The study reported here was conducted to determine the immunologic and clinical activity of PSA-TRICOM vaccination in chemotherapy-naïve patients with mCRPC and to complement a concurrent randomized multicenter trial [20
] employing the same PSA-TRICOM vaccine. These results, albeit in a limited number of patients, provide evidence for the following: (a) some patients receiving PSA-TRICOM achieve declines in PSA and a reduction in measurable soft tissue disease and (b) evidence of increased overall survival compared to what the Halabi nomogram would predict, especially in patients with less advanced or less aggressive disease as indicated by a predicted survival of ≥ 18 months. There is also evidence of a potential association between survival and patients' ability to mount T-cell responses to vaccine. The addition of GM-CSF to vaccine did not appear to increase T-cell responses to vaccine. While the number of patients in each of the four cohorts was small, there did not appear to be a clinical advantage to administering GM-CSF with vaccine compared to patients receiving vaccine alone, as the four groups tended to show similar overall survival outcomes.
While not a predetermined analysis in this study, the data suggesting which patients might benefit from vaccine may provide important insights for use of vaccine-mediated therapy, which has now demonstrated an overall survival advantage in patients with metastatic prostate cancer in randomized phase II and III trials [5
]. If and when therapeutic vaccines become approved in metastatic CRPC, practitioners will have to determine which patients are most likely to benefit from vaccine therapy and which patients should instead be treated with cytotoxic therapy.
In the present study, the median overall survival for all 32 enrolled patients was 26.6 months compared with a predicted survival by Halabi prognostic model of 17.4 months. Twelve of 15 patients with a Halabi predicted survival ≥ 18 months survived substantially longer than predicted (predicted median 20.9 months vs. an actual median overall survival that will meet or exceed 37.3 months). Subsequent therapies did not appear to influence survival differences seen between the two Halabi groups as similar proportions of each group received similar docetaxel therapy. Therefore, these data suggest that the Halabi nomogram may provide a potential method of delineating which patients benefit most from vaccine therapy.
In comparing the baseline characteristics of the patients on this study and those of the 1,101 CALGB study patients that led to the development of the Halabi prognostic model, the patient populations appear quite similar (see ). The observed overall survival of the validation set [2
] was 17.0 months compared with the patients in the PSA-TRICOM study whose predicted survival was 17.4 months, indicating that patients used to develop the Halabi nomogram appear to be quite similar to patients who were enrolled on this NCI trial.
While the patients on this study may be representative of patients used to develop the Halabi nomogram, some may question its value in the docetaxel-era of therapy for prostate cancer. We have now analyzed data from a recent docetaxel trial at our institution [29
] according to Halabi predicted survival (). Both the vaccine trial described here and the docetaxel trial enrolled chemotherapy naïve patients with mCRPC; both trials enrolled patients with similar predicted overall survival (see ) and both were conducted at the same institution. It is of particular interest that those patients in the docetaxel trial had a median overall survival of 15.5 months compared with a predicted survival of 16.5 months, adding weight to the use of the Halabi prediction as an estimate of overall survival in patients treated with standard therapy at this institution. As seen in , there was only a slight difference in predicted vs. actual median overall survival for patients treated with docetaxel regardless of whether they were in the < 18-month or ≥ 18-month Halabi predicted groups. These data do not support the notion that patients in the ≥ 18-month Halabi predicted survival group were “destined to do well anyway” when treated with any therapeutic regimen – the Halabi nomogram corrects for this. It is the differential of predicted vs actual median overall survival that should be assessed when examining potential effectiveness of a given therapy. The results seen with the docetaxel-treated patients are contrasted with those observed with the vaccine-treated patients, where there was a ≥ 16.4 month differential in predicted vs overall survival in the group of patients predicted to live ≥ 18 months (). A different nomogram [31
] (in addition to the Halabi nomogram) was also used to evaluate results of this trial. Employing that nomogram [31
], all patients on trial had a predicted median survival of 17.0 months vs the actual median overall survival of 26.6 months (difference of 9.6 months). Furthermore, there was a greater absolute increase in median overall survival vs. predicted survival seen in the subgroup of patients with a predicted survival of ≥ 18 months; thus these results are consistent with those seen with the Halabi nomogram.
The seven individual components of the Halabi nomogram were derived based on their individual ability to assess tumor aggressiveness and volume. Taken together, these factors may be of value in patients who are considered for vaccine-mediated therapy. Perhaps patients with more aggressive disease and a larger tumor burden (those with a Halabi predicted survival of <18 months) have more immunosuppressive factors from their tumor and this is why they are less likely to benefit as much from treatment with vaccine. Increased tumor burden has been correlated with immune suppression in both preclinical and clinical models and may limit the immune system's ability to respond to a vaccine mediated therapy.
As shown in , there was a trend (p=0.055) toward increased overall survival in patients with a ≥ 6-fold increase in PSA-specific T-cell responses post-vaccination. It is interesting to note that all but one patient with a ≥ 6-fold increase had a Halabi predicted survival of > 18 months, and the remaining patient was just at the 18 month threshold. Nonetheless, as pointed out above, one should not consider the analysis of PBMC T-cell responses to the vaccine antigen as a lone surrogate for vaccine efficacy or any clinical parameter. Preclinical studies have clearly shown [32
] that T-cell responses to tumor antigens not in the vaccine, but generated by cross-presentation of destroyed tumor cells to the immune system, can also be responsible for the immune-mediated destruction of tumor; moreover, T cells that have trafficked to the tumor site can be more indicative of vaccine efficacy than T cells obtained from PBMCs.
The analysis of Tregs from PBMC demonstrated that Treg function decreased post- vs pre-vaccination in patients who lived longer than predicted, while Treg function increased post- vs pre-vaccination for patients who survived less than predicted. Although these findings may be an artifact of the small sample size or may not be representative of what occurs in the tumor microenvironment, they may also support the concept that tumor burden influences immune responses to vaccines. Perhaps, patients who survived less than predicted had more tumor burden, which was responsible for more tumor-derived immunosuppressive factors such as TGF-β which in turn drives the function of Tregs, while the reciprocal is observed in the control of tumor in patients living longer than predicted,
The median overall survival in the control (empty vector) arm of the concurrent randomized, multi-center study employing PSA-TRICOM [22
] was 16.6 months for control vs 25.1 months for the PSA-TRICOM vaccine. The median overall survival for the study reported here employing PSA-TRICOM was 26.6 months (predicted median overall survival by the Halabi nomogram was 17.4 months). In view of the similar results in median overall survival of the two Phase II trials employing PSA-TRICOM vaccination, a subsequent larger, randomized, multi-center Phase III trial is planned. The results of the trial reported here also provide hypothesis-generating evidence that metastatic prostate cancer patients with poorer prognostic factors have a similar survival with vaccine therapy compared to that predicted by treatment with standard therapy (chemotherapy or second-line hormone therapy). However, patients with more favorable prognostic factors may have a longer survival when treated with vaccine-mediated therapy as compared with conventional systemic therapies alone, or treated first with vaccine followed by conventional therapies. Subsequent larger, randomized trials will be required to confirm this observation.