Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma.
OBJECTIVE
Eradication of post-treatment residual myeloma cells is needed to prevent relapses, and immunostimulatory monoclonal antibodies (mAb) such as anti-CD137, CTLA-4, CD40, etc., which enhance the immune response against malignancies, represent a means of achieving this purpose. This study explores anti-CD137 mAbs for multiple myeloma treatment in preclinical models of the disease because they safely augment tumor immunity and are in clinical trials for other cancers.


METHODS
The antitumor effect of anti-CD137 mAb on mouse plasmacytomas derived from HOPC and NS0 cell lines was studied and compared with that of anti-CTLA-4, anti-CD40, and anti-ICAM-2 mAbs. The antitumor effect of anti-CD137 mAb was also examined in a mouse syngeneic disseminated myeloma (5TGM1) model, which more closely resembles human multiple myeloma. Depletions of specific cell populations and gene-targeted mice were used to unravel the requirements for tumor rejection.


RESULTS
Agonistic mAb against CD137 and blocking anti-CTLA-4 mAb showed activity against i.p. HOPC tumors, resulting in extended survival of mice that also became immune to rechallenge. Anti-CD137 mAbs induced complete eradications of established s.c. NS0-derived tumors that were dependent on IFN-gamma, natural killer cells, and CD8(+) T lymphocytes. Natural killer cells accumulated in tumor draining lymph nodes and showed increased IFN-gamma production. Antitumor efficacy of anti-CD137 mAb was preserved in CD28-deficient mice despite the fact that CD28 signaling increases the expression of CD137 on CD8(+) T cells. Importantly, anti-CD137 mAb treatment significantly decreased systemic tumor burden in the disseminated 5TGM1 model.


CONCLUSIONS
The immune-mediated antitumor activity of anti-CD137 mAb in mouse models holds promise for myeloma treatment in humans.
Murillo
Oihana
O
Gene Therapy Unit, Centro de Investigación Médica Aplicada, Pamplona, Spain.
Arina
Ainhoa
A
Hervas-Stubbs
Sandra
S
Gupta
Anjana
A
McCluskey
Brandon
B
Dubrot
Juan
J
Palazón
Asís
A
Azpilikueta
Arantza
A
Ochoa
Maria C
MC
Alfaro
Carlos
C
Solano
Sarai
S
Pérez-Gracia
José L
JL
Oyajobi
Babatunde O
BO
Melero
Ignacio
I
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000188:drug therapy*; D010954:Plasmacytoma / Q000188:drug therapy* / Q000276:immunology; D016019:Survival Analysis; D047368:Tumor Burden; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9