T cell immunity to lymphoma following treatment with anti-CD40 monoclonal antibody.
In this study we demonstrate that treatment with anti-CD40 mAb eradicates a range of mouse lymphomas (BCL(1), A31, A20, and EL4), but only when used against i.v. tumor doses in excess of 10(7) cells. Only partial protection was seen against smaller tumor loads. We saw no evidence that anti-CD40 mAb changed the phenotype of the lymphomas or inhibited their growth in the initial period following treatment, but it did result in a rapid expansion of cytotoxic CD8(+) cells that was able to clear the neoplastic disease and provide long-term protection against tumor rechallenge. The CTL responses were blocked by mAb against a range of coreceptors and cytokines, including CD8, B7-1, B7-2, LFA-1, and IFN-gamma, but not CD4 or CTLA-4, indicating the presence of a conventional cellular Th1 response. Furthermore, we found evidence of cross-recognition between lymphomas (BCL(1) and A20) as measured by cytotoxicity and IFN-gamma responses in vitro and using tumor rechallenge experiments, suggesting common target Ags. Finally, although anti-CD40 was shown to stimulate NK cell killing, we could find no role for these cells in controlling tumor growth. These data underline the ability of anti-CD40 mAb to potentiate CTL responses and the potency of cellular immunity in eradicating large quantities of syngeneic tumor.
Tutt
Alison L
AL
Tenovus Research Laboratory, Cancer Sciences Division, University School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
O'Brien
Lyn
L
Hussain
Akmal
A
Crowther
Graham R
GR
French
Ruth R
RR
Glennie
Martin J
MJ
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D007113:Immunity, Innate; D007275:Injections, Intravenous; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D013601:T-Lymphocytes / Q000276:immunology*; D013945:Thymoma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D014407:Tumor Cells, Cultured
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019013:CD40 Antigens