A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma.

We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)-EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up. All patients demonstrated detectable transient expansion of CART-EGFRvIII cells in peripheral blood. Seven patients had post-CART-EGFRvIII surgical intervention, which allowed for tissue-specific analysis of CART-EGFRvIII trafficking to the tumor, phenotyping of tumor-infiltrating T cells and the tumor microenvironment in situ, and analysis of post-therapy EGFRvIII target antigen expression. Imaging findings after CART immunotherapy were complex to interpret, further reinforcing the need for pathologic sampling in infused patients. We found trafficking of CART-EGFRvIII cells to regions of active GBM, with antigen decrease in five of these seven patients. In situ evaluation of the tumor environment demonstrated increased and robust expression of inhibitory molecules and infiltration by regulatory T cells after CART-EGFRvIII infusion, compared to pre-CART-EGFRvIII infusion tumor specimens. Our initial experience with CAR T cells in recurrent GBM suggests that although intravenous infusion results in on-target activity in the brain, overcoming the adaptive changes in the local tumor microenvironment and addressing the antigen heterogeneity may improve the efficacy of EGFRvIII-directed strategies in GBM.

O'Rourke DM ，Nasrallah MP ，Desai A ，Melenhorst JJ ，Mansfield K ，Morrissette JJD ，Martinez-Lage M ，Brem S ，Maloney E ，Shen A ，Isaacs R ，Mohan S ，Plesa G ，Lacey SF ，Navenot JM ，Zheng Z ，Levine BL ，Okada H ，June CH ，Brogdon JL ，Maus MV ... -  《-》

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 ... -  《-》

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》

Pilot Trial of Adoptive Transfer of Chimeric Antigen Receptor-transduced T Cells Targeting EGFRvIII in Patients With Glioblastoma.

Goff SL ，Morgan RA ，Yang JC ，Sherry RM ，Robbins PF ，Restifo NP ，Feldman SA ，Lu YC ，Lu L ，Zheng Z ，Xi L ，Epstein M ，McIntyre LS ，Malekzadeh P ，Raffeld M ，Fine HA ，Rosenberg SA ... -  《-》

Anti-EGFRvIII Chimeric Antigen Receptor-Modified T Cells for Adoptive Cell Therapy of Glioblastoma.

Glioblastoma (GBM) is one of the most devastating brain tumors with poor prognosis and high mortality. Although radical surgical treatment with subsequent radiation and chemotherapy can improve the survival, the efficacy of such regimens is insufficient because the GBM cells can spread and destroy normal brain structures. Moreover, these non-specific treatments may damage adjacent healthy brain tissue. It is thus imperative to develop novel therapies to precisely target invasive tumor cells without damaging normal tissues. Immunotherapy is a promising approach due to its capability to suppress the growth of various tumors in preclinical model and clinical trials. Adoptive cell therapy (ACT) using T cells engineered with chimeric antigen receptor (CAR) targeting an ideal molecular marker in GBM, e.g. epidermal growth factor receptor type III (EGFRvIII) has demonstrated a satisfactory efficacy in treating malignant brain tumors. Here we summarize the recent progresses in immunotherapeutic strategy using CAR-modified T cells oriented to EGFRvIII against GBM.

Ren PP ，Li M ，Li TF ，Han SY ... -  《-》