Adoptive cellular therapy with tumor vaccine draining lymph node lymphocytes after vaccination with HLA-B7/beta2-microglobulin gene-modified autologous tumor cells.
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| Abstract |
Adoptive immunotherapy with anti-CD3-expanded lymphocytes from lymph nodes draining alloantigen gene-modified autologous tumor vaccines is an effective treatment of poorly immunogenic murine tumors. This phase I/II study was performed to determine the feasibility and toxicity of combining ex vivo gene transfer of autologous tumor cells and adoptive immunotherapy with anti-CD3-expanded tumor vaccine draining lymph node lymphocytes (TVDLN) in patients with metastatic melanoma and renal cell cancer (RCC). To facilitate the generation of tumor-specific lymphocytes in the TVDLN, autologous tumor cells were modified by gene transfer ex vivo to express the alloantigen HLA-B7, a modification that has the potential to enhance the immunogenicity of the tumor cells. After vaccination with gene-modified tumor cells, patients' lymph nodes were harvested; TVDLN lymphocytes were activated and expanded ex vivo with anti-CD3 and interleukin-2 (IL-2), and adoptively transferred to patients in combination with systemic IL-2. Twenty patients, nine with melanoma and 11 with RCC were treated. Tumor was harvested successfully in all 20 patients. Ex vivo gene transfer was performed using lipofection with a lipid: DNA plasmid complex containing the genes for HLA-B7 and beta2-microglobulin. The mean expression of HLA-B7 by autologous tumor cells after gene transfer was 4.53% (range 0.3%-12.1%). Lymph nodes were harvested from all 20 patients with a mean of 53 x 107 and 60 x 107 cells obtained from the gene-modified and unmodified tumor vaccine sites, respectively. Successful expansion of adequate TVDLN was accomplished in 19 of 20 harvests of unmodified vaccines and in 18 of 20 gene-modified vaccines. No major toxicities were noted after vaccination with autologous tumor cells or adoptive transfer of ex vivo activated TVDLN lymphocytes. Typical IL-2-related toxicities were observed in all patients. No objective tumor regressions were observed. MHC class I restricted, tumor-specific cytokine secretion was observed in lymphocytes from TVDLN and the peripheral blood of vaccinated patients.
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| Authors | Sybren L Meijer, Annemieke Dols, Walter J Urba, Hong-Ming Hu, John W Smith II, John Vetto, William Wood, Teri Doran, Yiwei Chu, Philip Sayaharuban, W Gregory Alvord, Bernard A Fox |
| Journal | Journal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) 2002 Jul-Aug Vol. 25 Issue 4 Pg. 359-72 ISSN: 1524-9557 [Print] United States |
| PMID | 12142559 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.) |
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