Info

aTwo Step Desensitization refers to two increments in dose given to each patient (e.g., first dose of 1 BPFU/ m2, second dose of 12 BPFU/ m2, and third to sixth doses of up to 120 BPFU/ m2). This is in contrast to all the other desensitization regimens which were "one-step" (e.g., first dose of 12 PFU/ m2, followed by second and subsequent doses of up to 120 BPFU/ m2).

aTwo Step Desensitization refers to two increments in dose given to each patient (e.g., first dose of 1 BPFU/ m2, second dose of 12 BPFU/ m2, and third to sixth doses of up to 120 BPFU/ m2). This is in contrast to all the other desensitization regimens which were "one-step" (e.g., first dose of 12 PFU/ m2, followed by second and subsequent doses of up to 120 BPFU/ m2).

models following iv administration of doses 100-fold below the maximum tolerated dose (MTD). In these tumor models, the response rate increased with higher doses or with more frequent dosing. For example, the incidence of tumor response in HT1080 fibrosarcoma xenografts in athymic mice increased from 55 to 100% by either raising the iv dose threefold or by increasing the number of doses from 1to 3 (21).

Unlike many cancer chemotherapeutic compounds, the mechanisms effecting efficacy and acute toxicity for PV701 are distinct (2). In these preclinical studies, PV701 antitumor effects resulted from virus replication within the tumor and required live virus, whereas acute toxicity was mediated by the induction of proinflammatory cytokines and was also seen with ultraviolet (UV)-killed virus. Also, in contrast to the traditional chemotherapeutic compounds, PV701 toxicity was principally associated with the first dose and was not cumulative. The term "desensitization" has been applied to describe the phenomenon whereby the first dose of PV701 reduces the toxicity of subsequent doses. Use of an initial "desensitizing dose" of PV701 allowed a 5- to 10-fold increase in the MTD for subsequent doses. Desensitization occurred as early as 24 h after the first PV701 dose and was also observed in severe combined immunodeficient (SCID) mice, indicating that this desensitization is not antibody mediated (23).

The first dose of PV701 induces increased serum levels of proinflammatory cytokines such as interferon (IFN)-a, IFN-^, and tumor necrosis factor-a (TNF-a). In rodents, the transient release of these cytokines accounts for the acute toxicity and the reduction in their release into the serum after repeat dosing likely accounts for the desensitization seen on repeat PV701 doses. A similar desensitization phenomenon has also been observed following administration of individual cytokines. For example, a tolerance to acute toxicity has been reported for repeat doses of IFN (24).

In addition to desensitization, PV701 toxicity was reduced in mice by slowing the rate of iv infusion. The same dose administered over 10 min vs 30 s was better tolerated in mice, whereas there was no loss in efficacy at the slower infusion rates. These pre-clinical findings indicated that a higher therapeutic index may be achievable by slowing the infusion rate.

Was this article helpful?

0 0

Post a comment