[PROC. AMER. ASSOC. CANCER RES. 40, March 1999]
Copyright © 1999 by the American Association for Cancer Research
#2061 Modulation of the immune response to recombinant adenoviruses. Gurnani, M., Shi, B., Zepeda, M.,
and Nielsen, L.L. Tumor Biology and Canji, Schering-Plough Res. Inst., Kenilworth, NJ 07033 and San Diego,
CA 92121.
SCH58500 is a novel therapeutic agent for gene therapy (GT) of cancer consisting of a replication-deficient, type 5
adenovirus (Ad) expressing human p53 tumor suppressor. SCH58500 has efficacy in a wide variety of cancer models
with nonfunctional p53 protein. One aspect of adenovirus-mediated GT which requires further study is the patient's
immune response against the Ad vector. In preclinical models, this is characterized by a rapid cellular response to Ad
administration and a later, neutralizing antibody response. We have previously shown both adenovirus- and
p53-mediated contributions to the activity of SCH58500. Several human tumor xenograft models and one
immune-competent, mouse tumor model were used to evaluate the effects of different immune modulators on cancer
efficacy. In scid-beige mice (defective T, B, and NK cells), anti-tumor efficacy was completely due to p53 expression,
with no Ad component. In tumor-bearing scid mice, the same result was achieved by intravenous anti-NK cell
antibody. These data emphasize the importance of NK cells in the Ad-mediated tumor response. Dexamethasone
(Dex) abrogated the cellular immune response against Ad in immune-competent FVB mice, thereby abolishing tumor
growth suppression caused by Ad after intraperitoneal or intratumoral dosing, but not antibody development.
Cyclophosphamide is the only DNA-damaging drug tested which did not enhance the efficacy of SCH58500 in human
tumor xenograft models. Further, cyclophosphamide neutralized all Ad activity after intraperitoneal dosing of
tumor-bearing FVB mice. These data suggest more complicated interactions between recombinant adenoviruses,
chemotherapy drugs, and the host immune system than previously suspected. |
