Adoptive cellular therapy with tumor vaccine draining lymph node lymphocytes after vaccination with HLA-B7/β2-microglobulin gene-modified autologous tumor cells

Sybren L. Meijer, Annemieke Dols, Walter J. Urba, Hong Ming Hu, John W. Smith, John Vetto, William Wood, Teri Doran, Yiwei Chu, Philip Sayaharuban, W. Gregory Alvord, Bernard A. Fox

    Research output: Contribution to journalArticle

    28 Citations (Scopus)

    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 β2-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 × 107 and 60 × 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.

    Original languageEnglish (US)
    Pages (from-to)359-372
    Number of pages14
    JournalJournal of Immunotherapy
    Volume25
    Issue number4
    DOIs
    StatePublished - 2002

    Fingerprint

    HLA-B7 Antigen
    Cancer Vaccines
    Vaccination
    Lymph Nodes
    Lymphocytes
    Genes
    Neoplasms
    Therapeutics
    Interleukin-2
    Adoptive Immunotherapy
    Isoantigens
    Renal Cell Carcinoma
    Melanoma
    Vaccines
    Adoptive Transfer

    Keywords

    • Adoptive immunotherapy
    • Melanoma
    • Renal cell cancer
    • Tumor vaccine

    ASJC Scopus subject areas

    • Cancer Research
    • Pharmacology
    • Immunology

    Cite this

    Adoptive cellular therapy with tumor vaccine draining lymph node lymphocytes after vaccination with HLA-B7/β2-microglobulin gene-modified autologous tumor cells. / Meijer, Sybren L.; Dols, Annemieke; Urba, Walter J.; Hu, Hong Ming; Smith, John W.; Vetto, John; Wood, William; Doran, Teri; Chu, Yiwei; Sayaharuban, Philip; Alvord, W. Gregory; Fox, Bernard A.

    In: Journal of Immunotherapy, Vol. 25, No. 4, 2002, p. 359-372.

    Research output: Contribution to journalArticle

    Meijer, Sybren L. ; Dols, Annemieke ; Urba, Walter J. ; Hu, Hong Ming ; Smith, John W. ; Vetto, John ; Wood, William ; Doran, Teri ; Chu, Yiwei ; Sayaharuban, Philip ; Alvord, W. Gregory ; Fox, Bernard A. / Adoptive cellular therapy with tumor vaccine draining lymph node lymphocytes after vaccination with HLA-B7/β2-microglobulin gene-modified autologous tumor cells. In: Journal of Immunotherapy. 2002 ; Vol. 25, No. 4. pp. 359-372.
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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 β2-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 × 107 and 60 × 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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    AU - Urba, Walter J.

    AU - Hu, Hong Ming

    AU - Smith, John W.

    AU - Vetto, John

    AU - Wood, William

    AU - Doran, Teri

    AU - Chu, Yiwei

    AU - Sayaharuban, Philip

    AU - Alvord, W. Gregory

    AU - Fox, Bernard A.

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    AB - 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 β2-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 × 107 and 60 × 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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