Autologous and MHC class I–negative allogeneic tumor cells secreting IL-12 together cure disseminated A20 lymphoma

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Abstract
Cytokine gene-modified tumor cells have increased immunogenicity and retain the antigenic repertoire of a particular neoplasia. However, practical concerns have led to an increased interest in allogeneic gene-transduced bystander cells as a broader source of cytokines for autologous tumor cell–based vaccines. Here, we show that allogeneic B78H1 major histocompatibility complex (MHC) class I–negative and –positive (H-2Kb– and Db-transfected) cells induced cytotoxic T lymphocytes (CTLs) and protection in BALB/c mice at comparable levels in response to a challenge with C26 (H-2d) colon carcinoma cells sharing the tumor-associated antigen envelope glycoprotein 70 (env-gp70) with both cell lines. Class I–negative B78H1 cells transduced to express interleukin-12 (IL-12) and mixed with autologous A20 tumor cells led to eradication of preestablished A20 lymphoma in 50% or 100% of treated mice after 3 or 4 vaccinations, respectively, whereas A20 cells alone or mixed with nontransduced B78H1 cured none or 50% of mice after 3 or 4 vaccinations, respectively. Immunization with the IL-12–producing bystander cell line increased tumor-specific proliferation and type 1 cytokine production by CD4+ T cells. By contrast, CD4 T-cell function appeared impaired after immunization with A20 cells alone or mixed with B78H1 cells. Indeed, only CD4+ T cells from IL-12–treated mice could be restimulated with anti-OX40 monoclonal antibody (mAb) in place of a fourth cellular boost. Moreover, the IL-12–based tumor vaccine induced expansion of tumor-specific interferon-γ (IFN-γ)–producing CD8+ T cells. These results are clinically relevant for the development of feasible IL-12 cancer vaccines based on engineered class I–negative bystander cells.