Adoptive cell therapy targeting common p53 neoantigens in human solid cancers

Abstract

Adoptive cell therapy (ACT) targeting neoantigens can achieve durable clinical responses in patients with cancer. Most neoantigens arise from rare mutations, requiring highly individualized treatments. To broaden the applicability of ACT targeting neoantigens, we focused on TP53 mutations commonly shared across different cancer types. Here, we describe a library of T cell receptors (TCRs) that can target TP53 mutations shared among 7.3% of patients with solid cancers. These TCRs recognized tumor cells in a TP53 mutation- and human leucocyte antigen (HLA)-specific manner both in vitro and in vivo. Patients with chemorefractory epithelial cancers treated with ex vivo-expanded autologous tumor infiltrating lymphocytes (TILs) naturally reactive with mutant p53 experienced limited clinical responses (2 PRs/12 patients), and we detected low frequencies, exhausted phenotypes, and poor persistence of the infused mutant p53-reactive TILs. Alternatively, we treated one patient with a chemorefractory breast cancer with ACT by transducing autologous peripheral blood lymphocytes with an HLA-A*02-restricted anti-p53R175H TCR. The infused cells exhibited an improved immunophenotype and prolonged persistence compared to the TIL ACT and the patient experienced an objective tumor regression (-55%) that lasted 6 months. Collectively, these data demonstrate the feasibility of off-the-shelf TCR-engineered cell therapies targeting shared p53 neoantigens to treat human cancers.

237 Neoantigen-specific expansion of tumor-infiltrating lymphocytes enables effective treatment of p53-mutant cancer in mice

“…[4][5][6] Additionally, ex vivo expansion of TILs often results in further reduction and differentiation of TILs specific for neoantigens. 7 The low frequencies and/or differentiated phenotype of TILs can contribute to ineffective ACT. Methods We developed a protocol to selectively expand neoantigen-specific TILs by in vitro stimulation of target neoantigens, termed NeoExpand.…”

“…While conventional TIL screening identified 3 T-cell receptors (TCRs), [8][9][10] NeoExpand enabled identification of 7 TCRs including the 3 TCRs identified by conventional screening. In vivo, 4196 TIL expanded through REP was ineffective in treating established TYK-nu human ovarian cancer cells that naturally expressed p53 R175H , 7 while the 4196 NeoExpand TILs effectively regressed the tumor in NSG mice. Single cell transcriptome analysis demonstrated that NeoExpand led to expansion of central memory/stem-like populations among the mutant p53-reactive clones in the 4196 TILs, while REP led to the depletion of the central memory/stem-like population.…”