Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic, castration-resistant prostate cancer

Abstract

PurposeWe conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms.Experimental designTwenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 × 107 dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis.ResultsNo serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13–0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17–0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS.ConclusionsIn patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in longer than expected survival. Concomitant chemotherapy did not preclude the induction of specific anti-tumor cytotoxic T cells.

Trial watch: Dendritic cell-based anticancer immunotherapy

“…1) involved autologous DCs exposed to autologous tumor-derived RNA, 196 tumor-cell lysates, [197][198][199][200][201][202][203] autologous tumor stem cell lysates, 204 self-renewing and proliferating autologous tumor cells, 205 allogeneic cancer cell line lysates, [206][207][208] TAAs or TAA-derived peptides [209][210][211][212][213][214][215][216][217][218] or a combination thereof. 219 Most clinical studies based on the latter approach preferred melanoma-associated differentiation antigens including premelanosome protein (PMEL; also known as gp100), antigens belonging to the melanoma antigen gene (MAGE) family, tyrosinase (TYR) and Melan-A (MLANA; also known as MART1) (Fig.…”

“…230 Regarding the distribution across different cancer types ( Fig. 1), patients harboring melanoma were most commonly enrolled in these trials, 186,196,198,205,213,221,223,227,[231][232][233][234] followed by patients with prostate cancer, 206,208,212,215 glioma or glioblastoma (GBM), 185,197,202,219 hepatocellular carcinoma, 204,211,220 non-small cell lung carcinoma (NSCLC), 207,214,230 renal cell carcinoma (RCC), 201,203 esophageal carcinoma, 216,226 and pancreatic ductal adenocarcinoma, 209,217 among others. Of note, only two trials included a wide range of advanced solid tumors refractory to previous treatments.…”

Caspase-2 and oxidative stress underlie the immunogenic potential of high hydrostatic pressure-induced cancer cell death

“…20 We have initiated multiple clinical trials for prostate, ovarian and lung cancer evaluating the potential of DCs loaded with HHP treated cancer cells to induce tumor cell-specific immune responses. 20,27 Nevertheless, HHP-treated cancer cells were utilized so far solely for pulsing of ex vivo cultured DCs but their direct use to induce antitumor immunity has not been validated. Here, we show in two different mouse tumor models that HHP-treated tumor cells evoke protective immune memory response when s.c. injected per se, i.e., without any adjuvant.…”

Immunotherapy for genitourinary cancer

“…This ongoing study randomized 1298 patients to receive or not PROSTVAC as the first-line treatment of patients with asymptomatic or minimally symptomatic mCRPC. DCVAC/PCa is manufactured by autologous mature DCs pulsed with killed LNCaP prostate cancer cells [138]. This vaccine was investigated in combination with docetaxel in a phase I/II trial in mCRPC patients.…”