Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer

Abstract

A concurrent multicenter, randomized Phase II trial employing a recombinant poxviral vaccine provided evidence of enhanced median overall survival (OS) (p = 0.0061) in patients with metastatic castrate-resistant prostate cancer (mCRPC). The study reported here employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. Thirty-two patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three costimulatory molecules. Patients received boosters with recombinant fowlpox containing the same four transgenes. Twelve of 32 patients showed declines in serum PSA post-vaccination and 2/12 showed decreases in index lesions. Median OS was 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). Patients with greater PSA-specific T-cell responses showed a trend (p = 0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF versus no GM-CSF. Patients with a Halabi predicted survival of <18 months (median predicted 12.3 months) had an actual median OS of 14.6 months, while those with a Halabi predicted survival of > or =18 months (median predicted survival 20.9 months) will meet or exceed 37.3 months, with 12/15 patients living longer than predicted (p = 0.035). Treg suppressive function was shown to decrease following vaccine in patients surviving longer than predicted, and increase in patients surviving less than predicted. This hypothesis-generating study provides evidence that patients with more indolent mCRPC (Halabi predicted survival > or =18 months) may best benefit from vaccine therapy.

Fig. 1

Patients 14 and 3 with soft tissue lesions demonstrate reductions in their index lesions on CT scan post-vaccine. a Demonstrates a 68% reduction in the right hilar lesion in Patient 14 after 3 months. b Demonstrates the reduction of a 2.2 cm right pelvic lymph node to 1.4 cm in Patient 3 after 6 months. There was also a decrease in mediastinal adenopathy (not shown)

Fig. 2

a The Kaplan–Meier curve for all 32 enrolled subjects demonstrates a median overall survival of 26.6 months. b There was a strong trend in the ability to mount a sixfold increase in PSA–T cells post-vaccine and an increase in overall survival

Fig. 3

The graph depicts actual overall survival, predicted overall survival and whether or not an individual survived greater than (in green) or less than (in red) Halibi predicted survival. In addition, yellow arrows demonstrate patients who remain alive. Asterisks depict greater than sixfold PSA–T-cell responses

Fig. 4

Patients were evaluated for their ability to produce antibody responses to the fowlpox vector post-vaccination. No difference in antibody titers to fowlpox post-vaccination was observed between patients with a Halabi predicted survival of ≥18 or <18 months

Fig. 5

The percent change in Treg function post-three vaccinations versus pre-vaccination stratified by actual overall survival versus Halabi predicted survival. Treg function was analyzed as previously detailed [28]