Prostate cancer vaccines

Figures & data

Table 1. Summary of recently completed and ongoing clinical trials

Vaccine	Description	Is it safe?	Latest completed clinical trials: (main findings)	Clinical trials active (a) or recruiting (r)
ProstVac VF (PSA-TRICOM)	Heterologous prime/multiple boosts vaccinia virus (PSA-CD54-CD58-CD80) – fowlpox virus (PSA-CD54-CD58-CD80)	Yes^19^,^20	●Phase II: Enhanced OS over control group by a median 8.5 mo^21 ●Phase II: Enhanced OS compared with Halabi nomogram prediction^22	●Phase III (r): Comparison of OS with or without GM-CSF (NCT01322490) ●Phase II (r): Comparison of disease progressions with flutamide and flutamide alone (NCT00450463)
ProstVac VF + ipilimumab (nivolumab)	ProstVac VF + dose-escalation trial of anti-CTLA4 antibody	Yes*^,^23	Phase I: Safe and tolerable*^,^23
ProstVac VF/ProstVac VF-like + docetaxel	ProstVac VF-like (rV-PSA + rV-CD80) prime/rF-PSA boost)	Yes^24	Phase II: Safe. Docetaxel does not inhibit vaccine specific T-lymphocyte responses^24
Ad5-PSA	PSA-encoding adenovirus 5– one administration with/without Gelfoam^® (Phase I) and three administrations with Gelfoam^® (Phase II)	Yes^25	Phase I: Safe. In Ad5-PSA/Gelfoam^® group 77% of PCa patients had detectable anti-PSA T cells^25	Phase II (r): Assessment of effect of Ad5-PSA on PSADT (NCT00583024 and NCT00583752)
Sipuleucel-T	Leukopheresed patients PBMCs transduced ex vivo with PAP-GM-CSF construct (PAP2024) an then reintroduced into patients	Yes^9^,^10	Phase III:IMPACT trial: Enhanced OS over placebo group by a median of 4.1 mo^12	Phase II (a):NCT00715078^a Phase II (a):NCT00715104^b Phase II (a):NCT00901342^c Phase IIIB (a):NCT00779402^d Phase II (r):NCT01306890^e Phase II (a):NCT01487863^f Phase II (a):NCT01431391^g
GVAX-PCa	Irradiated PCa cell lines, LNCaP and PC-3, that constitutively express GM-CSF – Prime/Boosts	Yes^26^,^27	Phase I/II (×2): Safe. Enhanced median survival (for high dose boosts) over radiotherapy and low dose boosts by 8.7 mo^26 and 11.9 mo^27 respectively
GVAX-PCa + docetaxel	GVAX-PCa + docetaxel compared with docetaxel alone in PCa patients with symptomatic metastatic CRPC	No - imbalance in deaths in the combined treatment group^28	Phase III: VITAL-2:^† terminated due to safety concerns.
GVAX-PCa + ipilimumab	GVAX-PCa (described above) + dose-escalation trial anti-CTLA4 antibody	Yes^††,^29	Phase I: Safe^†† (up to 3 mg/kg ipilimumab safe and well tolerated)
DNA-PAP	Multiple intradermal vaccinations of rhGM-CSF with a plasmid (pTVG-HP) encoding PAP	Yes^30	Phase I/II: Safe. 7/22 patients had ≥2-fold increase in PSADT	●Phase II (r): Comparison of GM-CSF ± DNA-PAP (NCT01341652) ●Phase II (a): Determine safety and immunogenicity (NCT00849121)
DNA-PSA	Multiple intradermal vaccinations of GM-CSF + IL-2 with a plasmid (pVAX) encoding PSA	Yes^31	Phase I: Safe. 2/3 patients (given high dose pVax/PSA) had significantly elevated levels of PSA-specific IFNγ^+ T cells
GMCI	AdV-tk/anti-herpetic prodrug (GCV) prior to prostatectomy	Yes^32^,^33	Phase I–II: Significant influx of CD8+ T cells No improvement in patient prognoses^34
GMCI + RT	AdV-tk/anti-herpetic prodrug (GCV) prior to prostatectomy + RT	Yes^74	Phase I/II: Safe. Good locoregional control but inadequate systemic control^72	Phase III (r): Comparing disease-free survival: GMCI + RT vs. placebo (NCT01436968)

* Grade 3–4 side effects observed with 3–10 mg/kg ipilimumab (colitis and neutropenia); ^†Phase III trials (×2) with GVAX-PCa were terminated, as discussed in the main text; ^††Hypophysitis and/or sarcoid alveolitis diagnosed in patients receiving 5 mg/kg ipilimumab; ^aAims to assess CD54 upregulation with varying fusion protein (PAP2024) concentrations; ^bAims to assess the immune response within prostate tissue following the neo-adjuvant administration of sipuleucel-T (prostatectomy specimens taken after sipuleucel-T vaccinations will be compared with tissue from the core biopsy specimen obtained prior to treatment); ^cAims to evaluate the magnitude of immune responses to sipuleucel-T in patients with metastatic prostate cancer; ^dAims to determine if sipuleucel-T is effective in early stage, non-metastatic prostate cancer patients (end-point: biochemical failure); ^eAims to quantify the risk of cerebrovascular events following sipuleucel-T therapy for all subjects with CRPC; ^fAims to evaluate the impact of concurrent or sequential administration of abiraterone acetate plus prednisone on product parameters of sipuleucel-T; ^gAims to evaluate immune responses in patients with non-metastatic prostate cancer when androgen deprivation therapy is started before or after sipuleucel-T. CRPC, castration-resistant prostate cancer; GCV, ganciclovir; GMCI, gene-mediated cytotoxic immunotherapy; GM-CSF, granulocyte macrophage colony-stimulating factor; IFNγ, interferon γ; IL-2, interleukin-2; OS, overall survival; PAP, prostate acid phosphatase; PBMC, peripheral blood mononuclear cell: PSA, prostate-specific antigen; PSADT, PDA doubling time; RT, radiotherapy.

Arlen PM, Skarupa L, Pazdur M, Seetharam M, Tsang KY, Grosenbach DW, et al. Clinical safety of a viral vector based prostate cancer vaccine strategy. J Urol 2007; 178:1515 - 20; http://dx.doi.org/10.1016/j.juro.2007.05.117; PMID: 17707059

 PubMed Web of Science ®Google Scholar

DiPaola RS, Plante M, Kaufman H, Petrylak DP, Israeli R, Lattime E, et al. A phase I trial of pox PSA vaccines (PROSTVAC-VF) with B7-1, ICAM-1, and LFA-3 co-stimulatory molecules (TRICOM) in patients with prostate cancer. J Transl Med 2006; 4:1; http://dx.doi.org/10.1186/1479-5876-4-1; PMID: 16390546

 PubMed Web of Science ®Google Scholar

Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 2010; 28:1099 - 105; http://dx.doi.org/10.1200/JCO.2009.25.0597; PMID: 20100959

 PubMed Web of Science ®Google Scholar

Gulley JL, Arlen PM, Madan RA, Tsang KY, Pazdur MP, Skarupa L, et al. Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother 2010; 59:663 - 74; http://dx.doi.org/10.1007/s00262-009-0782-8; PMID: 19890632

 PubMed Web of Science ®Google Scholar

Higano C, Saad F, Somer B, Curti B, Petrylak DP, Drake CG, et al. A phase III trial of GVAX immunotherapy for prostate cancer vs docetaxel plus prednisone in asymptomatic, castration-resistant prostate cancer (CRPC). Genitourinary Cancer Symposium: Proc Am Soc Clin Oncol, 2009:Abstract # LBA150.

 Google Scholar

Arlen PM, Gulley JL, Parker C, Skarupa L, Pazdur M, Panicali D, et al. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin Cancer Res 2006; 12:1260 - 9; http://dx.doi.org/10.1158/1078-0432.CCR-05-2059; PMID: 16489082

 PubMed Web of Science ®Google Scholar

Lubaroff DM, Konety BR, Link B, Gerstbrein J, Madsen T, Shannon M, et al. Phase I clinical trial of an adenovirus/prostate-specific antigen vaccine for prostate cancer: safety and immunologic results. Clin Cancer Res 2009; 15:7375 - 80; http://dx.doi.org/10.1158/1078-0432.CCR-09-1910; PMID: 19920098

 PubMed Web of Science ®Google Scholar

Burch PA, Breen JK, Buckner JC, Gastineau DA, Kaur JA, Laus RL, et al. Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer. Clin Cancer Res 2000; 6:2175 - 82; PMID: 10873066

 PubMed Web of Science ®Google Scholar

Small EJ, Fratesi P, Reese DM, Strang G, Laus R, Peshwa MV, et al. Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol 2000; 18:3894 - 903; PMID: 11099318

 PubMed Web of Science ®Google Scholar

Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al, IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:411 - 22; http://dx.doi.org/10.1056/NEJMoa1001294; PMID: 20818862

 PubMed Web of Science ®Google Scholar

Small EJ, Sacks N, Nemunaitis J, Urba WJ, Dula E, Centeno AS, et al. Granulocyte macrophage colony-stimulating factor--secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer. Clin Cancer Res 2007; 13:3883 - 91; http://dx.doi.org/10.1158/1078-0432.CCR-06-2937; PMID: 17606721

 PubMed Web of Science ®Google Scholar

Higano CS, Corman JM, Smith DC, Centeno AS, Steidle CP, Gittleman M, et al. Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer. Cancer 2008; 113:975 - 84; http://dx.doi.org/10.1002/cncr.23669; PMID: 18646045

 PubMed Web of Science ®Google Scholar

Small EJDT, Gerritsen WR, et al. A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC). 2009 Genitourinary Cancers Symposium (ASCO Annual Meeting Abstracts)2009:LBA150.

 Google Scholar

van den Eertwegh AJ, Versluis J, van den Berg HP, Santegoets SJ, van Moorselaar RJ, van der Sluis TM, et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13:509 - 17; http://dx.doi.org/10.1016/S1470-2045(12)70007-4; PMID: 22326922

 PubMed Web of Science ®Google Scholar

McNeel DG, Dunphy EJ, Davies JG, Frye TP, Johnson LE, Staab MJ, et al. Safety and immunological efficacy of a DNA vaccine encoding prostatic acid phosphatase in patients with stage D0 prostate cancer. J Clin Oncol 2009; 27:4047 - 54; http://dx.doi.org/10.1200/JCO.2008.19.9968; PMID: 19636017

 PubMed Web of Science ®Google Scholar

Pavlenko M, Roos AK, Lundqvist A, Palmborg A, Miller AM, Ozenci V, et al. A phase I trial of DNA vaccination with a plasmid expressing prostate-specific antigen in patients with hormone-refractory prostate cancer. Br J Cancer 2004; 91:688 - 94; PMID: 15280930

 PubMed Web of Science ®Google Scholar

Herman JR, Adler HL, Aguilar-Cordova E, Rojas-Martinez A, Woo S, Timme TL, et al. In situ gene therapy for adenocarcinoma of the prostate: a phase I clinical trial. Hum Gene Ther 1999; 10:1239 - 49; http://dx.doi.org/10.1089/10430349950018229; PMID: 10340555

 PubMed Web of Science ®Google Scholar

Miles BJ, Shalev M, Aguilar-Cordova E, Timme TL, Lee HM, Yang G, et al. Prostate-specific antigen response and systemic T cell activation after in situ gene therapy in prostate cancer patients failing radiotherapy. Hum Gene Ther 2001; 12:1955 - 67; http://dx.doi.org/10.1089/104303401753204535; PMID: 11686937

 PubMed Web of Science ®Google Scholar

Ayala G, Satoh T, Li R, Shalev M, Gdor Y, Aguilar-Cordova E, et al. Biological response determinants in HSV-tk + ganciclovir gene therapy for prostate cancer. Mol Ther 2006; 13:716 - 28; http://dx.doi.org/10.1016/j.ymthe.2005.11.022; PMID: 16480930

 PubMed Web of Science ®Google Scholar

Teh BS, Aguilar-Cordova E, Kernen K, Chou CC, Shalev M, Vlachaki MT, et al. Phase I/II trial evaluating combined radiotherapy and in situ gene therapy with or without hormonal therapy in the treatment of prostate cancer--a preliminary report. Int J Radiat Oncol Biol Phys 2001; 51:605 - 13; http://dx.doi.org/10.1016/S0360-3016(01)01692-3; PMID: 11597799

 PubMed Web of Science ®Google Scholar

Teh BS, Ayala G, Aguilar L, Mai WY, Timme TL, Vlachaki MT, et al. Phase I-II trial evaluating combined intensity-modulated radiotherapy and in situ gene therapy with or without hormonal therapy in treatment of prostate cancer-interim report on PSA response and biopsy data. Int J Radiat Oncol Biol Phys 2004; 58:1520 - 9; http://dx.doi.org/10.1016/j.ijrobp.2003.09.083; PMID: 15050332

 PubMed Web of Science ®Google Scholar