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.