Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination

Abstract

The recent success of chimeric antigen receptor (CAR)-T cell therapy for treatment of hematologic malignancies supports further development of treatments for both liquid and solid tumors. However, expansion of CAR-T cell therapy is limited by the availability of surface antigens specific for the tumor while sparing normal cells. There is a rich diversity of tumor antigens from intracellularly expressed proteins that current and conventional CAR-T cells are unable to target. Furthermore, adoptively transferred T cells often suffer from exhaustion and insufficient expansion, in part, because of the immunosuppressive mechanisms operating in tumor-bearing hosts. Therefore, it is necessary to develop means to further activate and expand those CAR-T cells in vivo. The Wilms tumor 1 (WT1) is an intracellular oncogenic transcription factor that is an attractive target for cancer immunotherapy because of its overexpression in a wide range of leukemias and solid tumors, and a low level of expression in normal adult tissues. In the present study, we developed CAR-T cells consisting of a single chain variable fragment (scFv) specific to the WT1/HLA-A*2402 complex. The therapeutic efficacy of our CAR-T cells was demonstrated in a xenograft model, which was further enhanced by vaccination with dendritic cells (DCs) loaded with the corresponding antigen. This enhanced efficacy was mediated, at least partly, by the expansion and activation of CAR-T cells. CAR-T cells shown in the present study not only demonstrate the potential to expand the range of targets available to CAR-T cells, but also provide a proof of concept that efficacy of CAR-T cells targeting peptide/major histocompatibility complex can be boosted by vaccination.

A Unique Family of Neuronal Signaling Proteins Implicated in Oncogenesis and Tumor Suppression

“…WT1 is an attractive target for cancer therapy because it is overexpressed in a wide range of leukemias and solid tumors, whereas in normal tissues it is expressed at low levels and negatively regulated by BASP1 (74). Chimeric antigen receptor (CAR)-T cells with antitumor activity have been developed by targeting processed surface peptides on cancer cells derived from the intracellular WT1 protein (116). CAR-T cells with a chimeric antigen receptor consisting of a single variable WT1-specific antibody fragment in complex with a major histocompatibility (MHC) protein were tested using a xenograft model.…”

“…CAR-T cells with a chimeric antigen receptor consisting of a single variable WT1-specific antibody fragment in complex with a major histocompatibility (MHC) protein were tested using a xenograft model. The antitumor effect of these CAR-T cells was further enhanced by vaccination with dendritic cells loaded with the corresponding antigen (116). Using subsidiary immunotherapeutical approaches to specifically target key molecules in carcinogenesis could therefore substantially expand the current options to treat cancer.…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…Besides, a recent proof-of-concept publication showed that also intracellular peptides can be targeted and that the efficacy of CAR T cells can be boosted by vaccination. The authors developed a CAR specific to a WT1/human leukocyte antigen (HLA)-A complex, and vaccination with dendritic cells loaded with the corresponding antigen led to CAR T cells expansion and activation, thus enhancing anti-leukemic activity in a xenograft model (76).…”

The Advent of CAR T-Cell Therapy for Lymphoproliferative Neoplasms: Integrating Research Into Clinical Practice

“…The development of CAR T cells for advanced solid tumors and relapsed/refractory AML, still associated with unfavorable prognosis despite recent therapeutic developments (210), has been limited by the absence of a suitable tumor-specific antigen (211,212) and severe and toxicities due to on-target off-tumor effects occurred in some trials (213)(214)(215)(216)(217). Thus, investigators are trying to find more suitable targets (218,219) and exploring strategies to promptly induce CAR T-cell exhaustion only when needed (220), such as mRNA electroporation (221,222) and inducible suicide genes (223). CARs co-targeting two or three antigens are also being developed, aiming at preventing possible off-tumor side effects but also at avoiding antigen escape risk (115,(224)(225)(226)(227)(228)(229).…”