To our knowledge, this follow-up analysis of patients with stage D0.5 prostate cancer enrolled in a randomized clinical study is the first published study to provide prospective data regarding OS in this rapidly increasing patient population. Median OS for all patients enrolled in this study was 5 years, which is consistent with more recent analyses in similar patients (7
With a median potential follow-up of more than 4 years, data from this analysis suggest that initial treatment with vaccine may potentially be associated with prolonged survival. A possible explanation for this may be that vaccine therapy initiates a dynamic process of host immune responses that can be exploited in subsequent therapies. Several recently published studies have noted this phenomenon. In a phase I study, 17 patients with advanced-stage cancer received a plasmid/microparticle vaccine directed against cytochrome P4501B1. Most patients who developed immunity to P4501B1 but required salvage therapy upon progression showed dramatic and durable responses to their next treatment regimen (9
). In another study, 29 patients with extensive small cell lung cancer received an adeno-p53 vaccine (10
). Patients who received chemotherapy immediately following vaccine therapy showed a high rate (61.9%) of objective clinical responses that were closely associated with induction or augmentation of immune response to vaccine. Finally, a recently completed randomized phase II study at the NCI used the same poxvirus-based vaccine approach described in the present study (11
). In that trial, 28 patients with metastatic androgen-independent prostate cancer were randomized to receive vaccine alone or vaccine plus docetaxel. Patients in the vaccine-alone arm were allowed to cross over to receive docetaxel at disease progression. The median progression-free survival on docetaxel following vaccine was 6.1 months, compared to 3.7 months on the same docetaxel regimen but without prior vaccine in a historical control. Similar findings were observed in a randomized multicenter study of the sipuleucel vaccine (12
), in which patients in both the vaccine arm (n = 51) and the placebo arm (n = 31) went on to receive docetaxel at progression. There was a striking and statistically significant increase in OS (hazard ratio: 1.90; P
= 0.023) with docetaxel treatment in patients having had prior vaccine vs. placebo.
As demonstrated in other stages of prostate cancer, for all stage D0.5 patients enrolled in this study, an on-study PSADT of ≤ 3 months resulted in shorter OS compared to patients with a PSADT of > 3 months (median 5.1 years vs. 3.1 years; P
= 0.045) (13
). However, in this small study, baseline differences in prior therapy, PSA value, and Gleason score did not have an impact on OS. The present follow-up analysis revealed a trend toward improved OS in patients randomized to receive vaccine. An exploratory subgroup analysis performed according to treatment randomization suggests which D0.5 prostate cancer patients were more likely to benefit from vaccine-based therapy. Patients with either a baseline Gleason score of ≤ 7 or baseline serum PSA < 20 ng/dl had an apparent increase in OS if they were randomized to the vaccine arm. Both these characteristics are consistent with less pathologically aggressive disease and lower tumor volume. A history of radiation therapy was a predictor which was potentially associated with improved OS in patients randomized to the vaccine arm compared to patients randomized to the nilutamide arm. The prior radiation acting as a positive predictor of survival benefit in the vaccine arm could be due to the fact that prior radiation could have led to tumors’ cell destruction, which in turn led to cross-presentation of prostate tumor-associated antigens to T cells. Thus subsequent vaccination could actually have been an “immune booster.”
Related to this, we have previously shown (14
) that radiation of tumor can lead to alteration of the phenotype of tumor cells in terms of upregulation of tumor-associated antigens and also making them more susceptible to T-cell killing. The above data thus suggest that vaccine-based therapy should be utilized in patients with a lower tumor burden that allows the immune system to mount an effective response (20
There were 11 patients in this trial who were positive for the HLA-A2 allele and could thus be evaluated using an A2 PSA peptide. None of the three HLA-A2 positive patients in the nilutamide arm showed induction of PSA-specific T-cell responses either pre- or post-three monthly cycles of therapy. Four of eight patients in the vaccine arm showed at least a 2-fold increase in PSA-specific T cells after three monthly vaccinations, with one patient having a greater than a 9-fold increase in PSA-specific T cells. One patient had a 15-fold increase in PSA-specific T cells after 11 months in treatment, and another patient had a 17-fold increase in PSA-specific T cells after 14 months of treatment. This has been described in more detail previously (6
) at the approximately 2-year post-treatment follow-up. None of the patients in this study had previously received chemotherapy. A previous study in patients with metastatic cancers demonstrated a negative association between the number of previous chemotherapy treatments and the magnitude of T-cell response to vaccine (P
= 0.032) (21
). That same study also showed a positive relationship between the magnitude of T-cell response to vaccine and longer time since last chemotherapy (P
= 0.005). Thus, patients who had received multiple cycles of chemotherapy, or who had received chemotherapy shortly before initiating vaccine therapy, mounted less effective immune responses to vaccine.
Of the 20 crossover patients in this study, the 12 patients who crossed from vaccine to nilutamide at PSA progression had improved OS from enrollment compared to the eight patients who crossed from nilutamide to vaccine (P
= 0.045). This suggests that for patients with D0.5 prostate cancer who receive combination therapy, the greatest benefit may be derived by those who receive vaccine early in their treatment program. There is also increasing evidence that androgen-deprivation therapy (ADT) may potentiate immune responses in prostate cancer (22
). ADT increases infiltration of the prostate by both cytolytic and antigen-presenting T cells within 4 weeks of administration (23
). The greater influx of T cells to the prostate may be the result of increased antigen presentation to the T cells (24
The survival analysis presented here has several limitations. The crossover component does not allow for any conclusions about the efficacy of vaccine alone in the D0.5 population, and survival analyses for crossover patients are potentially biased since they include only the subset of patients retrospectively determined to have received a crossover treatment. Furthermore, this subgroup analysis selects for healthier patients and eliminates patients with rapidly progressing disease. However, this does not affect the OS for all patients randomized in the study. Also, the small number of patients in each arm makes definitive conclusions problematic, increases the possibility of undetected imbalances between the two arms despite randomization, and limits the interpretation of subgroup analyses. Finally, although the two arms were relatively well balanced, at time of enrollment, patients in the vaccine arm had a longer time from diagnosis of D0.5 disease and a slightly lower PSADT. These two factors may have actually favored overall survival for the patients enrolled in the nilutamide arm. However, even accounting for these limitations it is clear that patients with tumor characteristics consistent with slow growth and small volume, and who received vaccine earlier in their treatment regimen, may exhibit improved OS.
Based on the results reported here, we have initiated a randomized study in D0.5 prostate cancer patients using a PSA-based vaccine combined with ARA therapy upfront vs. ARA therapy alone, to determine whether combination therapy can provide clinical benefit by delaying onset of metastatic disease and extending OS. The vaccine in this study is a next-generation poxviral vaccine consisting of PSA plus a triad of costimulatory molecules (B7-1, ICAM-1, and LFA-3) designated TRICOM. This study involves a primary vaccination with rV-PSA-TRICOM and multiple booster vaccines with rF-PSA-TRICOM. PSA-TRICOM is safe and has a proven ability to mount T-cell-specific responses (25
). This study is currently accruing patients at the National Cancer Institute in Bethesda, Maryland.