Background Adoptive cell therapies (ACT) targeting neoantigens arising from somatic mutations in cancer cells can successfully treat advanced solid cancers. Most neoantigens are rare and targeting them via ACT would require highly individualized therapies. Instead, we focused on p53 mutations shared among a broad range of patients. In this study, we have identified tumor infiltrating lymphocytes (TILs) and T cell receptors (TCR) recognizing p53 mutations and evaluated the efficacy of ACT targeting p53 neoantigens.
Methods Patient TILs were screened for reactivity against p53 mutations. Twelve patients with positive p53 neoantigen screening received autologous TIL ACT. One patient received TCR-engineered peripheral blood lymphocytes (PBL) ACT.
Results From 77 patient samples, TILs recognizing both ‘hotspot’ and ‘non-hotspot’ p53 mutations were detected in 21 patient TILs (table 1). ACT using an HLA-A*02-restricted TCR targeting p53(R175H) led to regression of TYK-nu ovarian cancer cells that were p53(R175H)+ and HLA-A*02+ in NSG mice. Treatment of 12 patients with chemo-refractory epithelial cancers with autologous TILs targeting p53 neoantigens resulted in limited clinical responses (2 partial responses). We detected low frequencies, exhausted phenotypes, and poor persistence of the infused mutant p53-reactive TILs (table 2). Alternatively, we engineered peripheral blood lymphocytes (PBL) to express anti-mutant p53 TCRs. We retrovirally expressed the HLA-A*02:01-restricted anti-p53(R175H) TCR that had been tested preclinically in patient 4349’s autologous PBL. This approach improved anti-mutant p53 TCR expression and T cell persistence relative to the autologous TIL treatments. Patient 4349 with chemo-refractory breast cancer received 5.3e10 cells and, at 14-weeks post-ACT, she experienced significant regression of the metastases in the pericardium and chest wall, as well as the subcutaneous tumor deposits based on RECIST criteria (down 55%). Single cell RNA sequencing of PBLs at 6 weeks post-ACT revealed a cluster of circulating T cells with a central-memory and stem cell-like phenotype that expressed SELL (CD62L), IL7R, TCF7 (TCF1) and LEF1, suggesting long-term immunity against the p53 neoantigen. The patient recurred at 6 months post-ACT with a metastasis that exhibited loss of heterozygosity of a portion of chromosome 6 that included HLA-A*02.
Conclusions We have established a library of anti-mutant p53 TCRs that could potentially be used to treat 7.3% of patients with solid cancers that express the corresponding p53 mutation and HLA. One breast cancer patient treated with TCR-engineered PBLs targeting p53R175H experienced an objective response lasting 6 months. Collectively, our data demonstrate the feasibility of targeting shared p53 neoantigens by ACT for the treatment of solid cancers.
Ethics Approval This study was approved by the Investigational Review Board at the National Cancer Institute in accordance with an assurance filed with and approved by the U.S. Department of Health and Human Services and was registered at https://clinicaltrials.gov under NCT00068003, NCT01174121 and NCT03412877.
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