EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss.

Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues. We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma. At elevated doses, infusion with EGFRvIII mCAR T cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIII(NEG) tumors, suggesting generation of host immunity against additional tumor antigens. All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies.

Sampson JH ，Choi BD ，Sanchez-Perez L ，Suryadevara CM ，Snyder DJ ，Flores CT ，Schmittling RJ ，Nair SK ，Reap EA ，Norberg PK ，Herndon JE 2nd ，Kuan CT ，Morgan RA ，Rosenberg SA ，Johnson LA ... -  《-》

EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

Miao H ，Choi BD ，Suryadevara CM ，Sanchez-Perez L ，Yang S ，De Leon G ，Sayour EJ ，McLendon R ，Herndon JE 2nd ，Healy P ，Archer GE ，Bigner DD ，Johnson LA ，Sampson JH ... -  《PLoS One》

Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma.

Shen CJ ，Yang YX ，Han EQ ，Cao N ，Wang YF ，Wang Y ，Zhao YY ，Zhao LM ，Cui J ，Gupta P ，Wong AJ ，Han SY ... -  《Journal of Hematology & Oncology》

Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma.

Morgan RA ，Johnson LA ，Davis JL ，Zheng Z ，Woolard KD ，Reap EA ，Feldman SA ，Chinnasamy N ，Kuan CT ，Song H ，Zhang W ，Fine HA ，Rosenberg SA ... -  《-》

Antitumor efficacy of chimeric antigen receptor T cells against EGFRvIII-expressing glioblastoma in C57BL/6 mice.

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in hematological tumors. However, many challenges remain in improving the efficacy of CAR T cells in solid tumors. The epidermal growth factor receptor variant III (EGFRvIII) is only expressed in tumors but barely found in normal tissues, making it a good target for CAR T therapy. It is reported that 31-64% of glioblastoma (GBM) patients are EGFRvIII positive. Here we report the robust antitumor activities of CAR T cells targeting EGFRvIII-expressing mouse GBM cells. In vitro and in vivo, 806-28Z CAR T cells were able to lyse GL261/EGFRvIII cellsin a dose-dependent manner. A low dose of 806-28Z CAR T cells suppressed GL261/EGFRvIII tumor growth, whereas a high dose of 806-28Z CAR T cells completely eradicated xenograft tumors. Higher concentrations of granzyme B in mice plasma were correlated with increased CAR T cells infusion. Enhanced CD8+ T cells infiltration within the tumors were detected by immunohistochemistry in sections from the mice treated by CAR T cells. The 806-28Z CAR T cells can also inhibit the growth of antigenic heterogeneous GBM tumors. More importantly, additional rechallenge experiments indicated that GL261/EGFRvIII cells or parental GL261 cells could not grow in the cured mice. Therefore, the cell dose is a crucial determinant for CAR T efficacy against EGFRvIII-expressing GBM and granzyme B release is a predictive marker for the antitumor efficacy of CAR T cells.

Chen M ，Sun R ，Shi B ，Wang Y ，Di S ，Luo H ，Sun Y ，Li Z ，Zhou M ，Jiang H ... -  《-》