Clinical Cancer Research Vol. 6, 3395-3399, September 2000
© 2000 American Association for Cancer Research
The Development of Conditionally Replicative Adenoviruses for Cancer Therapy1
David T. Curiel2
University of Alabama at Birmingham, Birmingham, Alabama 35294-3300
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ABSTRACT
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Replicative
viral agents represent a novel approach for treating neoplastic
disease. Tumor cell killing by the viral agent is achieved by direct
consequence of the viral replication. Relative sparing of nontumor is,
however, required to provide a therapeutic index of utility for cancer
treatment. To this end, an ideal viral agent would, thus, possess
several logical attributes, including stability and efficiency for
infection and lateral spread in vivo, a preference for
replication in tumor versus nontumor cells, and the
capability of avoiding early detection—and eradication—by the immune
system. To date, none of the agents has exhibited optimal
characteristics with regard to the aforementioned attributes.
Adenovirus, however, has lent itself to a process of extensive
engineering that is dealing with each and every one of the major
requirements and that is realizing its clinical potential. An advanced
understanding of the cancer phenotype, as well as achievements in
functionally exploiting viral plasticity, predicate the design and
realization of conditionally replicative adenoviral agents with
improved characteristics for cancer therapy.
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Introduction
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The use of replicative viral agents represents a novel approach to
neoplastic disease. In this strategy, target tumor cell killing by the
viral agent is achieved by direct consequence of the viral replication
(1)
. Furthermore, relative sparing of nontumor
cells provides a therapeutic index of potential utility for
cancer treatment. On this basis, it is apparent that the specificity of
the viral agent for achieving tumor cell killing via replication
("oncolysis") is the functional key to successful exploitation of
these agents for therapy. To this end, an ideal viral agent would,
thus, possess several logical attributes: (a) such
viruses must have the capacity to infect target cells in
situ, that is, within the stringency imposed by direct in
vivo delivery. Thus, a level of stability in the in
vivo context is mandated to achieve an effective initial inoculum.
Furthermore, such stability in the in vivo context would be
critical for allowing replicated viruses to infect laterally, a key
process to realizing effective amplification; and (b) the
viral agent should possess a relative preference for replication in
tumor versus nontumor cells. Thus, a useful viral agent
would be well characterized in terms of entry biology and replicative
physiology, such that these steps might be modified to achieve the
desired tumor cell specificity, if thus required. Specifically,
modulation of viral tropism, either by alteration of the initial
attachment/entry steps or by modification of the functional aspects of
viral genome replication and progeny-virus packaging, offers a means to
achieve such specificity. Another potentially useful property for
replicative viruses would be the capability of avoiding early detection
and eradication by the immune system. Although a variety of viral
agents have been used as replicative agents—including Bunyamwara,
Coxsackievirus, dengue, mumps, Newcastle disease virus, vaccinia, West
Nile virus, and adenovirus—none of the agents has exhibited optimal
characteristics vis-à-vis the aforementioned desired
attributes (2, 3, 4)
.
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Attributes of Adenovirus Recommend Its Use
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With respect to candidate replicative viral agents, adenoviruses
possess many relevant attributes that recommend their use in this
context (5)
. In this regard, adenoviral vectors have been
used extensively for a variety of gene therapy applications (6
, 7)
. In these various gene therapy schemas, adenovirus has
exhibited an unparalleled efficiency allowing effective infection of
target cells in the context of in vivo gene delivery.
This attribute would logically predicate the ability of replicative
adenoviruses to achieve a high initial inoculum to target tumor cells
when used as a replicative agent. Of note, the entry pathway of the
virus has been extensively characterized (8)
. On this
basis, tropism modifications of the adenovirus have allowed rerouting
of the virus through heterologous cellular pathways to allow
achievement of cell specific gene delivery (9)
. Such
biological plasticity would thus, in theory, allow infectious
specificity to be achieved via restriction of binding exclusively to
tumor cells. In addition, the replication cycle of the adenovirus has
been the subject of investigation for several decades
(10)
. Consequently, there exists a large database of
information with respect to the viral regulatory mechanisms involved in
the replicative cycle (11
, 12) . Thus, from the standpoint
of inoculum efficiency and replicative specificity, adenovirus vectors
offer potential utility as a conditionally replicative viral agent by
providing the basis by which to modify the parent virus toward the
requirements of a true CRAD reagent.
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Engineering Conditionality of Replication
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Specificity of Replication Based on Tumor Biology.
Initial attempts to derive
CRADs3
focused on the
achievement of tumor selective replication (6)
. In this
regard, by using the knowledge that components of the adenovirus
replication cycle intrinsically interact with specific functional
cellular proteins, one strategy has been the generation of CRAD vectors
targeted to biological factors modified in cancer cells (Fig. 1)
. One such attenuated virus, containing
mutations within an adenoviral early-transcribed gene, was developed to
replicate only in cells lacking the cell cycle control protein p53
(6)
. Of note, cell cycle regulatory proteins, such as p53,
are mutated in nearly all actively growing tumors (13)
;
thus, the dependence of viral replication on the presence or absence of
these proteins represents an ideal regulatory mechanism that
potentially provides tumor-specific replication. On this basis, a
mutated adenovirus, termed dl1520, was derived that contains two
deletions within the E1B-55 gene. Initial studies
carried out with this agent demonstrated therapeutic potential, with
the achievement of tumor regression and even complete elimination of
tumors in some murine xenograft models (6
, 14)
. These
findings resulted in the rapid translation of the virus into human
Phase I, and then Phase II, clinical trials for carcinoma of the ovary
and of head and neck cancer treatment (15)
. Of note,
however, studies by Turnell et al. (16)
, and
Goodrum et al. (17)
determined that actual
specificity of viral replication of dl1520 is not attributable to the
absence or presence of p53 but is based on the timing of viral
replication in tumor cells or other undefined (18
, 19)
factors. Replication of dl1520 is, therefore, not strictly linked to
the presence of p53. In addition, replication in normal human primary
cells has been noted (20)
. Thus, though the initial
concept of targeting replication to the presence of a functional
p53 gene was not realized with this virus, empiric efficacy
in tumor treatment has been suggested.
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Fig. 1. Schematic representation of types of CRAD
agents. Depicted are genomes of CRAD agents with illustration of the
basis of conditional replication. For Type I CRADs, the design strategy
of the transcomplementing genome is shown. Wild-type adenovirus
(Ad-wt) has an intact E1 gene that
triggers early gene expression and adenovirus replication. A
nonreplicative adenovirus (Ad) has a complete deletion of
E1A and thus cannot propagate except in the context of
E1A-expressing packaging cells. A conditionally
replicative Ad may be derived by partial deletions of E1
in which tumor cells provide the missing functions to allow
replication. Ideally, the transcomplementing functions will be present
in tumor cells but not in nontumor cells. For Type II CRADs,
conditional expression of the E1A gene is achieved via a
tumor-specific promoter. To achieve this end, replacement of the
native E1 promoter with the tsp would ideally allow E1
expression only in promoter-inductive tumor cells. This
E1 expression could then trigger a replicative cycle for
the adenovirus. Again, tumor-selective induction of the promoter is the
basis of specificity. CMV, cytomegalovirus.
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Specificity of Replication Based on Transcriptional Control.
Given the inability to achieve absolute specificity with engineered
replicative viruses via the aforementioned approach, investigators have
used other methods (Table 1)
. In this
regard, an alternate means for obtaining tumor specific adenoviral
replication has been developed based on exploiting heterologous
transcriptional control regions, or promoters, to restrict replication
of the adenovirus to tumor. This has been accomplished by placing an
essential adenoviral gene under the control of a heterologous genetic
regulatory element the expression of which is limited to specific
tissues or tumors. Two groups have demonstrated the validity of this
model by using such tumor-specific transcriptional regulatory elements,
which control the essential early adenoviral genes (Table 1
;
Refs. 7
, 21
). In these instances, practical considerations
dictated the strategy of heterologous control of the E1A
gene. In addition, direct antitumor affects of E1A, based on apoptosis
induction may be exploited in this manner (22)
. In this
regard, the existence of E1A-transcomplementing cell lines, plus
available plasmid packaging systems (23)
, allows for
facile construction and rescue of such recombinant adenoviruses.
A variety of CRAD strategies have exploited this design strategy. In
this regard, recognizing that levels of PSA are elevated in the
prostate of individuals with prostate cancer, the transcriptional
promoter sequences of the PSA gene have been configured into adenoviral
vectors to regulate E1 transcription (7)
. In mouse
xenograft models, this replicative adenovirus eradicated large
PSA-expressing tumors and abolished PSA production with a single
intratumoral injection. Yu et al. (24)
have
presented studies using a CRAD vector containing dual promoter
regulation within the E1 region with promoters separately controlling
expression of E1A and E1B. This replicative adenovirus was demonstrated
to lyse PSA expressing cells with a selectivity of 10,000-fold over
that of non-PSA-expressing cells. An alternative approach uses
sequences that drive the expression of the HCC marker
-fetoprotein, a gene that is singularly expressed in
dividing hepatocytes and HCC (21)
. In addition, binary
systems have also been developed as a means to achieve delivery that
transcomplements E1A (25
, 26) .
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Multimodality Treatments
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In addition to use as single agents, replication-competent
adenoviruses have also been exploited in the context of combination
treatment with conventional anticancer approaches. In this regard,
several groups have examined the efficacy of this approach by
configuring a toxin gene, such as cytosine deaminase or
herpes thymidine kinase, into the context of replicative
adenoviruses. In addition, Freytag et al.
(27)
have developed a replicative adenovirus that is
configured with a thymidine kinase/cytosine
deaminase fusion gene . The resultant toxin product kills cells
with the administration of the prodrug, besides increasing the
sensitivity of the tumor to radiation. Wildner et al.
(28
, 29)
and Heise et al. (30)
have demonstrated that both of the therapy schemes bring additive
effects to replicative viral cancer therapy. Furthermore, the resultant
bystander effect seen from toxin-expressing cells is such that
nontransduced tumor cells may likewise be eradicated, thereby
accomplishing an additional mechanism for the achievement of an
amplified antitumor effect. It has been proposed that utilization of
this method may add a measure of safety to the use of oncolytic viruses
in that one can effectively control the spread of virus via the
addition of the prodrug analogue, which would selectively ablate
virus-infected cells.
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Obstacles for Clinical Application of CRADs
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Despite the various theoretical advantages of replicative
adenoviral agents, the various strategies for use of CRADs will only
allow true utility if they account for all of the relevant aspects of
tumor biology.
Scarcity of Adenoviral Receptors in Human Tumors.
From the standpoint of inoculum efficiency, it has been noted that
primary tumor is relatively refractory to adenoviral infection compared
with cell line counterparts. This phenomenon is shown to occur on the
basis of a relative deficiency of the primary adenovirus receptor CAR
(31
, 32)
. Clearly, the resistance of tumor targets to
adenoviral infection will restrict not only the efficiency of the
initial inoculum but also the ability of the virus to infect laterally
postreplication. On this basis, in the absence of CRAD vectors that
will infect with true tumor cell specificity, replicative
adenoviral agents will at least need to possess the ability to achieve
CAR-independent gene transfer (31)
. Indeed, such
fundamental limits as tumor refractoriness to adenoviral infection may
represent the major barrier to realizing the full benefit of CRAD
agents translated into the clinical context at this point.
True Tumor Specificity.
From the standpoint of replicative specificity, a number of design
aspects used to date potentially undermine the goal of true tumor
specificity. In the first regard, although transcomplementation of E1A
offers practical advantages, a number of limits must be taken into
account. In this regard, a number of tumors exhibit E1A-like activity
and are, thus, capable of transcomplementing E1A(-) viruses (33
, 34)
. Indeed, this capacity has actually been exploited in the
design of a class of CRAD agents that exploit interleukin
6-inducible E1A-like activity (33)
. The presence of
intrinsic E1A-like activity would clearly operate to undermine the
design of CRAD agents with E1A under control of tumor-specific
promoters. In addition, promoter function in the adenoviral genome
context is idiosyncratic, as has been noted in the context of a variety
of adenoviral vectors designed to achieve transcriptional targeting of
transgenes to tumor cells. Furthermore, this dysregulation of promoters
is likely to be of even greater consequence in the context of cellular
physiology induced by the replicative cycle of adenovirus. To address
this, specific endeavors to understand heterologous promoter function
in a CRAD context must be undertaken. Additional steps to maintain the
fidelity of such promoters will require development and validation.
Although some initiatives in this direction have been applied for
adenovirus vectors, their relevance for CRAD vectors remains to be
determined.
Adenoviral Interaction with the Immune System.
Another key factor relevant to realizing the full therapeutic potential
of CRAD agents is the interaction of the adenovirus with the immune
system. In this regard, therapeutic efficacy of replicative adenovirus
is predicated on the idea that replication and lateralization within
tumors could occur without impairment via host eradication of the virus
by immune mechanisms. Of note, Bramson et al.
(35)
have suggested that the intratumoral environment is a
relatively privileged site in regard to adenoviral interaction with the
immune system. Thus, appropriate physiology may exist within the tumor
to allow further gain in viral amplification. On the other hand, Ikeda
et al. (36)
. have shown that immunosuppression
limits the utility of replicative herpes virus for antitumor therapy.
On this basis, it may be argued that steps to attenuate the host immune
response to adenovirus are rational. Although a variety of
immunological approaches have been used to try to limit the host immune
response to adenoviral vectors (37
, 38)
, their use in the
context of replicative adenoviruses raises particular safety
concerns. Furthermore, at this time, mouse and rat tumors do not
support efficient replication of human adenoviruses, so that syngeneic
immunocompetent rodent tumor models are not available to evaluate the
interaction between CRAD and the human immune system. Clearly, future
studies are necessary to address the issue of immunomodulation of
CRADs.
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The Clinical Indications for Using CRADs
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Clinical translation of CRAD agents has progressed rapidly through
Phase I and Phase II trials. These efforts have largely been carried
out in the context of local or locoregional disease. This fact reflects
the verity that the current generation of CRAD agents generally
exhibits the promiscuous tropism of parent adenoviruses. On this basis,
tumor-specific delivery is restricted to anatomical locations whereby
the virus may be delivered and contained locally. This aspect of CRADs
has limited the use of these agents for disseminated diseases, in
which systemic delivery would be mandated. Thus, the ability to
achieve cell-specific gene delivery via tropism modification of the
parent virus would be required to allow the application of CRAD agents
in the important context of disseminated disease (39)
. One
key aspect of such a scenario is that the amplifying principle nature
of CRADs may allow the use of a much lower dose of administered
adenovirus. On this basis, it may, in fact, be more feasible to use
CRADs in a systemic manner for disseminated disease than to use
adenoviral vector counterparts. This is especially relevant in
the context of severe host reaction to i.v. injected adenovirus
limiting the therapeutic efficacy of treatment (40)
.
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Conclusion
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Despite these caveats, CRADs clearly represent antitumor agents of
exciting promise. A greater understanding of precise patterns of
tumor-specific gene expression will clearly offer additional venues for
the derivation of viral tumor-specific replication. These endeavors
will likewise be fostered by technologies to improve promoter
specificity—via direct engineering of the adenoviral genome (41
, 42)
as well as via shuffling— and promoter evolution
methods (43)
. In addition, dramatic strides have
been made in adapting adenoviral vectors for cell-specific gene
delivery. Clearly, these technologies will complement recent National
Cancer Institute-directed efforts to a full characterization of unique
surface molecules that distinguish tumor cells. Thus, on this
basis, an advanced understanding of the cancer phenotype, as well as
achievements in functionally exploiting viral plasticity, predicates
the design and realization of CRAD agents with more improved
characteristics for cancer therapy.
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ACKNOWLEDGMENTS
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We thank Connie H. Weldon for her administrative assistance.
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FOOTNOTES
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by NIH Grants R01
CA68245 and R01 CA83821; National Cancer Institute Grant N01 CO-97110;
grants from the Susan B. Komen Breast Cancer Foundation, CapCURE
Foundation, and Cancer Treatment Research Foundation; United States
Army Department of Defense Grant PC 970193; and United States
Department of Defense Grant PC 991018. 
2 To whom requests for reprints should be
addressed, at Division of Human Gene Therapy, Departments of Medicine,
Pathology and Surgery, Gene Therapy Center, University of Alabama at
Birmingham, 1824 6th Avenue South, Room WTI 620, Birmingham, AL
35294-330. Phone: (205) 934-8627; Fax: (205) 975-7476; E-mail: david.curiel{at}ccc.uab.edu
3 The abbreviations used are: CRAD,
conditionally replicative adenovirus/adenoviral; PSA,
prostate-specific antigen; HCC, hepatocellular carcinoma; CAR,
Coxsackie and adenovirus receptor.
Received 4/13/00;
revised 6/20/00;
accepted 6/27/00.
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Top
ABSTRACT
Introduction
