MONTREAL-Altering genes to express therapeutic cytokines may represent
an improved approach to direct delivery of these increasingly
utilized recombinant proteins, Michael T. Lotze, MD, said during
a plenary session at the 19th International Congress of Chemotherapy
Although cytokines will be among the most useful agents for clinical
treatment of a multitude of infectious diseases and malignancies
in the future, he predicted, many of these products are currently
associated with considerable toxicities.
Dr. Lotze and his colleagues in the Department of Surgery, University
of Pittsburgh Medical Center, are exploring techniques by which
genes that control expression of appropriate proteins may be introduced
into cells. It is hoped that antitumor cytokines, for example,
expressed by cells with altered genes, will exert their effects
with reduced toxicity.
According to Dr. Lotze, T-cell growth factors may be thought of
as either "growth factors" (ie, IL-2) or "die factors"
(antiapoptosis factors, ie, IL-10, IL-12, interferon-gamma).
And while different cytokines sometimes share common receptors,
intracellular signaling may be quite distinct.
Some cytokines, such as IL-10, are considered to have immunosuppressive
properties, while others enhance cellular reactivity. Many cytokines
can have both immunosuppressive and immunostimu-lating properties,
depending on how the proteins are generated, he said.
In their own preclinical studies, Dr. Lotze and his colleagues
observed that IL-4 promoted cellular activity. The
combination of IL-1 plus IL-4 had excellent antitumor activity;
and despite toxicity (capillary leak syndrome), the combination
of IL-2 plus IL-4 was also active against tumors.
Based on these findings, Dr. Lotze and his colleagues developed
a cancer vaccine protocol using IL-4 transfected autologous fibroblasts.
A total of 18 patients were treated with high levels of IL-4,
delivered into the skin of patients' backs via transfected fibroblasts.
Interim findings of the study include expression of message for
up to 7 days, induction of VCAM and E-selectin on dermal epithelium,
generation of tumor-specific CD4+ cells in patients with melanoma,
profound lymphocytic infiltration, and correlation of VCAM expression
with S100+ dendritic cell infiltration, Dr. Lotze said.
He also described a new protocol involving IL-12 delivered with
retroviral vectors that was designed to administer high doses
without the severe toxicities associated with direct IL-12 treatment.
Studies of IL-12 have demonstrated enhanced tumor immunogenicity,
delayed tumor progression, and increased survival in animals.