A Phase I clinical trial of immunotherapy with interferon-gamma gene-modified autologous melanoma cells: monitoring the humoral immune response.
BACKGROUND
Tumor cells transduced with cytokine genes provide immunogenic vaccines for cancer immunotherapy.


METHODS
A Phase I clinical trial was conducted for the specific active immunization of melanoma patients with interferon-gamma (IFN-gamma) gene-modified autologous melanoma tumor cells. Short term melanoma cultures were transduced retrovirally with the gene for human IFN-gamma. The genetically modified melanoma cells secreted biologically active IFN-gamma and showed enhanced expression of major histocompatibility complex class I and class II surface antigens. These cells were inactivated by irradiation (50 gray) and were cryopreserved for the vaccine. Twenty melanoma patients were enrolled in this clinical trial. The immunizations were administered in escalating doses once every 2 weeks for 3 months. The first and second injections consisted of 2 million cells, followed by 6 million for the third and fourth injections, and then 18 million for the fifth and sixth injections. The humoral immune responses of the patients were assessed by enzyme-linked immunoadsorbent assay, radioimmunoassay, and radioimmunoprecipitation.


RESULTS
Thirteen of the 20 patients completed the immunization protocol. Eight of these 13 patients showed a humoral immunoglobulin (Ig)G response against autologous and allogeneic melanoma cells. The other five patients either had no detectable antimelanoma antibodies or showed a weak IgG response that did not rise significantly above the preimmune level. All the sera contained low or undetectable levels of antimelanoma IgM antibodies. The IgG response increased progressively in titer during the course of immunization. The positive sera showed preferentially strong binding to melanoma cell lines and some cross-reactivity to nonmelanoma tumors. A 75-80 kD antigen on melanoma cells was immunoprecipitated by postimmune sera of 3 of the responding patients. Preimmune sera from these three patients and sera from other patients immunized with a standard nontransduced melanoma cell vaccine failed to precipitate this antigen. Two patients with significant increases in serum IgG had clinical tumor regression, and two additional patients with low serum IgG response had transient shrinkage of nodular disease during therapy.


CONCLUSIONS
These data suggest that gene therapy with IFN-gamma-transduced melanoma cells is safe and worthy of further investigation in patients with less advanced stage malignant melanoma. The ability to monitor changes in the humoral responses of the immunized patients has been demonstrated.
Abdel-Wahab
Z
Z
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Weltz
C
C
Hester
D
D
Pickett
N
N
Vervaert
C
C
Barber
J R
JR
Jolly
D
D
Seigler
H F
HF
D019496:Cancer Vaccines; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis*; D016233:Immunotherapy, Active; D007371:Interferon-gamma / Q000235:genetics*; D008285:Major Histocompatibility Complex / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D011863:Radioimmunoassay; D015531:Radioimmunoprecipitation Assay; D012074:Remission Induction
D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D007371:Interferon-gamma