Blood, 15 January 2003, Vol. 101, No. 2, pp. 568-575
IMMUNOBIOLOGY
Autologous and MHC class I-negative allogeneic tumor cells
secreting IL-12 together cure disseminated A20 lymphoma
Antonio Curti,
Mariella Parenza, and
Mario P. Colombo
From the Immunotherapy and Gene Therapy Unit, Istituto
Nazionale per lo Studio e la Cura dei Tumori, Milan,
Italy.
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-
(IFN-)-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.
