Phase I study of autologous tumor vaccines transduced with the GM-CSF gene in four patients with stage IV renal cell cancer in Japan: clinical and immunological findings.

Abstract

We produced lethally irradiated retrovirally GM-CSF-transduced autologous renal tumor cell vaccines (GVAX) from six Japanese patients with stage IV renal cell cancer (RCC). Four patients received GVAX ranging from 1.4 x 10(8) to 3.7 x 10(8) cells on 6-17 occasions. Throughout a total of 48 vaccinations, there were no severe adverse events. After vaccination, DTH skin tests became positive to autologous RCC (auto-RCC) in all patients. The vaccination sites showed significant infiltration by CD4(+) T cells, eosinophils, and HLA-DR-positive cells. The kinetic analyses of cellular immune responses using peripheral blood lymphocytes revealed an enhanced proliferative response against auto-RCC in four patients, and cytotoxicity against auto-RCC was augmented in three patients. T cell receptor beta-chain analysis revealed oligoclonal expansion of T cells in the peripheral blood, skin biopsy specimens from DTH sites, and tumors. Western blot analysis demonstrated the induction of a humoral immune response against auto-RCC. Two of the four patients are currently alive 58 and 40 months after the initial vaccination with low-dose interleukin-2. Our results suggest that GVAX substantially enhanced the antitumor cellular and humoral immune responses, which might have contributed to the relatively long survival times of our patients in the present study.

• Authors: Kenzaburo Tani, Miyuki Azuma, Yukoh Nakazaki, Naoki Oyaizu, Hidenori Hase, Junko Ohata, Keisuke Takahashi, Maki OiwaMonna, Kisaburo Hanazawa, Yoshiaki Wakumoto, Kouji Kawai, Masayuki Noguchi, Yasushi Soda, Reiko Kunisaki, Kiyoshi Watari, Satoshi Takahashi, Utako Machida, Noriharu Satoh, Arinobu Tojo, Taira Maekawa, Masazumi Eriguchi, Shinji Tomikawa, Hideaki Tahara, Yusuke Inoue, Hiroki Yoshikawa, Yoshitsugu Yamada, Aikichi Iwamoto, Hirofumi Hamada, Naohide Yamashita, Koh Okumura, Tadao Kakizoe, Hideyuki Akaza, Makoto Fujime, Shirley Clift, Dale Ando, Richard Mulligan, Shigetaka Asano
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 10 Issue 4 Pg. 799-816 (Oct 2004) ISSN: 1525-0016 [Print] United States
• PMID: 15451464 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antigens, CD
• Cancer Vaccines
• Cytokines
• HLA-DR Antigens
• Receptors, Antigen, T-Cell, alpha-beta
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Aged
• Antigens, CD (analysis)
• CD4-CD8 Ratio
• Cancer Vaccines (adverse effects, genetics, therapeutic use)
• Carcinoma, Renal Cell (immunology, metabolism, therapy)
• Cytokines (immunology)
• Female
• Granulocyte-Macrophage Colony-Stimulating Factor (genetics)
• HLA-DR Antigens (analysis)
• Humans
• Kidney Neoplasms (immunology, pathology, therapy)
• Lung Neoplasms (secondary)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Male
• Middle Aged
• Neoplasm Staging
• Receptors, Antigen, T-Cell, alpha-beta (analysis)
• Skin Tests
• Transduction, Genetic
• Vaccination (methods)