A. Cytotoxic: Ad5PSE-DT-A/tox176 and
Ad5/RSV-TK
There are several gene-encoded cytotoxins, such as
ricin and diphtheria toxin, that can be specifically expressed in a tissue of
interest under the control of gene specific promoters. Prior to development of
a viral vector, a series of eight recombinant toxins were evaluated for
cytotoxicity against prostate cancer cells (Rodriguez et al, 1998). Only
diphtheria toxin (DT) and ricin were capable of killing all prostate cancer
cell lines tested, regardless of p53 status, by both apoptotic and
non-apoptotic pathways. Following these analyses, the catalytic A-chain of
diphtheria toxin was placed under the control of the prostate specific antigen
promoter and enhancer (PSE) in a non-replication competent adenoviral vector,
Ad5PSE-DT-A (Li et al, 2002). A second vector with a less toxic DT version,
tox176, was also generated (van der Poel et al, 2001). Results of xenograft models
treated with Ad5PSE-DT-A were promising, with long term survival of over one
year in 80% of animals treated by intratumoral injection. However, due to
production and toxicity issues, these viruses have not yet been pursued for
clinical translation.
The first adenoviral gene therapeutic applied
clinically for prostate cancer was ADV/RSV-TK,
followed by treatment with gancyclovir (GCV), for patients with local
recurrence following radiation therapy (Herman et al, 1999). This virus
expresses the HSV-TK gene by the non tissue-specific, constitutively active
Rouse Sarcoma Virus (RSV) long terminal repeat promoter (Chen et al, 1994).
Preclinical animal models demonstrated decreased tumor volume and metastasis
when Ad5/RSV-TK was administered intratumorally (Eastham et al, 1996; Hall et
al, 1997), with additive benefits when combined with hormone ablation or
radiation therapies (Atkinson and Hall, 1999, Chhikara et al, 2001, Hall et al,
1999). The HSV-TK strategy is especially appealing due to the Òbystander effectÓ
where neighboring non-infected cells are also susceptible to cell death
(Freeman et al, 1993, Mesnil et al, 1996). The virus was also tested as an
adjuvant therapy in mouse models, where it was applied to the tumor bed
following surgery, and was not found to significantly delay recurrence (Sukin
et al, 2001).
Clinical studies with Ad5/RSV-TK taught much about the
safety, efficacy, pharmacokinetics, and immune response (with both single and
repeated intraprostatic injections) for in
situ PCa gene therapy (Herman et al, 1999; Shalev et al, 2000). Most
reactions to viral injection were mild, and all were resolved completely once
the therapy was completed. Therapeutic response was apparent in several
patients by evidence of decreases in serum PSA over extended periods and
prolongation of the PSA doubling time (PSADT). Increased levels of CD8+
T cells in peripheral blood and prostate needle biopsies, which also correlated
with prostatic apoptosis, indicated that an immune response may aid in the
effect of the therapy (Miles et al, 2001). This effect was enhanced when
combined with radiation (Satoh et al, 2004).
The initial study found no evidence of aberrant viral
replication and demonstrated that no virus shed to the serum or nasal passages,
negating the need to perform these type evaluations in future trials. Viral DNA
was temporarily present in the urine of those patients treated at the highest
level (1011 Infectious Units (IU)).
The results of these pioneering studies have been
invaluable in paving the way for clinical trials of in situ gene therapy for prostate cancer (Table 1). While the results with this virus are encouraging for
local recurrence or as a neoadjuvant to radiation therapy for primary
treatment, the need to convert these types of vectors to systemic therapy has
been omnipresent. Several transcriptionally targeted HSV-TK vectors have been
developed for this purpose (Blackburn et al, 1998; Gotoh et al, 1998; Koeneman
et al, 2000; Pramudji et al, 2001; Furuhata et al, 2003); however, to date,
only one of these has been translated into a clinical trial (Kubo et al, 2003).
B. Corrective: INGN 201 and SCH58500
The p53 tumor suppressor gene is considered to be one
of the most frequently mutated genes in human cancer (Hollstein et al, 1994).
In prostate cancer, p53 mutation correlates with disease stage, where mutation
is a rare event for primary tumors and is more frequently associated with
advanced and metastatic disease (Bookstein et al, 1993; Navone et al, 1993;
Eastham et al, 1995; Brooks et al, 1996). p53 based corrective gene therapy was
originally developed and evaluated for head and neck squamous cell carcinoma
and non-small cell lung cancer (Clayman et al, 1998; Roth et al, 1998). Local
recurrent and advanced local prostate cancer was an ideal model for these
viruses as they could be directly injected into the prostate and therapeutic
response monitored by serum PSA levels (Sweeney and Pisters, 2000).
Transfection of wild type p53 into p53 mutant prostate
cancer cells had previously been shown to result in growth suppression (Isaacs
et al, 1991). Additionally, adenoviral p53 transduction has been shown to
result in a high percentage of apoptotic death (Yang et al, 1995). Several
independent groups have confirmed the efficacy of p53 expressing adenoviral
gene therapy in multiple prostate cancer animal models. While every cell wonÕt
be transduced in a tumor environment, an anti-angiogenic bystander effect has
been demonstrated (Bouvet et al, 1998; Nishizaki et al, 1999). Additionally,
p53 expression has been shown to sensitize tumor cells to chemotherapy and
radiation (Badie et al, 1998; Blagosklonny and El-Deiry, 1998; Nielsen et al,
1998). These pre-clinical results have led to the translation of two p53
expressing adenovirus, INGN 201 and SCH58500, into phase I and II clinical
trials for locally advanced or locally recurrent prostate cancer. Results of
these trials have not yet been reported in the literature.
C. Immunologic: AdmIL-12
Interleukin-12 (IL-12) is a heterodimer composed of a
disulfide linked heavy (40 kD) and light (35 kD) chain (Rodolfo and Colombo,
1999). IL-12 induces a multitude of immuno-stimulatory effects including the
differentiation of CD4 and CD8 type 1 cells, stimulation of antigen presenting
cells, enhanced natural killer (NK) cell activity, a switch from Ig to IgG2a,
and induction of several pro-inflammatory cytokines. When compared to other
cytokines, IL-12 was found to be the most efficient in curing mice with
established syngeneic mammary tumors (Cavallo et al, 1997). However, systemic
administration of IL-12 can be toxic to humans and has led patient deaths
(Cohen, 1995; Golab and Zagozdzon, 1999). Therefore, local administration or
gene therapeutic expression of IL-12 is now being evaluated.
The adenovirus AdmIL-12, expressing both p40 and p35
cDNA of mouse IL-12, was originally designed and tested in a breast tumor model
(Bramson et al, 1996). This virus performed well in an intralesionally injected
orthotopic mouse prostate cancer model, suppressing growth of established
tumors and metastases, which resulted in increased survival (Nasu et al, 1999,
Sanford et al, 2001). Tumors demonstrated NK cell activity and infiltration of
CD4+ and CD8+ T cells. These responses were enhanced with
co-expression of B7-1 in a single construct, AdmIL-12/B7, resulting in some
long term cures (Hull et al, 2000). Similar results were found with an ex vivo strategy, where macrophage or
dendritic cells were harvested, infected with AdmIL-12, and then directly
injected into tumors, which gives the potential of tumor antigen presentation
in draining lymph nodes for a greater systemic effect (Satoh et al, 2003; Saika
et al, 2004). There are currently two phase I clinical trials investigating in situ administration of IL-12
expressing adenoviral vectors for post-radiation locally recurrent disease. The
results of these trials have yet to be published.
D. Conditionally replicating adenovirus
(CRADs): CG7060 and CG7870
The first tissue specific conditionally replicative
adenovirus was developed for the treatment of prostate cancer (Rodriguez et al,
1997). By placing the viral E1A gene under the control of the PSA promoter and
enhancer (PSE), viral replication was limited to prostate cells. This strategy
offers the promising attributes of tissue specificity and local amplification,
which should be valuable for the future goal of systemic treatment. The virus,
CG7060 (previously known as CN706 and CV706), was quickly translated into
clinical trials as an intra-prostatically injected agent for patients with
local recurrence following radiation therapy. This initial phase I trial
injected between 1011-1013 viral particles at between 20
to 80 sites, as determined by a Òviral dosimetricÓ algorithm based on a
potential killing zone of 1 cc per injection site (DeWeese et al, 2001; Li et
al, 2003). Safety was clearly established and the maximum tolerable dose was
not reached. Prostatic replication was evident both by examination of post
treatment biopsies, where nuclear adenovirus was visible by electron
microscopy, and also by a second burst of virus detected in the serum at 2-8
days post infection. Therapeutic response was evident by a greater than 50%
drop in serum PSA in patients treated with the highest viral doses. These
promising results led to further improvements of CN706 and further clinical
trials.
The second virus, CG7870 (previously CV787), was
developed using two prostate specific promoters, the rat probasin promoter and
the human PSE driving viral E1A and E1B genes, respectively (Yu et al, 1999).
Additionally, CG7870 contained the viral E3 region, a region that is often
deleted in first generation vectors. E3 is not required for viral replication,
but aids in immune evasion and viral release (Lichtenstein et al, 2004). This
new version was capable of eliminating established tumors when administered i. v. through the mouse tail vein, a
task the original CG7060 virus was unable to complete (Yu et al, 1999).
CG7870 initially entered the clinic in a similar
manner to CG7060, as an intra-prostatic applied gene therapy for local
recurrent disease. CG7870 has further been applied in combination trials with
external beam radiation therapy (the benefits of combination therapy are
discussed below). Most importantly, CG7870 is the first adenoviral gene therapy
vector to enter PCa clinical trials as a single intravenously administered
agent, and also in combination with docetaxel. The results of these studies
have not yet been thoroughly described; however, promising results from both
the national meetings of the American Association of Gene Therapy (ASGT) and
the American Society of Clinical Oncology (ASCO) suggest that CG7870, as a
single i. v. administered agent, is
capable of eliciting reductions in serum PSA of patients with hormone
refractory metastatic cancer (Wilding et al, 2004). These results, although
modest and preliminary, implicate the ability of the virus to reach metastatic
sites and elicit a biologic response. This is promising as immunologic
clearance, hepatic clearance, and significant depletion by non-target CAR
positive cells has been predicted to severely limit i. v. applied therapies (see de-targeting section below). We do not
wish to overstate these results; however, we are enthusiastic that if
non-targeted vectors can provide therapeutic some response, then even small
improvements in viral targeting may be enough to cause a more meaningful
outcome for metastatic disease, especially if combined with other therapies.
E. Oncolytic and cytotoxic: Ad5-CD/TKrep
The first tumor oncolytic adenovirus, ONYX-015, was
designed for conditional replication in p53 mutant tumor cells (Bischoff et al,
1996). The viral design was based on the hypothesis that the E1B-55K gene,
known to be responsible for binding and inactivation of p53, would not be required
for viral replication in tumor cells harboring p53 mutations. ONYX-015
demonstrated tumor selective replication and has since been clinically tested
in multiple malignancies (McCormick, 2003). However, several groups later found
that ONYX-015 could replicate in cells with wild type p53 and p19ARF (Edwards
et al, 2002, Rothmann et al, 1998). The true mechanism behind ONYX-015 tumor
selective replication has been controversial. However, the original group has
now provided new evidence that tumor selective replication reflects a
differential late viral gene export mechanism and not p53 or p19ARF status
(O'Shea et al, 2004). Regardless of mechanism, ONYX-015 appears to have a
selective replication advantage in tumor cells when compared to non-tumor cells.
In 1998, Freytag and colleagues generated a similar
conditionally replicating adenovirus, Ad5-CD/TKrep, by generating two early stop codons in the E1B-55K gene
(Freytag et al, 1998). Ad5-CD/TKrep
also contains a cytotoxic fusion gene of both cytosine deaminase (CD) and
HSV-TK with the aim of combining viral replication, prodrug therapy, and
radiotherapy for cancer treatment. Ad5-CD/TK demonstrated a similar replication
profile to ONYX-015, produced concentration depended cell killing with
5-fluorocytosine (5-FC) and/or GVC, and dose dependently sensitized cells and
xenograft tumors to radiation in combination with pro-drug therapy (Freytag et
al, 1998, 2002; Rogulski et al, 2000). Pre-clinical PCa mouse models of
biodistribution and toxicity demonstrated that intra-prostatically administered
Ad5-CD/TKrep was capable of spreading
and replicating to numerous urologic tissues, including the bladder, seminal
vesicles, and testes, with no vertical germ-line transmission of the virus in
offspring (Paielli et al, 2000).
In clinical trials, a single intraprostatic dose of
Ad5-CD/TKrep followed by combined
5-FC/GVC therapy demonstrated safety and evidence of therapeutic response by
short term decreases in serum PSA of several patients with local recurrent
prostate cancer. The original three-pronged approach of Ad5-CD/TKrep, 5-FC/GVC, and external beam
radiation was later taken into phase I trials and also demonstrated safety and
similarly described decreases in serum PSA of several patients, especially for
those receiving longer term pro-drug treatments (Freytag et al, 2003).
Intraprostatic transgene expression lasted up to three weeks following
administration. Clinical trials combining Ad5-CD/TKrep and radiation are still on-going in phase I/II format and
should further define safety and efficacy profiles. While ONYX-015 has been
clinically tested for intravenous administration (Nemunaitis et al, 2001), to
date Ad5-CD/TKrep has only been
tested as an intraprostatic agent.
III. Combination of adenoviral gene therapy and radiation
Local radiation, either in the form of external beam
radiation or by the intraprostatic placement of radioactive ÒseedsÓ, is an
effective means of both treating low risk local prostate cancer and also of
managing or ÒdebulkingÓ high risk local disease. The combination of adenoviral
gene therapy and radiation therapy has been approached on a number of levels,
including corrective, cytotoxic, and oncolytic adenoviral gene therapies. It
appears that pre-treatment of cells with radiation results in increased
transgene expression, a technique applicable to all strategies (Zeng et al,
1997). Additionally, radiation-inducible promoters have been developed (Marples
et al, 2000). Collis et al. have recently reviewed the combination of radiation
therapy and gene therapy in prostate cancer (Collis et al, 2003). Therefore, we
will only briefly review a few applications.
Ionizing radiation induces double stranded breaks,
which are repaired by either homologous recombination or Non-Homologous End
Joining (NHEJ), both of which are initiated by the DNA-PK complex (Collis et
al, 2005). As a linear double-stranded DNA (dsDNA) genome, the adenovirus must
take specific actions to avoid recognition and concatamerization initiated by
DNA-PK. Two viral proteins, E4orf3 and E4orf6, bind to and inhibit the DNA-PK
complex (Boyer et al, 1999). Additionally, the viral gene products of E4orf3/6
and E1B-55K cooperate to inhibit the action of the MRE-11 complex, which is
known to play an important role in NHEJ repair (Stracker et al, 2002). The
inhibition of dsDNA break repair in combination with radiation therapy can lead
to cell death by apoptosis or reproductive cell death (Taccioli, 1998 and
Chernikova, 1999), thus leading to additive or synergistic therapeutic effects.
It is unclear what combination of viral genes best
enhances radiation therapy. For example, E40rf6 alone does not appear to
sensitize tumors to radiation (Collis et al, 2003). Some conditionally
replicating viruses, such as CG7060 and CG7870, express E1A and therefore also
express E4orf3/6 and E1B-55K. These viruses demonstrate a synergistic response
when combined with radiation (Chen et al, 2001). Ad5-CD/TKrep expresses E1A and therefore should also express E4orf3/6, but
does not express E1B-55K. The additive effects E4orf3/6 +/- E1B-55K and
radiation have not yet been evaluated. CG7060, CG7870, and Ad5-CD/TKrep have all entered phase I and II
clinical trials in combination with radiation therapy for the treatment of
local recurrent and high risk local disease. Since the addition of the
adenoviral gene therapy does not appear to add significantly to the toxicity of
radiation therapy, acceptance of this combination is likely to meet with little
resistance if efficacy can be truly demonstrated.
The tumor suppressor gene p53 has been referred to as
the guardian of the genome for its involvement in selecting cell cycle arrest
or apoptosis when faced with cellular stress, such as ionizing radiation. Thus,
several groups have found additional tumor suppression and apoptosis when
combining p53-based gene therapy and radiation (Colletier et al, 2000; Cowen et
al, 2000; Sasaki et al, 2001). This is in contrast to some in vitro studies which suggest that intact cell cycle checkpoints
are not required for efficient radiation therapy (Waldman et al, 1997; DeWeese
et al, 1998). The combination of the constitutively expressing p53 adenovirus,
INGN 201, and radioactive seeds is in clinical trials. Results should provide
some clarity to the value of such combination therapies.
The combination of adenoviral cytotoxic strategies and
radiation therapy is also logical. For example, DNA damaging agents, such as
5-FU, have previously been shown to sensitize cells to radiation (Smalley et
al, 1991). The combination of radiation with GCV has also been effective. As
described briefly above, combination of the ADV/RSV-TK
+ GCV with radiation resulted in
significantly decreased tumor volume and growth of lung metastases (Chhikara et
al, 2001). Also, the dual suicide gene therapy vector Ad5-CD/Tkrep + 5-FC and/or GCV has demonstrated
additional therapeutic effects with radiation in animal models (Freytag et al,
2002). Both HSV-TK and replicating double suicide adenoviral gene therapy
vectors are being combined with radiation therapy in phase I and II clinical
trials for local prostate cancer (Teh et al, 2001, 2002, 2004).
IV. Combination of adenoviral gene therapy and chemotherapy
The combination of chemotherapy and adenoviral gene
therapy is successful for many of the same reasons described above with
radiation. Replication competent virus drive cells into S-phase, potentially
making them more sensitive to chemotherapeutic agents. For example, the E1A
gene itself is capable of enhancing chemotherapeutic toxicity (Sanchez-Prieto
et al, 1996). This co-insult of S-phase progression and viral replication with
DNA damaging agents is clearly additive and may be synergistic (Heise et al,
2000; You et al, 2000). The combination of CG7870 with microtubule stabilizing
agents paclitaxel and docetaxel has also shown synergy in animal models (Yu et
al, 2001). Combined intravenously administered CG7870 and docetaxel are
currently in phase II clinical trials for advanced metastatic prostate cancer.
As would be expected, corrective gene therapy
strategies are also enhanced when combined with chemotherapeutics. Adenoviral
mediated expression of p53 has been shown to chemo- sensitize several different
cancers to cisplatin therapy (Fujiwara et al, 1994; Song et al, 1997). This
effect was consistent with multiple DNA damaging chemotherapeutics in many cell
line backgrounds, where microtubule targeting agents were only enhanced by p53
in a few cell lines (Blagosklonny and El-Deiry, 1998). In contrast, other
groups have found improved responses with p53 expression and paclitaxel in
multiple tumor types (Nielsen et al, 1998). This enhancement may come through
advanced transduction efficiency, which can occur with low dose paclitaxel
(Nielsen et al, 1998; Li et al, 2002). Further evaluation of p53 and
microtubule targeted agents will likely provide clarity to the benefit for
prostate cancer.
Pro-drug therapies such as HSV-TK + GVC and CD + 5-FC
induce DNA damage and therefore induce DNA repair machinery. Topoisomerase I
(Topo I) plays a role in DNA replication and repair by relaxing supercoiled DNA
with single strand breaks, in a mechanism where the enzyme is covalently linked
to the 3Õ-end of the strand break. The topoisomerase inhibitor, topotecan,
stabilizes the covalently linked DNA/Topo I complex and inhibits the pending
ligation reaction (Rothenberg, 1997). The combination of HSV-TK gene therapy
with topotecan demonstrates enhanced cell killing and animal survival in colon
cancer models (Wildner et al, 1999). Such studies have not been completed in
prostate cancer models; however, topotecan alone has not been found to be an
effective agent in treating prostate cancer (Klein et al, 2002).
V. Adenoviral biodistribution: the need for transduction targeting
While direct tumor injection has been an effective
means for evaluating safety and efficacy of adenoviral gene therapy for
prostate cancer, the long-term goal of cancer gene therapy is to exploit the
targeting and delivery capabilities of the virus for systemic therapy of
metastatic disease. However, the broad tropism of the virus leads to
sequestration of the administered viral dose to non-target tissues, especially
the liver. This sequestration is significant, with approximately 70-75% of the
viral dose residing in the liver of mice intravenously injected with type 5 virus
(Fechner et al, 1999; Wood et al, 1999; Leissner et al, 2001). Route of
administration can alter biodistribution to certain tissues (Kass-Eisler et al,
1994; Huard et al, 1995); however, a significant enough portion of the
therapeutic pool is still sequestered to non-target tissues, likely resulting
in a reduced therapeutic response when compared to direct injection. The
biodistribution also presents potential toxicity problems for systemic
administration of non-transcriptionally targeted cytotoxic virus. Therefore,
there has been much effort to de-target viral infection away from natural
tropism, especially to the liver, and to re-target infection to specific tissue
types. There are several mechanisms to achieve this, as shown in Figure 3. Below we briefly focus on
mechanisms to re-target viral infection.
A. De-targeting adenoviral tropism
The term Òde-targetingÓ describes viral vectors that
have been altered so that they no longer bind and infect cells through their
natural mechanism. The molecular interactions of adenoviral cell binding
through fiber/CAR have been well characterized. Specifically, the C-terminal
knob portion of fiber mediates viral binding to cells via CAR (Figure 1A) (Henry et al, 1994; Louis et
al, 1994). The knob structure is composed of two sheets of b-strands, the R-sheet (containing b-strands G, H, I, and D), which interacts directly
with the receptor, and the S-sheet (containing b-strands C, B, A, and J), which faces the inward
portion of the knob trimer (Xia et al, 1994; Bewley et al, 1999). A series of
papers have described the required CAR interacting domains of fiber knob
through competition assays with soluble knobs, fiber pseudotyping, and genetic
mutation of the fiber gene in the viral genome (Jakubczak et al, 2001, Kirby et
al, 1999, Kirby et al, 2000, Roelvink et al, 1999, Santis et al, 1999). These
results have clearly demonstrated that adenovirus can be de-targeted from CAR
mediated infection in vitro. However,
it is becoming clear that knob mutations alone are not sufficient enough for
de-targeting adenoviral tropism to the liver (Alemany and Curiel, 2001;
Leissner et al, 2001; Mizuguchi et al, 2002; Smith et al, 2003).
Additional mutations of the viral penton base RGD
sequence, which is known to interact with cellular integrins to invoke viral
internalization (Wickham et al, 1993), have been combined with fiber mutation;
however, the effects on in vivo
tropism are unclear. Some studies have described little to no change in hepatic
infection with both Fiber and Penton de-targeting (Martin et al, 2003, Smith et
al, 2003), where others have demonstrated significant liver de-targeting with
this combination (Einfeld et al, 2001; Koizumi et al, 2003; Akiyama et al,
2004). Heparin sulfate proteoglycans (HSG) have also been described to play a
role in hepatic infection via a putative HSG binding domain on the fiber shaft
(Dechecchi et al, 2000, 2001). Mutations of this domain have been shown to
decrease CAR mediated viral infection in
vitro, and to significantly decrease liver
tropism
in vivo when combined with Fiber and
Penton base mutations (Smith et al, 2003).Ad discussed below, fibers from alternative
adenoviral serotypes may also aid in de-targeting.
Route of administration combined with de-targeting has
also been shown to effect liver transduction. Akiyama and colleagues have shown
that the natural tropism of intraperitoneally (i. p.) administered adenovirus is to the mesothelium of abdominal
tissues (Akiyama et al, 2004). The combination of CAR ablation and i. p. administration inhibits viral
infection to the mesothelium, leading to viral entry to the bloodstream,
followed by infection of the liver parenchyma. Interestingly, i. p. injection of vectors abated for
both CAR and integrin binding resulted in bloodstream entry and long term viral
persistence without liver parenchyma infection. The efficiency to escape to the
bloodstream was dependant upon the initial viral dose, but occurred in a
non-linear manner suggesting a saturable process. Further investigations of the
effects of de-targeting and route of administration in animal models should aid
in the ability to alter viral biodistribution in favor of tumor infection.
B. Re-targeting adenoviral tropism
Adenoviral re-targeting has been a major focus of the
gene therapy field for the last decade and has been reviewed in detail by
several groups (Wickham, 2003; Everts and Curiel, 2004; Glasgow et al, 2004).
Re-targeted vectors are defined as those that have been modified to bind and
infect via additional receptors beyond the natural tropism patterns. Initial
studies in re-targeting involved swapping fiber genes or knobs from various
serotypes to demonstrate broad changes in infection profiles (Gall et al, 1996;
Krasnykh et al, 1996). These types of fiber swap vectors simultaneously
de-target and re-target to a whole different class of cells and tissues. For
example, the fiber protein of subgroup B adenoviruses uses CD46 rather than CAR
as a cellular receptor (Gaggar et al, 2003). Chimeric serotype 5 adenovirus
displaying the subgroup B serotype 35 fiber have been shown to decrease liver
(and other non-target tissue) infection when compared to serotype 5 fiber, and
to show increased ability to transduce some hematopoietic and malignant cells
(Bernt et al, 2003; Sakurai et al, 2003; Nilsson et al, 2004).
Much effort has also been placed in designing
bi-functional targeting agents, such as bi-functional antibodies, where one
half binds the virus and the other half to a cellular receptor (Douglas et al,
1996; Wickham et al, 1996; Watkins et al, 1997; Dmitriev et al, 2000).
Bifunctional targeting strategies can have the advantage of both viral de-targeting,
by binding to and blocking Fiber CAR interaction domains, and re-targeting.
However, difficulties associated with production and clinical translation of
bi-functional agents has driven the field toward genetically based
re-targeting.
Re-targeting peptides can be genetically incorporated
and displayed on either the carboxy-terminus (Wickham et al, 1996, 1997) or the
HI-loop of the fiber gene (Dmitriev et al, 1998; Krasnykh et al, 1998; Einfeld
et al, 1999) to increase tropism beyond CAR expressing cells. Additional sites
for peptide insertion have been identified in the Penton base (Wickham et al,
1996), Hexon (Vigne et al, 1999; Wu et al, 2003), and Protein IX (Dmitriev et
al, 2002). Most of the initial fiber targeting strategies applied broad tropism
targeting motifs, such as poly-lysine, RGD, or fiber knobs from alternative
serotypes. Such strategies will be easily translated to tissues known to lose
CAR expression during carcinogenesis, such as bladder cancer (Sachs et al,
2002; van der Poel et al, 2002). However, there are additional pharmaceutical
options for these tissue types, such as histone deacetylase inhibitors, which
upregulate CAR expression (Kitazono et al, 2001; Sachs et al, 2004). Prostate
cancer, on the other hand, has been shown to retain CAR expression and
therefore would likely not benefit from broad tropic targeting strategies
(Rauen et al, 2002). The combination of de-targeting and more specific
re-targeting may be required for prostate cancer. Such cell-specific targeting
has been demonstrated for endothelial cells by first identifying cell binding
peptides through phage display, and then incorporating them into the fiber
HI-loop (Nicklin et al, 2001, Nicklin et al, 2000). However, to date, no such
transductionally targeted adenovirus has been designed for prostate. We have
recently applied phage display to identify two peptides that bind to the
extracellular portion of the Prostate Specific Membrane Antigen (PSMA) (Lupold
and Rodriguez, 2004), a protein highly expressed on the surface of advanced
prostate cancer cells (see Ghosh and Heston for Review (Ghosh and Heston,
2004)). We are currently in the process of developing genetically re-targeted
vectors with these peptides. The concept of PSMA targeted adenovirus was
recently confirmed using bifunctional antibodies (Henning et al, 2005, Kraaij
et al, 2005), so we are therefore optimistic that a genetically based
re-targeting mechanism could be successful.
VI. Combining transcriptional and transductional targeting
The most pressing need of adenoviral gene therapy is
in metastatic disease. These types of studies are in their infancy, and to date
only a single i. v. administered,
transcriptionally targeted, adenoviral vector has been tested in clinical
trials for prostate cancer. As described above, preliminary reports from CG7870
suggest that enough virus can avoid liver and blood clearance to reach the
tumor and elicit a therapeutic response (Wilding et al, 2004). Although these
results are preliminary, they suggest that drastic improvements in de-targeting
may not be required to significantly improve therapeutic effect. The
application of some of the above discussed de-targeting and re-targeting
advances would likely improve the responses elicited by this vector.
Pre-clinical results from non-prostatically targeted vectors have already begun
to demonstrate the benefits of combining transcriptional and transductional
targeting. For example, the combination of ovarian specific transcriptional
targeting and transductional targeting (via a bi-specific fusion protein)
decreased liver and spleen transgene expression by 47% and 68%, respectively,
while increasing tumor transgene expression by 30% (Barker et al, 2003). Other
groups have reported similar increases in specificity and efficacy in other
tissue models, both in vitro and in vivo (Barnett et al, 2002; Work et
al, 2004). While there have been no dual-targeted prostate-specific vectors
reported to date, it is likely that some will soon be described. The
combination of current transductional targeting advances, existing
transcriptionally targeting vectors, and chemotherapy will likely increase
responses in metastatic disease trials.
VI. Conclusions
Adenoviral vectors have been widely studied as cancer
gene therapeutics. Their safety and efficacy profiles have shown much promise
as in situ administered gene therapy
agents in prostate cancer clinical trials. Additional laboratory studies have
determined efficient means to re-target adenoviral transduction to improve
bio-distribution, which should result in improved toxicity profiles and
therapeutic responses. The promise of combining both prostate specific
transductional targeting and prostate specific therapeutic effect is clear for
advanced metastatic disease.
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