Generation of humanized mice using leukapheresis or human fetal liver (HFL) derived CD34+ cells.

Redirected T cells did not show persistence in the blood of tumor bearing humanized mice

Supplementary Materials and Methods, References

Immune modulatory ligand expression on the investigated tumor cell line

List of differentially regulated cell cycle genes with Log2FC values.

Abstract Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Experimental Design: Fibroblast activation protein (FAP)–specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Δ-CD28 CAR was tested clinically in a patient with MPM. Results: All the three CARs demonstrated FAP-specific functionality in vitro. Gene expression data indicated a distinct activity profile for the Δ-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Δ-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Δ-CD28 CAR could be detected for up to 21 days and showed functionality. Conclusions: Overall, anti-FAP-Δ-CD28/CD3ζ CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981–93. ©2018 AACR.

Meeting abstracts Median survival of advanced malignant pleural mesothelioma (MPM) is less than 2 years, and novel treatments are urgently needed. Immunotherapy with adoptive T cell transfer is an attractive approach that could be added to current therapeutic concepts. Fibroblast activation protein

Meeting abstracts Adoptive transfer of re-directed T cells which are engineered to express receptors that target tumor-associated molecules and signal T cell effector functions has emerged as an effective therapeutic approach for cancer. Chimeric antigen receptors (CARs) are recombinant receptors