Androgen blockade enhances response to melanoma vaccine.
BACKGROUND
Because preclinical studies suggest an interaction between androgens and the immune system, we used a murine model to determine whether androgen blockade with flutamide might enhance the immunogenicity of an irradiated melanoma cell vaccine.


METHODS
Forty C57BL/6 male mice were randomly assigned to four treatment groups: flutamide + RPMI (Group A), flutamide + irradiated B16 murine melanoma cells (Group B), placebo + RPMI (Group C), and placebo + irradiated B16 cells (Group D). Splenocyte proliferation and secretion of interleukin-2 and interferon-gamma were assayed after coculturing splenocytes with irradiated B16 cells. Antibody-dependent cellular cytotoxicity (ADCC) against B16 cells was determined using peripheral blood lymphocytes. To examine the effect of treatment on tumor growth, a second set of 40 mice assigned to Groups A, B, C, and D underwent tumor challenge 7 days after the last treatment.


RESULTS
Splenocyte proliferation was significantly higher in the two groups receiving flutamide at 50 mg/kg x 7 days (29% in Groups A and B vs 3% in Group C and 7% in Group D). Secretion of interferon was significantly higher in mice receiving flutamide + irradiated B16 cells (15.2 pg/ml in Group B vs 0, 1.7, and 4 pg/ml in Groups A, C, and D, respectively; P = 0.0024). Differences in interleukin secretion were not significant. ADCC was 26% in Group B vs 15, 8, and 22% in Groups A, C, and D, respectively (P = 0.0001). In the tumor challenge experiment, the rate of survival was 10% higher in mice receiving irradiated B16 + flutamide than in mice receiving irradiated B16 alone.


CONCLUSIONS
Flutamide can enhance immune responses to an irradiated whole-cell melanoma vaccine. A clinical study of immunotherapeutic androgen blockade is warranted.
Hsueh
Eddy C
EC
Department of Surgical Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA. hsuehe@jwci.org
Gupta
Rishab K
RK
Lefor
Alan
A
Reyzin
Gary
G
Ye
Wei
W
Morton
Donald L
DL
D000726:Androgen Antagonists / Q000627:therapeutic use*; D000818:Animals; D019496:Cancer Vaccines / Q000627:therapeutic use*; D004357:Drug Synergism; D005485:Flutamide / Q000627:therapeutic use*; D016233:Immunotherapy, Active; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011897:Random Allocation; D013154:Spleen / Q000166:cytology / Q000276:immunology
D000726:Androgen Antagonists; D019496:Cancer Vaccines; D007376:Interleukin-2; D005485:Flutamide; D007371:Interferon-gamma