Use of adenoviruses encoding CD40L or IL-2 against B cell lymphoma.
Some B cell lymphomas lack important costimulatory properties that could prevent them from being used as cell based vaccines. Infection of A20 B lymphoma cells with a replication-defective adenovirus encoding murine (m) CD40L, but not mIL-2, produces an antigen presentation phenotype with upregulation of MHC Class I/II, induction of B7-1/2 molecules and production of MIL-12 and MIP-1alpha. Subcutaneous vaccination with irradiated Ad-mCD40L-infected- or Ad-mIL-2-infected-A20 cells generated A20-specific CD8+ T cell responses and cross reactive A20 Ig antibodies. Only vaccination with Ad-mCD40L-infected A20 cells produced a significant delay in tumor growth and long-term survival (p = 0.0039). Stronger protective immunity to A20 challenge was generated by intravenous priming with A20 cells infected with Ad-mCD40L, Ad-mIL-2 or their combination followed by a boost immunization with A20 cells activated with syngeneic fibroblasts expressing CD40L. Compared to Ad-LacZ-infected A20 priming, the combination priming was most effective followed by Ad-mCD40L and Ad-mIL-2 (p = 0.0027, p = 0.0027, p = 0.0163 respectively). Significant A20-specific CD8+ T cell-mediated cytotoxicity was only demonstrated in splenocytes from these groups of vaccinated animals. By contrast, ELISPOT assay of splenocytes from all A20 prime/boosted vaccinated groups demonstrated increases in gamma-interferon release by T cells elicited by in vitro stimulation either with A20 cells or another syngeneic 2PK-3 lymphoma, indicating the presence of cross reactive immunity. Similarly anti-A20 immunoglobulin antibodies generated after vaccination were not necessarily A20 idiotype-specific. Direct therapy of pre-established tumors was achieved with the combination of Ad-mCD40L and Ad-mIL-2 given at Days 4 and 8 at the tumor site with a significant long-term survival of 85% of tumor-bearing mice (p = 0.0001). Our study strongly supports the use of Ad-CD40L and Ad-IL-2 combination therapy for the treatment of patients with B cell lymphoma.
Meziane
El Kahina
el K
CRUK Immunology Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, United Kingdom.
Bhattacharyya
Tapan
T
Armstrong
Anne C
AC
Qian
Cheng
C
Hawkins
Robert E
RE
Stern
Peter L
PL
Dermime
Said
S
D000256:Adenoviridae; D000818:Animals; D000917:Antibody Formation; D017951:Antigen Presentation; D023201:CD40 Ligand / Q000235:genetics* / Q000276:immunology*; D019496:Cancer Vaccines; D005260:Female; D005347:Fibroblasts; D006801:Humans; D007111:Immunity, Cellular; D007167:Immunotherapy; D007376:Interleukin-2 / Q000235:genetics* / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D013154:Spleen / Q000166:cytology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D019496:Cancer Vaccines; D007376:Interleukin-2; D023201:CD40 Ligand