Clinical and immunologic effects of intranodal autologous tumor lysate-dendritic cell vaccine with Aldesleukin (Interleukin 2) and IFN-{alpha}2a therapy in metastatic renal cell carcinoma patients

Abstract

Purpose: To evaluate the clinical and immunologic outcomes of DC (dendritic cell) vaccine with interleukin (IL)-2 and IFN-alpha 2a in metastatic renal cell carcinoma patients.

Experimental design: Eighteen consented and eligible patients were treated. Peripheral blood monocytes were cultured ex vivo into mature DCs and loaded with autologous tumor lysate. Treatment consisted of five cycles of intranodal vaccination of DCs (1 x 10(7) cells/1 mL Lactated Ringer's solution), 5-day continuous i.v. infusion of IL-2 (18MiU/m2), and three s.c. injections of IFN-alpha 2a (6MiU) every other day. Response Evaluation Criteria in Solid Tumors criteria were used for disease assessment. Correlative immunologic end points included peripheral blood lymphocyte cell phenotype and function as well as peripheral blood anti-renal cell carcinoma antibody and cytokine levels.

Results: All patients received between two and five treatment cycles. Toxicities consisted of known and expected cytokine side effects. Overall objective clinical response rate was 50% with three complete responses. Median time to progression for all patients was 8 months, and median survival has not been reached (median follow up of 37+ months). Treatment-related changes in correlative immunologic end points were noted and the level of circulating CD4(+) T regulatory cells had a strong association with outcome. Pre-IP-10 serum levels approached significance for predicting outcome.

Conclusions: The clinical and immunologic responses observed in this trial suggest an interaction between DC vaccination and cytokine therapy. Our data support the hypothesis that modulation of inflammatory, regulatory, and angiogenic pathways are necessary to optimize therapeutic benefit in renal cell carcinoma patients. Further exploration of this approach is warranted.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Figures

Fig. 1

Overall and progression free survival: PFS: , OS; , PFS.

Fig. 2

Treatment effect on lymphocyte cell populations in the peripheral blood: A, CD3, CD4, CD8, and natural killer (CD3-CD56+) cells as percentage of peripheral blood lymphocytes. B, IP-10 serum levels before and after therapy for all patients (n = 8) and prelevels for responding patients (R; n = 4) and nonresponding patients (NR; n = 4). C, CD4+ IL4+ T Cells (TH2) as a percentage of CD3+ lymphocytes for all patients ( ), nonresponders (■), and responding patients (□).

Fig. 3

A, Treg cell functional assay (n = 6); left, results of a proliferation assay to quantify suppression of CD4 proliferation by Treg. Right, compares functional suppression in the responding patients (□) and nonresponding patients . B, percentage of Treg(CD4+CD25+FoxP3+) in the peripheral blood lymphocyte population before and after treatment. C, comparison of the percentage of circulating Treg cells in the lymphocyte and CD3+ cell population for responding (□) and nonresponding patients (■) before and after treatment.