Failure of vaccination with idiotypic protein or DNA, (+/-IL-2), the depletion of regulatory T cells, or the blockade of CTLA-4 to prolong dormancy in mice with BCL1 lymphoma.
Immunization of mice with the idiotype (Id) immunoglobulin from the murine B cell lymphoma, BCL1, before inoculating tumor cells can induce tumor dormancy. In this model, the tumor cells grow for a short period of time and then regress. The mice live for months or years with approximately 1 million tumor cells in their spleens. Some mice relapse due to decreases in the anti-Id antibody titers or the development of mutations in the residual tumor cells which render them refractory to negative signaling by the anti-Id antibody. In this study we determined whether we could eliminate the residual dormant cells by using a DNA vaccine against the Id or by immunomodulation of T-cell subsets in vivo. Our results demonstrate that dormancy can be maintained by further immunizations with either the BCL1 Id protein or DNA vaccine encoding its single-chain Fv fragment. We also found that a cytotoxic T-cell response was not induced by either in vivo administration of vaccine alone or by the vaccine plus interleukin-2. In addition the injection of anti-cytotoxic T-lymphocyte-associate antigen did not prolong dormancy. Finally, the in vivo administration of anti-CD25 to deplete regulatory T cells did not prolong dormancy. Dormancy in this model is dependent primarily upon anti-Id antibodies, our results suggest that other strategies to target residual dormant BCL1 cells are warranted. They also suggest that the elimination of dormant tumor may represent a greater challenge than the elimination of primary tumors.
Pop
Laurentiu M
LM
Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, Texas 75390-8576, USA, and Cancer Sciences Division, Southampton University Hospitals, UK.
Smallshaw
Joan E
JE
Tucker
Thomas F
TF
Stevenson
Freda K
FK
Vitetta
Ellen S
ES
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D060908:CTLA-4 Antigen; D002460:Cell Line; D019938:Cyclin D1 / Q000627:therapeutic use*; D007130:Immunoglobulin Idiotypes / Q000276:immunology / Q000627:therapeutic use*; D016233:Immunotherapy, Active; D007376:Interleukin-2 / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D015375:Receptors, Interleukin-2 / Q000276:immunology; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D019444:Vaccines, DNA / Q000627:therapeutic use*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007130:Immunoglobulin Idiotypes; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D019444:Vaccines, DNA; D019938:Cyclin D1