A Pilot Trial of Tumor Lysate-Loaded Dendritic Cells for the Treatment of Metastatic Renal Cell Carcinoma

Abstract

Cultured tumor lysate-loaded dendritic cells (TuLy-DC) have been demonstrated in vitro to stimulate potent immune modulations and generate significant antitumor response. We report the results of a pilot trial of TuLy-DC vaccine for patients with metastatic renal cell carcinoma (mRCC). Fourteen mRCC patients underwent nephrectomy to obtain autologous TuLy prepared by subjecting tumor cells to 3 freeze/thaw cycles. Dendritic cells were generated from peripheral blood CD14+ precursors cultured in the presence of GM-CSF, IL-4, and 10% autologous serum. Patients received one vaccination of TuLy alone as an immunologic control, followed by 3 weekly vaccinations of DC-TuLy injected intradermally in the midaxillary region. Peripheral blood lymphocytes were collected before and after weekly vaccines and were assessed for changes in phenotype, cytotoxicity, and cytokine profile. The TuLy-DC vaccine was successfully prepared and administered to 12 patients, whereas 2 patients did not receive vaccine treatment due to declines in postoperative performance status. The vaccines were well tolerated, with only grade 1 toxicities noted. One patient had a partial response to treatment that did not correspond to any significant change in immunologic profile. This pilot trial demonstrated both the safety and feasibility of reliably preparing a DC-based vaccine for mRCC patients. Our data suggest that autologous TuLy-DC vaccines generate only limited clinical response. Further clinical studies are needed to identify the most potent treatment regimen that can consistently mediate an antitumor immune response in vivo.

Generation of RAGE‐1 and MAGE‐9 peptide‐specific cytotoxic T‐Lymphocyte lines for transfer in patients with renal cell carcinoma

“…36,[39][40][41][42]45 So far, few RCC-associated antigens are known and have been clinically evaluated. 46,[48][49][50][51] We discovered by SSH that MAGE-9, originally described by De Plaen et al, 73 is also expressed in RCC 52 and have explored here its potential as an additional therapeutic target for RCC.…”

“…[36][37][38][39] Vaccination-induced remissions and an increase in the 5-year survival rate to 70% have been observed. [40][41][42] Application of tumor antigen cDNA 43 or of DC transduced with tumor antigen mRNA or cDNA 44,45 has been reported also to improve survival time, albeit to a minor degree. For antigen-specific vaccination in RCC, 46,47 so far MUC1, HSP96 and MN/CAIX have been used.…”

Therapeutic approaches in metastatic renal cell carcinoma

“…In another study, DC vaccination was associated with stable disease in 71% of 22 patients, with a duration of up to 19 months, with three (14%) having an objective response. The median time to progression was 5.7 months [113][114][115]. Thus these results are within the range of monotherapeutic approaches with other immunotherapeutic agents.…”

“…Thus these results are within the range of monotherapeutic approaches with other immunotherapeutic agents. Cultured tumour lysate-loaded DC vaccines also generated only a limited clinical response [113][114][115][116]. Further results should be awaited before this therapeutic approach can be recommended for the standard treatment of patients with metastases and a low tumour burden.…”

Immunotargeting of Melanoma

“…Human DCs are generated by isolation of immature DCs from blood (Fong et al, 2000) and differentiation ex vivo in the presence of IL-4 and GM-CSF, myeloid progenitor cells (CD34 +) or monocytes (CD14 +) (Sallusto et al, 1994). Obtained immature DCs can be pulsed with tumor cell lysates (Nair SK et al 1997) or synthetic peptides (Gitlitz et al, 2003), modified with genes encoding tumor antigens or tumor cells RNA (Ashley et al, 1997). For immunization are also used hybrids of DCs with tumor cells (Avigan et al, 2004).…”