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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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