University of Southern California, Keck School of Medicine
, Los Angeles, California 90033
sdiaz@genome2.hsc.usc.edu
The first Phase II clinical trial to study the combination of a
replicating viral agent with chemotherapy indicates that cancer gene therapy
may finally be on the road to success. (
879−885).
SQUAMOUS CELL CARCINOMA of the head and neck afflicts approximately 500,000
patients per year. The first-line treatment, chemotherapy, induces a response
in only 30−40% of patients, and tumors frequently recur. Alternative
cancer therapy approaches have been based on oncolytic viruses, which selectively
attack tumor, but not normal, cells. One of these, ONYX-015, was initially
tested in a Phase I clinical trial in April 1996. In this issue, Khuri
et al. report that ONYX-015, when combined with chemotherapy, promotes
tumor regression in patients with recurrent squamous cell cancer of the head
and neck1.
ONYX-015 is a modified adenovirus − a DNA virus that takes over the
cell's protein synthesis machinery, replicates, then lyses the host cell to
release its progeny. In wild-type adenovirus, the early regulatory protein
E1B-55kDa binds to and inactivates the host cell's p53 protein2
to promote its own replication. Without E1B-55kDa, adenovirus is incapable
of replication3. However, researchers observed that an E1B-55kDa
mutant adenovirus, ONYX-015, could replicate in and lyse p53-negative, but
not p53-positive, human tumor cells4. As p53 is mutated in 45−70%
of all cases of head and neck cancers, ONYX-015 was developed as a tumor cell-specific
therapeutic agent.
Tumor-selective destruction has been observed in squamous cell carcinoma
patients receiving ONYX-015; however, clinical benefit was observed in less
than 15% of patients. Khuri et al. studied the effects of ONYX-015
in combination with standard chemotherapy1. 30 patients with
recurrent squamous cell cancer of the head and neck were evaluated for their
response to a combination of chemotherapy (cisplatin and 5-fluorouracil) and
ONYX-015, which was injected directly into tumors1.
The combined therapy was well tolerated and did not cause significant levels
of toxicity. The treatment caused an objective response (at least a 50% reduction
in tumor size) in 19 cases, with 8 complete responses1. Tumors
as large as 10 cm in diameter regressed completely and none of the tumors
that demonstrated an objective response had progressed after a mean follow-up
of 5 months. The authors concluded that the tumor response rate, complete
response rate and time to tumor progression rate after combined therapy were
better than those observed after therapy with cisplatin and 5-fluorouracil
alone. Furthermore, biopsy samples indicated that ONYX-015 replicates within
tumor tissue but does not replicate in normal tissue.
The concept of using a gene therapy vector that selectively replicates
in and kills tumor cells has been around for a number of years, but the regulatory
concern of putting a replicating vector in patients prevented acceptance of
the idea until recently. Now, a number of approaches based on this concept
are being investigated. Replicating oncolytic viruses are advantageous because
they would theoretically be able to reach widespread metastases. Furthermore,
vectors such as ONYX-015 could probably be made even more effective if they
incorporated suicide genes like herpes simplex thymidine kinase and/or cytosine
deaminase.
The field of gene therapy has had a history of unexpected turns. ONYX-015
is another. The first irony in the field was the use of 'gene therapy'
(actually gene transfer), not for a genetic disease as everyone expected,
but for marking tumor-infiltrating lymphocytes in patients with malignant
melanoma5. The first gene therapy clinical trial was for the
genetic disease ADA deficiency in 1990 (ref. 6),
and by March 1995, there were 32 trials for genetic diseases, including 16
for cystic fibrosis and 16 for a range of other monogenic diseases. Although
it seemed that cystic fibrosis would be the first gene therapy success, hemophilia
was the first genetic disease for which encouraging clinical data were reported7.
Of the 277 gene therapy clinical trials reported by the National Institutes
of Health Recombinant DNA Advisory Committee (NIH RAC) in May 1999, 70% were
for treatment of cancer and only 5% were for treatment of cardiovascular diseases.
Therefore, it seemed that cancer would be the first 'acquired'
disease that would be successfully treated by gene therapy. However, researchers
soon after announced that direct injection of the vascular endothelial growth
factor gene induced new blood vessel formation in cardiovascular disease patients8.
Cancer is still the disease most frequently targeted by gene therapy. According
to the March 2000 NIH RAC database, of the 350 gene therapy clinical trials,
67% are for cancer. Of those, 31% use in vitro immunotherapies, 32%
use in vivo immunotherapies, 15% are based on pro-drug suicide therapies,
and only 2% are using a 'vector-directed cell lysis' approach.
It is therefore ironic that the first anti-cancer clinical success has arisen
from the last approach and that the vector does not even carry a 'therapeutic'
gene.
So with all its twists and turns, gene therapy seems to be turning the
corner after a very bad year. Not only has the field been criticized for too
much hype and too few successes, but in September 1999, an 18-year old patient
died as a direct result of a gene therapy intervention. But gene therapy has
also achieved success in four early stage clinical trials − each one,
surprisingly, using a different delivery system. We have witnessed the treatment
of severe combined immunodeficiency with a retroviral vector9,
hemophilia with an adeno-associated viral vector7, cardiovascular
disease with naked plasmid DNA8 and cancer therapy using an
oncolytic adenovirus1. Although the increased oversight and
new monitoring requirements will improve future gene therapy trials, what
the field really needs are successes in Phase III trials.
Khuri, F.R. et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nature Med.6, 879-885 (2000). | Article | PubMed | ISI | ChemPort |
Barker, D.D. & Berk, A.J. Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection. Virology156, 107-121 (1987). | Article | PubMed | ISI | ChemPort |
Yew, P.R & Berk, A.J. Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein. Nature357, 82-83 (1992). | Article | PubMed | ISI | ChemPort |
Heise, C. et al. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nature Med.3, 639-645 (1997). | Article | PubMed | ISI | ChemPort |
Rosenberg, S.A. et al. Gene transfer into humans - immunotherapy of patients with advanced melanoma, suing tumor-infiltrating lymphocytes modified by retroviral gene transduction. N. Engl. J. Med.323, 570-578 (1990). | PubMed | ISI | ChemPort |
Blaese, R.M. et al. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science270, 475-480 (1995). | PubMed | ISI | ChemPort |
Kay, M.A. et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nature Genet.24, 257-261 (2000). | Article | PubMed | ISI | ChemPort |
Isner, J.M. & Asahara, T. Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J. Clin. Invest.103, 1231-1266 (1999). | PubMed | ISI | ChemPort |
Cavazzana-Calvo, M. et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science288, 669-672 (2000) | Article | PubMed | ISI | ChemPort |
