Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy

TY - JOUR

T1 - Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy

AU - Chheda, Zinal S

AU - Kohanbash, Gary

AU - Okada, Kaori

AU - Jahan, Naznin

AU - Sidney, John

AU - Pecoraro, Matteo

AU - Yang, Xinbo

AU - Carrera, Diego A

AU - Downey, Kira M

AU - Shrivastav, Shruti

AU - Liu, Shuming

AU - Lin, Yi

AU - Lagisetti, Chetana

AU - Chuntova, Pavlina

AU - Watchmaker, Payal B

AU - Mueller, Sabine

AU - Pollack, Ian F

AU - Rajalingam, Raja

AU - Carcaboso, Angel M

AU - Mann, Matthias

AU - Sette, Alessandro

AU - Garcia, K Christopher

AU - Hou, Yafei

AU - Okada, Hideho

N1 - © 2018 Chheda et al.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - The median overall survival for children with diffuse intrinsic pontine glioma (DIPG) is less than one year. The majority of diffuse midline gliomas, including more than 70% of DIPGs, harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 of histone 3 variant 3 (H3.3). From a CD8+ T cell clone established by stimulation of HLA-A2+ CD8+ T cells with synthetic peptide encompassing the H3.3K27M mutation, complementary DNA for T cell receptor (TCR) α- and β-chains were cloned into a retroviral vector. TCR-transduced HLA-A2+ T cells efficiently killed HLA-A2+H3.3K27M+ glioma cells in an antigen- and HLA-specific manner. Adoptive transfer of TCR-transduced T cells significantly suppressed the progression of glioma xenografts in mice. Alanine-scanning assays suggested the absence of known human proteins sharing the key amino acid residues required for recognition by the TCR, suggesting that the TCR could be safely used in patients. These data provide us with a strong basis for developing T cell-based therapy targeting this shared neoepitope.

AB - The median overall survival for children with diffuse intrinsic pontine glioma (DIPG) is less than one year. The majority of diffuse midline gliomas, including more than 70% of DIPGs, harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 of histone 3 variant 3 (H3.3). From a CD8+ T cell clone established by stimulation of HLA-A2+ CD8+ T cells with synthetic peptide encompassing the H3.3K27M mutation, complementary DNA for T cell receptor (TCR) α- and β-chains were cloned into a retroviral vector. TCR-transduced HLA-A2+ T cells efficiently killed HLA-A2+H3.3K27M+ glioma cells in an antigen- and HLA-specific manner. Adoptive transfer of TCR-transduced T cells significantly suppressed the progression of glioma xenografts in mice. Alanine-scanning assays suggested the absence of known human proteins sharing the key amino acid residues required for recognition by the TCR, suggesting that the TCR could be safely used in patients. These data provide us with a strong basis for developing T cell-based therapy targeting this shared neoepitope.

KW - Journal Article

U2 - 10.1084/jem.20171046

DO - 10.1084/jem.20171046

M3 - Journal article

C2 - 29203539

SN - 0022-1007

VL - 215

SP - 141

EP - 157

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

IS - 1

ER -