Targeted immunotherapy of solid cancers with chimeric antigen receptor (CAR) T cells
and immunocytokines are attractive options in that they both rely on the specificity
of tumor-targeted antibodies. Since carcinoembryonic antigen (CEA) expression in both
colon and breast cancers is correlated with poor prognosis, it was chosen as a model
tumor target in immunocompetent CEA transgenic (CEATg) mice. A second-generation anti-CEA
CAR derived from CEA-specific antibody T84.66 was used to treat murine MC38 colon
or E0771 breast carcinomas transfected with CEA. Anti-CEA CAR vs. mock transduced
T cells exhibited a CEA-specific cytotoxic and IFN
dose response to both CEA transfected cell lines vs. their CEA-negative controls.
Anti-CEA CAR vs. mock transduced T cells delayed the median survival of CEA transfected
s.c. MC38 or orthotopic E0771 tumor-bearing CEATg mice by 2 days. With the addition
of one-day prior cyclophosphamide (CY) lymphodepletion, anti-CEA CAR T cell treatment
delayed the median survival of MC38/CEA and E0771/CEA tumor-bearing CEATg mice by
ten and 3 days, respectively. Since CAR T cells require IL2 for survival and expansion,
anti-CEA-IL2 immunocytokine (ICK) treatment was performed post CAR T cell therapy.
Single ICK treatment 1 day after CY plus anti-CEA CAR T cell therapy in the MC38/CEA
model, and two ICK treatments every 3 days after CY plus anti-CEA CAR T cell therapy
in the E0771/CEA model were ineffective, while four ICK treatments every 3 days after
CY plus anti-CEA CAR T cell therapy completely eradicated MC38/CEA tumor growth and
induced tumor immunity when the mice were re-challenged with tumor. These studies
show the therapeutic potential of anti-CEA CAR T cells combined with ICK to treat
CEA-positive tumors.
Abbreviations: CAR: Chimeric antigen receptor, CEA: Carcinoembryonic antigen, CEACAM5, ICK: Immunocytokine, CY: Cyclophosphamide, CEATg mouse: transgenic CEA mouse, TDLN: Tumor-draining lymph node