuptakeviamultiplepathways,most
prominentlymacropinocytosisandreceptor-mediated
endocytosis. These antigen uptake mechanisms
target the internalization of antigen to intracellular
compartments linked to HLA class I and class II
processing pathways.
29
This approach is designed
to be tissue-specificity and to break tolerance to the
self-antigen. The final cellular product (APC8015)
is suspended in lactated Ringer’s and delivered for
infusionwithin 18hours of suspension.
Clinical evidence for immunotherapy with
sipleucel-T
Two early phase III randomized, double-blind,
placebo-controlled trials with sipuleucel-T, (trials
D9901andD9902A)comparingsipuleucel-T toplacebo
in men with asymptomatic, mCRPC demonstrated
significantly prolonged survival.
30
However, these
smaller initial trials were combined for an initial
FDAfilingwhich led to the need to initiate a larger
randomized, double-blind, placebo-controlled Phase
III clinical registration trial known as the IMPACT
study (Immunotherapy forProstateAdenoCarcinoma
Treatment)(D9902B). Theseresultshavebeenpresented
previously and led to the approval of sipuleucel-T.
4
Briefly, in the 512patient IMPACT study, themedian
OS was 25.8 months for men receiving sipuleucel-T
51
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