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Gene Therapy for Thoracic Cancers
Annals of Internal Medicine
- April, 2000
Full
Article
Recent
advances in the understanding of growth factors, molecular
oncology, and tumor immunology have provided the rationale for
several strategies for cancer gene therapy (73). Some of these
approaches are being tested in clinical trials in patients
with lung cancer and malignant mesothelioma. A summary of
published clinical trials for thoracic cancers is shown in
Table 3. Because none of the currently available vectors
distribute systemically, therapeutic approaches have focused
on treatment of localized disease or induction of an immune
response capable of eliminating distant tumor cells.
Tumor Suppressor Gene Replacement Therapy
(p53)
One of the most common genetic abnormalities in non-small-cell
lung cancer is mutation of the tumor suppressor gene p53 (73).
Preclinical work showed that delivery of wild-type p53 to lung
cancer cell lines with deleted or mutated p53 caused some
degree of apoptosis (especially in combination with the
antitumor drug cisplatin) (83). In animal models, transduction
of a subset of cells in tumors with vectors encoding wild-type
p53-induced tumor regression (84), suggesting the existence of
a "bystander effect" by which transduced cells
inhibit the growth of nontransfected cells. Although the
mechanism of this effect is still not completely defined (85),
possible pathways include release of angiogenesis inhibitors
(86), activation of the Fas/Fas ligand system (87), and
immunologic response.
Three phase I clinical trials in humans using gene transfer of
p53 have been reported (Table 3 ). In all three trials, viral
vectors encoding wild-type p53 were injected into the tumors
of patients with non-small-cell lung cancer by means of a
bronchoscope or percutaneous computed tomography-guided
needles. In the first trial (74), a retroviral vector was
used. The treatments were well tolerated, with minimal side
effects. Some evidence of gene transfer was noted in patients
given higher doses, and a subgroup of patients showed evidence
of stabilization or regression of the injected tumors;
however, no effects on noninjected tumors were noted. In the
other two trials, adenoviral vectors were used (77, 78).
Swisher and colleagues (78) used monthly injections of an
adenovirus p53 vector in conjunction with administration of
cisplatin. Treatment was well tolerated, and despite repeated
doses of vector that induced antiadenoviral antibodies, gene
transfer was detected in most patients receiving higher doses.
Transient local control was observed in one third to one half
of the participants.
Intratumoral injection of adenoviral p53 for the treatment of
lung cancer thus seems to be well tolerated, safe, and perhaps
capable of local antitumor effects. However, because of the
lack of systemic efficacy, the ultimate clinical utility of
this approach will probably be limited to the few patients
with nonresectable disease that is not or cannot be controlled
with local radiation therapy.
Suicide Gene Therapy
Another approach to the treatment of localized cancer is
suicide gene therapy. In this therapy, a gene encoding an
enzyme that catalyzes conversion of a normally nontoxic agent
to a toxic substance is delivered to tumor cells. The toxic
substance then eradicates tumor cells (88). The most widely
used strategy has been introduction of the thymidine kinase
gene from herpes simplex virus (HSV tk) into mammalian cells.
This enzyme converts the normally nontoxic nucleoside analogue
ganciclovir to a toxic form. The success of the HSV
tk-ganciclovir approach is bolstered significantly by the
presence of a "bystander effect" (89). This involves
the transfer of toxic metabolites from transduced cells to
nontransduced cells through gap junctions (90) and the
generation of an immunostimulatory environment in vivo that
enhances immune responses (91).
On the basis of success in animal models, Sterman and
colleagues (79) conducted a phase I clinical trial of a
replication-incompetent adenoviral vector encoding HSV tk that
was delivered intrapleurally to 21 patients with pleural
mesothelioma. After vector instillation, patients received
systemic ganciclovir therapy for 2 weeks. As shown in Table 3,
dose-limiting toxicity was not reached; side effects were
minimal; and dose-related gene transfer was confirmed in 11 of
20 evaluable patients, in whom gene transfer was clearly
detectable on immunostaining at tumor surfaces that penetrated
up to 30 to 50 cell layers (79). However, strong
antiadenoviral immune responses, including high titers of
neutralizing antibody and proliferative T-cell responses, were
generated with no obvious adverse clinical effects (15).
Although clinical responses were not consistently seen, 1
patient remains tumor-free 3 years after treatment and partial
tumor regression was observed in several of the patients who
received the higher doses of vector. Further modifications to
the study protocols include escalation of the dose of
ganciclovir, multiple administrations of vector, and
combination of vector instillation with surgical tumor
debulking.
Immunogenetic Therapy
One attractive approach to the treatment of disseminated
cancer is to make a subset of tumor cells more recognizable to
the immune system, thus allowing widespread immune-mediated
tumor destruction. Various gene therapy approaches have been
developed with this goal in mind (92).
On the basis of the idea that expression of a foreign
transgene might augment antitumor immunity, a phase I trial
studied the transfer of the bacterial gene ß-galactosidase
into lung cancer tumor nodules by using
replication-incompetent adenovirus (75, 76) (Table 3 ). Ten
patients were injected with increasing doses of the vector by
using a bronchoscope. Evidence of transgene expression in the
nodules was obtained, and strong antiadenoviral and
antitransgene immune responses (both humoral and cell
mediated) were noted. Somewhat surprisingly, some localized
antitumor responses were observed, suggesting an antitumor
immunologic response.
Ex vivo approaches are also being developed. For example, on
the basis of animal data (93) and encouraging phase I data in
prostate cancer (94), a multicenter immunotherapy trial in
lung cancer has been established in which tumor cells will be
harvested, infected ex vivo with adenovirus-encoding
granulocyte-monocyte colony-stimulating factor, and reinjected
intradermally into patients.
Results of a phase I clinical trial in pleural mesothelioma
that used a recombinant vaccinia virus expressing the human
interleukin-2 gene have been reported (80, 81) (Table 3 ). The
vaccinia virus-interleukin-2 vector was injected repeatedly
into palpable chest wall masses of six patients with
advanced-stage malignant mesothelioma. Toxicity was minimal,
and no clinical or serologic evidence of spread of vaccinia
virus to patient contacts was seen. No patient had significant
tumor regression, and minimal intratumoral cellular immune
responses were detected. In future gene therapy approaches to
mesothelioma, vaccinia virus-interleukin-2 may show improved
efficacy in a more replication-competent form or as part of a
"cocktail" of cytokine genes delivered by way of
vaccinia virus (such as interleukin-2, interleukin-12, and
granulocyte-monocyte colony-stimulating factor).
Suicide Gene Therapy plus Immunotherapy
Several animal studies have suggested that the combination of
adenoviral vectors encoding HSV tk with adenoviral vectors
expressing certain cytokines (for example, interleukin-2 or
interferon-{alpha}) can enhance therapeutic efficacy by
augmenting antitumor responses (91, 95). No clinical trials
using such combinations have yet been reported; however,
Schwarzenberger and colleagues (82) reported a phase I
clinical trial in patients with malignant mesothelioma in
which an irradiated ovarian carcinoma cell line retrovirally
transfected with HSV tk (PA1-STK cells) was instilled
intrapleurally, followed by systemic administration of
ganciclovir (Table 3 ). The rationale behind this trial is
that the PA1-STK cells will migrate to areas of intrapleural
tumor after instillation and will facilitate bystander killing
of mesothelioma cells after ganciclovir infusion. To date, 14
patients have been treated. The treatment produced minimal
side effects but no obvious clinical responses. Preliminary
findings have shown significant increases in the percentage of
CD8 T lymphocytes in pleural fluid after instillation of
PA1-STK cells (96).
To access the full text of this article visit: http://www.annals.org/cgi/content/full/132/8/649
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