MVA-MUC1-IL2 vaccine immunotherapy for patients post-prostatectomy with rising PSA and no evident metastases

Abstract

Background: Over-expression, non-polarity and under glycosylation of the mucin glycoprotein molecule, MUC1, are associated with many cancers, making MUC1 an attractive target antigen for vaccine immunotherapy of cancer. MVA (Modified Vaccinia Ankara), a highly attenuated Vaccinia virus,, is non-propagative in most mammalian cells and has an excellent safety profile. We have produced a recombinant MVA expressing MUC1 and IL2 (TG4010). Murine studies have shown that TG4010 can induce a MUC1 specific immune response associated with the elimination of MUC1 expressing tumors. In a Phase I study of TG4010 in patients with late stage, MUC1 expressing cancers, TG4010 was well tolerated and showed some evidence on efficacy. The excellent TG4010 tolerance has been confirmed in 158 patients so far recruited in 4 Phase II studies. In the study described, TG 4010 is assessed for efficacy in prostate cancer and which compares two schedules of administration. Methods: A randomized, two stage Simon design, two arm (15/25 patients stage 1/2 per arm), phase II study in patients with prostate cancer. Inclusion criteria include: patients post prostatectomy (either surgery or radiotherapy) with rising PSA (over 2 ng/ml and doubling within a 10 month period) and no evidence of metastatic disease. Arm 1: TG4010 is injected weekly at a dose of 108 pfu TG4010 for six weeks, then every three weeks until PSA progression. Arm 2: patients are treated with TG4010 every three weeks until PSA progression. Primary endpoint: Objective response as defined by a decrease of 50% or more in the PSA level compared to baseline. Secondary endpoints: modification in the rate of PSA increase; and increased time to treatment failure. Results : The treatment is well tolerated with injection site reactions, being the most common adverse event noted. At this time 22 patients have been enrolled. No objective responses, as defined by a 50% decrease in PSA, have yet been observed. Interim statistical analysis shows a significant increase in the PSA doubling times in both arms. In arm 1 (weekly injection schedule)the PSA doubling time was increased with respect to pre-baseline rate (P < 0.0001). The change in the rate of PSA increase in Arm 2 is less striking, but significant (P < 0.038). The difference between the two arms is also significant (P < 0.0056) indicating that the schedule of weekly immunizations is more effective that immunization every three weeks. All patients in Arm 1 (weekly schedule) experienced an increase in PSA doubling times (PSA-DT), with an average of 5 fold increase in PSA-DT in that group. Conclusion : Immunization of patients post-prostatectomy with TG4010, is safe and has a significant impact on PSA doubling time. As there is increasing evidence to suggest PSA doubling time is a clinically important parameter, the effect observed in patients treated with MVA-MUC1-IL2 has the potential to translate into a meaningful clinical benefit. It could provide a new therapeutic opportunity by delaying the time to administration of the hormone therapy, which is known to have distressing side effects.