ZURICH Intralesional adenoviral vector-delivered interferon-gamma gene transfer is a novel and promising immunotherapy for primary cutaneous lymphomas, Dr. Mirjana Urosevic said at the annual meeting of the European Society for Dermatological Research.
Although adenovirus is the most utilized vector in the field of gene therapy, in the setting of primary cutaneous lymphoma the adenoviral vector is not merely a gene therapy delivery system. It has therapeutic activity in its own right, according to Dr. Urosevic of the University of Zurich.
She and her colleagues found that adenoviral vector activates innate immunity and induces type 1 interferons, most prominently interferon-α(1FN-α), a toll-like receptor agonist that stimulates antitumor immunity and has strong antiproliferative and antiangiogenic effects. They demonstrated this in gene expression profile studies of skin lesions obtained before and after treatment in 20 patients with various primary cutaneous lymphomas.
The appeal of adenovirus-mediated interferon-gamma (IFN-γ gene transfer is that it provides a complementary two-pronged approach to immunotherapy, calling forth both innate and adaptive immunity. The adenovirus induces IFN-α, while the gene insert comprised of human cDNA induces IFN-γ, a type II interferon. Both IFN-α and IFN-γ are believed to be crucial for the most efficient tumor rejection.
In preliminary studies, the researchers found that adenovirus-mediated IFN-γ gene transfer provided impressive clinical efficacy. Favorable responses have been universal in the small number of treated patients with cutaneous B-cell lymphomas. The majority of patients with cutaneous T-cell lymphomas have also responded.
Although direct intralesional injection of IFN-α or IFN-γ also results in tumor regression, adenovirus-mediated IFN-γ gene transfer is better tolerated, as it induces the patient's own cells to produce the interferons. It's a local intralesional therapy without systemic toxicity, said Dr. Urosevic.
The chief side effect is pain at the injection site lasting no longer than an hour. A strong local erythematous reaction can also occur. In addition, patients lacking antibodies to adenovirus experience febrile episodes in response to the initial injections.
The primary cutaneous lymphomas are uncommon malignancies characterized by accumulation of clonal T or B lymphocytes in the skin. Most are indolent chronic diseases with a good prognosis, so the preference is for low-morbidity treatments that provide good control for long periods, she said. The primary cutaneous lymphomas don't offer tumor antigens as targets for immunotherapy, but nonspecific immunostimulation can be applied using cytokines such as IFN-α and IFN-γ.
The primary cutaneous B-cell lymphomas are a heterogeneous group of disorders defined by skin involvement without extracutaneous disease at the time of diagnosis. They account for about one-quarter of all primary cutaneous lymphomas.
Two of the three major subtypes of primary cutaneous B-cell lymphomas in the World Health Organization classificationmarginal zone B-cell lymphoma and follicle center lymphomaparticularly lend themselves as a testing ground for less aggressive treatments such as immunotherapy because they are low-grade lymphomas that progress slowly, often over decades. The third major subtypelarge B-cell lymphoma, leg typeis considerably more aggressive and doesn't qualify for immunotherapy, Dr. Urosevic explained.
There are at present no approved therapies for primary cutaneous B-cell lymphomas. The most widely used treatments are surgery and radiotherapy. Off-label therapies include corticosteroids, rituximab, and imiquimod.
Adenovirus-mediated IFN-γ gene transfer is being developed by Transgene SA of Strasbourg, France, the company that funded the study. A phase II clinical trial in 40 patients with radiotherapy-resistant primary cutaneous B-cell lymphomas is under way.
The treatment regimen entails once-weekly injections for 3 weeks followed by a 2-week pause to assess for disease progression. If the disease is stable or there is an objective response, weekly treatment resumes. Recently, however, Dr. Urosevic and colleagues showed that if the genes for IFN-α and IFN-γ are induced shortly after treatment starts, a later favorable therapeutic response is predicted.
Successfully treated lesionsand in many cases untreated ones as wellslowly disappear, with complete responses often seen after three to six injections.