Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study.
Despite novel targeted agents, prognosis of metastatic renal cell cancer (RCC) remains poor, and experimental therapeutic strategies are warranted. Transfection of tumor cells with co-stimulatory molecules and/or cytokines is able to increase immunogenicity. Therefore, in our clinical study, 10 human leukocyte antigen (HLA)-A(*)0201(+) patients with histologically-confirmed progressive metastatic clear cell RCC were immunized repetitively over 22 weeks with 2.5-40 × 10(6) interleukin (IL)-7/CD80 cotransfected allogeneic HLA-A(*)0201(+) tumor cells (RCC26/IL-7/CD80). Endpoints of the study were feasibility, safety, immunological and clinical responses. Vaccination was feasible and safe. In all, 50% of the patients showed stable disease throughout the study; the median time to progression was 18 weeks. However, vaccination with allogeneic RCC26/IL-7/CD80 tumor cells was not able to induce TH1-polarized immune responses. A TH2 cytokine profile with increasing amounts of antigen-specific IL-10 secretion was observed in most of the responding patients. Interferon-γ secretion by patient lymphocytes upon antigen-specific and non-specific stimulation was substantially impaired, both before and during vaccination, as compared with healthy controls. This is possibly due to profound tumor-induced immunosuppression, which may prevent induction of antitumor immune responses by the gene-modified vaccine. Vaccination in minimal residual disease with concurrent depletion of regulatory cells might be one strategy to overcome this limitation.
Department of Hematology, Oncology and Tumor Immunology, Charité-University Medicine Berlin, Campus Virchow-Klinikum and Campus Berlin-Buch, Berlin, Germany. joerg.westermann@charite.de
J
J
Westermann
A
A
Flörcken
G
G
Willimsky
A
A
van Lessen
J
J
Kopp
A
A
Takvorian
K
K
Jöhrens
A
A
Lukowsky
C
C
Schönemann
B
B
Sawitzki
H
H
Pohla
R
R
Frank
B
B
Dörken
D J
DJ
Schendel
T
T
Blankenstein
A
A
Pezzutto
D000328:Adult; D000368:Aged; D018122:B7-1 Antigen / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D006680:HLA Antigens / Q000032:analysis; D006801:Humans; D015851:Interleukin-7 / Q000276:immunology*; D007680:Kidney Neoplasms / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
D018122:B7-1 Antigen; D019496:Cancer Vaccines; D006680:HLA Antigens; D015851:Interleukin-7