Details

Autor(en) / Beteiligte

• O’Rourke, Donald M.
• Nasrallah, MacLean P.
• Morrissette, Jennifer
• Melenhorst, Jan J.
• Lacey, Simon F.
• Mansfield, Keith
• Martinez-Lage, Maria
• Desai, Arati
• Brem, Steven
• Maloney, Eileen
• Mohan, Suyash
• Wang, Sumei
• Verma, Gaurav
• Navenot, Jean-Marc
• Shen, Angela
• Zheng, Zhaohui
• Levine, Bruce L.
• Okada, Hideho
• June, Carl H.
• Maus, Marcela V.

Titel

Abstract LB-083: Phase I study of T cells redirected to EGFRvIII with a chimeric antigen receptor in patients with EGFRvIII+ glioblastoma

Ist Teil von

• Cancer research (Chicago, Ill.), 2016-07, Vol.76 (14_Supplement), p.LB-083-LB-083

Erscheinungsjahr

2016

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Abstract We initiated a Phase I study of intravenous delivery of autologous T cells re-directed to the EGFR variant III mutation by means of a lentiviral vector encoding a chimeric antigen receptor (CAR). Patients with recurrent glioblastoma (GBM) have their tumors screened for the presence of the EGFRvIII mutation by a next-generation sequencing based assay. Eligible patients undergo leukapheresis for collection of autologous T cells, which are genetically modified ex vivo to express the EGFRvIII CAR, expanded, and then cryopreserved for infusion. We report results on the nine patients we have treated. We targeted a challenging subset of GBM patients, with multi-focal residual, progressive disease refractory to standard and experimental therapies, including temozolomide, bevacizumab, and radiation. To date, we have found that infusion of 1-5×10⁁8 CART-EGFRvIII cells is feasible to manufacture and infusion is safe, without evidence of off-tumor toxicity or cross-reactivity to wild type EGFR. No clinical or laboratory signs of systemic cytokine release syndrome have been observed, though elevations in serum IL-6 occur concurrently with CART-EGFRvIII expansion in the peripheral blood. One patient developed non-convulsive status epilepticus nine days after CART-EGFRvIII infusion, which resolved with standard treatment and anti-cytokine therapy. All patients have had significant expansion of CART-EGFRvIII cells between 7-10 days post-infusion, as measured by flow cytometry and quantitative PCR in peripheral blood samples. Five patients have undergone surgical resection of tumor between 6-120 days after infusion, and pathologic evaluation has demonstrated infiltration of activated CAR T cells, recruitment of new T cells (as assessed by next generation T cell receptor deep sequencing), and specific EGFRvIII target antigen loss in GBM cells in some cases. These findings provide evidence that CART-EGFRvIII cells are safe, without evidence of off-target toxicity or cytokine release syndrome, and are immunologically active. The data also suggest a mechanism of antigen editing by activated CART-EGFRvIII cells that track to specific EGFRvIII GBM cells. Citation Format: Donald M. O’Rourke, MacLean P. Nasrallah, Jennifer Morrissette, Jan J. Melenhorst, Simon F. Lacey, Keith Mansfield, Maria Martinez-Lage, Arati Desai, Steven Brem, Eileen Maloney, Suyash Mohan, Sumei Wang, Gaurav Verma, Jean-Marc Navenot, Angela Shen, Zhaohui Zheng, Bruce L. Levine, Hideho Okada, Carl H. June, Marcela V. Maus. Phase I study of T cells redirected to EGFRvIII with a chimeric antigen receptor in patients with EGFRvIII+ glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-083.