Retrovirally expressed 4-1BBL dramatically increases proliferation and in vivo persistence of adoptively transferred CD19-targeted T cells, promoting complete tumor elimination. (131.16)

Abstract

Abstract Human T cells transduced with a chimeric antigen receptor (CAR) composed of an antibody-derived scFv fragment and the CD3ζ chain can recognize and kill tumor cells on binding to the targeted membrane antigen. The co-transduction of a CAR along with CD80 and 4-1BBL induces auto-costimulation enabling high in vivo T cell expansion and tumor rejection in a prostate tumor model. Here we investigated this concept in T cells harboring either a first generation anti-CD19 CAR (19z1) or a second generation CAR (1928z), which additionally comprises the CD28 cytoplasmic domain. We compared the proliferation and anti-tumor activity of 19z1+, 19z1-4-1BBL+, 19z1-CD80+4-1BBL+, 1928z+ and 1928z-4-1BBL+ transduced T cells in a pro B cell leukemia model (NALM-6). Seven days after IV injection into NALM-6 bearing NOD/SCID/IL2Rγnull mice, 1928z-4-1BBL+ CD8 and CD4 T cells accumulated in the bone marrow and the spleen 100 times more than 19z1+ T cells and 10 times more than 1928z+ T cells, corroborating in vitro proliferative responses to repeated antigen exposure. An increased proportion of central memory CD8 T cells was observed in all groups treated with 4-1BBL-expressing cells. Within 15 days, in vivo bioluminescence imaging showed total tumor regression in the 1928z-4-1BBL+ T cell-treated group and partial regression in the other groups. Thus, constitutive 4-1BBL expression drives high proliferation of anti-tumor CD8 T cells, promoting central memory T cell persistence and tumor eradication.