Abstract
Mutant p53-specific T cells were isolated from patients with metastatic epithelial cancers.
Major finding: Mutant p53-specific T cells were isolated from patients with metastatic epithelial cancers.
Concept: Patient-derived TILs were screened for responses to neoantigens derived from TP53 hot spot mutations.
Impact: T cells targeting common p53 neoantigens could be broadly used for adoptive cell therapy.
The adoptive transfer of tumor-infiltrating lymphocytes (TIL) specific to neoantigens derived from mutated genes has been described for several types of cancer. However, this approach to date has been based on private mutations unique to individual patients. Targeting driver mutations that are frequent across many patients has the potential to provide broader applicable adoptive T-cell therapies. Malekzadeh and colleagues conducted a TP53-focused screening for neoantigens derived from TP53 hot spot mutations that elicit a specific T-cell response. Of the patients enrolled in the study, 65% exhibited TP53 mutations, and 24% of these patients had TP53 mutations in previously identified hot spots. The screen was conducted by coculturing patient-derived TILs purified from metastases together with autologous antigen-presenting cells (APC) with predicted p53-derived neoepitopes presented either by intracellular expression through electroporation with TP53-mutant tandem minigenes or extracellularly by pulsing with mutated peptides. Of 28 evaluable patients, 11 (39%) had mutated TP53-reactive T cells restricted to HLA class I or II, and a total of 9 unique T-cell receptors derived from helper (CD4) and cytotoxic (CD8) T cells recognizing 7 different mutant p53-derived neoepitopes were isolated. The isolated TILs and gene-engineered T cells recognized tumor cell lines expressing the HLA and naturally processed mutant p53. These results show that neoepitopes derived from common p53 mutations are able to elicit specific T-cell responses. The ability of the characterized T cells to eliminate metastatic cancer will be evaluated in future clinical trials. This neoantigen screening approach also may serve as a model for targeting other highly mutated genes in cancer.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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