Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma - PubMed (original) (raw)

Clinical Trial

Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma

Ying Waeckerle-Men et al. Cancer Immunol Immunother. 2006 Dec.

Abstract

Background: Dendritic cell (DC)-based immunotherapy is a promising approach to augment tumor antigen-specific T cell responses in cancer patients. However, tumor escape with down-regulation or complete loss of target antigens may limit the susceptibility of tumor cells to the immune attack. Concomitant generation of T cell responses against several immunodominant antigens may circumvent this potential drawback. In this trial, we determined the immunostimulatory capacity of autologous DC pulsed with multiple T cell epitopes derived from four different prostate-specific antigens in patients with advanced hormone-refractory prostate cancer.

Patients and methods: Autologous DC of HLA-A*0201(+) patients with hormone-refractory prostate cancer were loaded with antigenic peptides derived from prostate stem cell antigen (PSCA(14-22)), prostatic acid phosphatase (PAP(299-307)), prostate-specific membrane antigen (PSMA(4-12)), and prostate-specific antigen (PSA(154-163)). DC were intradermally applied six times at biweekly intervals followed-in the case of an enhanced immune response-by monthly booster injections. Immune monitoring during the time of ongoing vaccinations (12-59 weeks) included ex vivo ELISPOT measurements, MHC tetramer analysis and in vitro cytotoxicity assays.

Results: Of the initial six patients, three qualified for long-term multi-epitope DC vaccination. This regime was tolerated well by all three patients. The vaccination elicited significant cytotoxic T cell responses against all prostate-specific antigens tested. In addition, memory T cell responses against the control peptides derived from influenza matrix protein and tetanus toxoid were efficiently boosted. Clinically, the long-term DC vaccination was associated with an increase in PSA doubling time.

Conclusions: DC-based multi-epitope immunotherapy with repeated boosting in men with hormone-refractory prostate carcinoma is feasible and generates efficient cellular antitumor responses.

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Figures

Fig. 1

Fig. 1

Phenotype of DC generated from PBMC of patients with hormone-refractory prostate carcinoma. a Representative surface molecule expression pattern of mature DC from P12. DC were collected after 48 h activation with proinflammatory cytokines and stained with the indicated mAbs for phenotypic analysis with flow cytometry (filled histograms), respectively. Open line histograms represent stainings with isotype matched control antibodies. b In vitro migration capacity of matured DC. Matured DC were tested for CCR7-dependent migration towards CCL19 (dark gray bars) and CCL21 (light gray bars). Medium without cytokines was used to record spontaneous migration (open bars). The percentage of migrated DC was calculated as the mean±SEM of duplicate measurements

Fig. 2

Fig. 2

T cell responses of three patients (P04, P12, and P16) to prostate and control antigens as determined by ELISPOT analysis. ELISPOT assays were performed with PBMC obtained at the time points indicated within the panels. Shown are the number of spots per 106 PBMC obtained in the presence of indicated peptides PSCA14–22 (PSCA), PAP299–307 (PAP), PSMA4–12 (PSMA), PSA154–163 (PSA), influenza matrix58–66 (Flu) or tetanus toxoid (TT) after subtraction of the number of spots obtained with the same PBMC in the absence of antigen. The values represent the mean of duplicates±SEM

Fig. 3

Fig. 3

In vitro restimulation of antigen-specific CTL obtained from patients after the eighth vaccination and assessment of functional activity. a MHC class I peptide-multimer staining after in vitro restimulation of PBMC of the indicated vaccinated patients. PBMC were restimulated for 7 days with FluM or PSCA peptides, respectively. Values in the upper right quadrant of the dot plot indicate the percentage of multimer-binding CD8+ lymphocytes. The data represent one of three independent experiments with similar results. b Cytotoxic activity of FluM and PSCA-specific CTL, which were stimulated as described in a, was determined in 51Cr release assays using T2 cells as peptide-labeled (closed symbols) or unpulsed (open symbols) target cells. c Cytotoxicity of PSCA-specific CTL to human prostate carcinoma cells. PSCA-specific CTL obtained in two vaccinated patients after one cycle of in vitro restimulation as described in a were tested for their ability to lyse human prostate carcinoma cell lines LNCaP (HLA-A*0201 + and PSCA +) or PC3 (HLA-A*0201 − and PSCA +). LNCaP and PC3 cells were either pulsed with exogenous PSCA or control peptide Flu (for LNCaP only), or were left without peptide pulse. Experiments were performed at an effector/target cell ratio of 30:1. Pooled data from two independent experiments are represented as mean±SEM

Fig. 4

Fig. 4

Clinical responses in DC vaccinated patients determined by serial PSA measurements. Linear regression of log-transformed PSA values was used to determine the slopes. PSADT was calculated as indicated in Patients, materials and methods. Arrows indicate time point of vaccination

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References

    1. Jones GW, Mettlin C, Murphy GP, Guinan P, Herr HW, Hussey DH, Chmiel JS, Fremgen AM, Clive RE, Zuber-Ocwieja KE. Patterns of care for carcinoma of the prostate gland: results of a national survey of 1984 and 1990. J Am Coll Surg. 1995;180:545–554. - PubMed
    1. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–1512. doi: 10.1056/NEJMoa040720. - DOI - PubMed
    1. Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513–1520. doi: 10.1056/NEJMoa041318. - DOI - PubMed
    1. Markiewicz M, Kast WM. Advances in immunotherapy for prostate cancer. Adv Cancer Res. 2003;87:159–194. doi: 10.1016/S0065-230X(03)87297-4. - DOI - PubMed
    1. Tjoa BA, Simmons SJ, Elgamal A, Rogers M, Ragde H, Kenny GM, Troychak MJ, Boynton AL, Murphy GP. Follow-up evaluation of a phase II prostate cancer vaccine trial. Prostate. 1999;40:125–129. doi: 10.1002/(SICI)1097-0045(19990701)40:2<125::AID-PROS8>3.0.CO;2-Y. - DOI - PubMed

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