Table 2.
Clinical trials with PSA-targeted poxviral vaccines
| Ref. | Type of trial | N | Vaccine | Dose/schedule | Results |
|---|---|---|---|---|---|
| [14] | Phase I in pts with rising PSA after radical prostatectomy | 6 | rV-PSA | rV-PSA | Minimal toxicity. Durable PSA response. |
| [15] | Phase I in pts with rising PSA after definitive primary treatment or metastatic disease | 33 | rV-PSA | rV-PSA (2.65×106) rV-PSA (2.65×107) rV-PSA (2.65×108) 10 pts received GM-CSF |
14/33 pts had stable PSA for ≥ 6 mos. 9 pts stable for 11–25 mos. 6 pts progression-free with stable PSA. PSA-specific T-cell response to PSA-3. |
| [16] | Phase I in mCRPC | 42 | rV-PSA | rV-PSA monthly ×3 | Increase in proportion of PSA-specific T cells after vaccination. In vitro assay showed these T cells could lyse PSA-expressing tumor cells. |
| [19, 20] | Phase II in pts with biochemical progression after local therapy | 64 | rV-PSA (V) rF-PSA (F) |
Sequential F monthly, then every 3 mos. Arm A: FFFF Arm B: FFFV Arm C: VFFF |
At 19.1 mos: 45.3% PSA progression-free. 78.1% clinically progression-free. Trend favoring VFFF treatment schedule. 47% had increase in PSA-reactive T cells. Median time to PSA progression: 9.2 and 9.1 mos for arms A and B respectively; 18.2 mos for arm C (rV-PSA prime and rF-PSA boost; p = 0.15 by logrank test). |
| [23] | Phase II in localized disease | 30 | rV-PSA + rV-B7.1, followed by monthly rF-PSA boost ×7 (vaccine) | Arm A: vaccine + RT Arm B: RT only Adjuvants: GM-CSF and low-dose IL-2. RT given between 4th and 6th vaccinations. |
13/17 pts had ≥3-fold increase in PSA-specific T cells. Evidence of de novo generation of T cells to other prostate-associated antigens not found in vaccine (antigen spreading). |
| [24, 73] | Phase II in nonmetastatic CRPC | 42 | rV-PSA + rV-B7.1, followed by rF-PSA monthly boost (vaccine) | Arm A: vaccine Arm B: nilutamide Cross-over to both treatments allowed at progression. Adjuvants: GM-CSF 100 mcg s.c., D1-4 and low-dose IL-2 (6 MIU/M2). |
Median OS 4.4 years from date of enrollment. Trend toward improved OS for pts initially randomized to vaccine arm (median 5.1 vs. 3.4 years; p = 0.13). |
| [69, 100] | Randomized phase II in mCRPC | 28 | rV-PSA + rV-B7.1, followed by rF-PSA monthly boost (vaccine) | Arm A: vaccine + docetaxel Arm B: vaccine alone (cross-over allowed) Adjuvant: GM-CSF |
Equivalent immune responses for vaccine and vaccine + docetaxel. Median PFS on docetaxel was 6.1 mos after receiving vaccine vs. 3.7 mos with same regimen in historic control. Median OS: 21.6 mos vs. 15.5 mos Halabi-predicted. |
| [25] | Pilot study in localized disease | 18 | rV-PSA + rV-B7.1, followed by rF-PSA monthly boost ×7 | rV-PSA + rV-B7.1 followed by monthly boosts with rF-PSA ×8 cycles. GM-CSF 100 mcg on D1-4, IL-2 0.6 MIU/M2 on D8-21 s.c. | 5/8 HLA-A2+ pts had increased PSA-specific T cells. |
| [43] | Phase I in mCRPC | 15 | PROSTVAC-V/F | Cohort 1: FFF Cohort 2: VFFF Cohort 3: VFFF + recombinant GM-CSF Cohorts 4 & 5: VFFF + rF-GM-CSF Adjuvant: rF-GM-CSF |
Time to clinical progression on vaccine: 20.5 weeks. No measurable response seen. PSA-specific immune response in 4/6 HLA-A2+ pts. Decrease in PSA velocity in 9/15 pts. |
| [44] | Phase II in mCRPC | 32 | PROSTVAC-V/F | PROSTVAC-V followed by PROSTVAC-F boosts until progression. Adjuvant: GM-CSF |
Median OS: 26.6 mos (vaccine) vs. 17.4 mos (Halabi-predicted). |
| [88] | Randomized phase II in mCRPC | 125 | PROSTVAC-V/F | Arm A: PROSTVAC-V prime on D1 with PROSTVAC-F on weeks 3, 5, 9, 13, 17, and 21. Adjuvant: GM-CSF Arm B: control empty vector |
No difference in PFS (p = 0.6). OS: 25.1 mos vs. 16.6 mos (HR 0.56; p = 0.0061). |
| [74] | Randomized phase II in nonmetastatic CRPC | 26 | PROSTVAC-V/F + flutamide | Arm A: flutamide alone Arm B: PROSTVAC-V followed by PROSTVAC-F boosts until progression + flutamide. Adjuvant: GM-CSF |
Median time to progression: 223 days for vaccine vs. 85 days for flutamide combination. |
| [101] | Pilot study in locally recurrent disease after radiation | 21 | PROSTVAC-V/F | rV-PSA-TRICOM prime. I.p. rF-PSA-TRICOM boost with i.p. rF-GM-CSF. Cohorts 3–5: i.p. rF-GM-CSF Cohort 5: concurrent s.c. and i.p. boosts. Prime: D1. Boosts: D29, 57, and 85. |
18/21 pts had stable or improved PSA on study. 16/21 pts had stable or improved PSA DT. 4/8 evaluable pts had immune response by ELISPOT. 11/15 pts had decreased or stable Treg function. Biopsies pre- and post-vaccination showed increases in immunologic tumor infiltrates. |
| [75] | Phase I in mCRPC | 30 | PROSTVAC-V/F + ipilimumab | rV-PSA-TRICOM D1. rF-PSA-TRICOM D15, 29, then monthly. Ipilimumab 1, 3, 5, or 10 mg/kg in sequential dose levels monthly. | Median time to radiographic progression for CN pts: 5.9 mos. OS 31.8 mos vs. Halabi-predicted 18.5 mos. 2-yr survival rate: 74%. Median OS for CN pts: 30.9 mos. No significant difference in OS based on dose level. 4/6 evaluable pts at higher dose levels had > 2-fold increase in antigen-specific T-cell responses. |
| [102] | Phase II in pts with PSA progression after local therapy | 50 to step 1 19 to step 2 |
PROSTVAC-V/F | PROSTVAC-V/F with GM-CSF monthly for 3 cycles, then every 12 weeks. | Pre-treatment PSADT: 4.4 mos vs 7.7 mos on-treatment PSADT. Overall biochemical response rate: 2%. 25 pts had stable disease. |
CN = chemotherapy-naïve; CR = complete response; i.p. = intraprostatic; mos = months; OS = overall survival; PR = partial response; PSADT = PSA doubling time; pts = patients; RT = radiotherapy; s.c. = subcutaneous; Treg = T regulatory cell
PROSTVAC: poxviral vector expressing PSA and TRICOM