Although TP53 is the most frequently mutated gene across all cancers and encodes the tumor suppressor p53 protein, TP53-targeted therapies have not demonstrated efficacy beyond in vitro models and immunotherapies targeting mutant TP53 are not currently available. A study by Malekzadeh et al evaluating antigen-experienced T cells in peripheral blood lymphocytes of patients with metastatic solid epithelial cancers expressing TP53 hotspot mutations found that peripheral blood was a noninvasive source of T cells targeting TP53 mutations for cell therapy.
The study was published in Clinical Cancer Research.
Study Methodology
KEY POINTS
- The peripheral blood could be a viable noninvasive option for any patient with a tumor expressing a TP53 mutation, including those with inoperable cancers.
- Identification of TP53 mutations from circulating tumor DNA using a liquid biopsy could make peripheral blood lymphocytes the sole source for neoantigen and T cells.
The researchers isolated peripheral blood cells from nine patients with tumors that had p53 mutations. The patients were chosen on the basis of availability of pretreatment leukapheresis and tumor-infiltrating lymphocytes (TILs) screening results, and had received prior therapies—including surgery, chemotherapy, and radiotherapy—as standard of care. Ficoll-Hypaque was used to isolate peripheral blood lymphocytes from leukapheresis and the cells were cryopreserved for further use. All the patients had a confirmed TP53 mutation by whole-genome sequencing.
Because the frequency of T cells in peripheral blood is about 0.1% of the frequency within the tumor, the researchers developed an in vitro stimulation method to expand the number of T cells to a level that was detectable in their assays. The expanded T cells were then tested in cell cultures for reactivity to mutant p53.
Study Results
The researchers found that peripheral blood T cells from five of the nine patients were reactive for mutant p53 in cell cultures. All five of the patients also had p53-reactive T cells within their tumors. Four patients without p53-reactive T cells in their peripheral blood lacked p53-reactive T cells within their tumors. The p53-reactive T cells were selective for mutated p53 and were not reactive against normal p53 in these experiments.
“Peripheral blood lymphocytes [were] a noninvasive source of T cells targeting TP53 mutations for cell therapy and can provide a window into intratumoral p53 neoantigen immune responses,” concluded the study authors.
“Our results indicate that an obstacle to performing adoptive cell therapy, which is the need to resect tumors with surgical procedures to obtain T cells, may not be necessary.... [T]hese findings bring us closer to the practical application of targeting common cancer mutations, such as those in p53.”— Steven A. Rosenberg, MD, PhD
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Translational Relevance
The study’s findings suggest that the peripheral blood could be a viable noninvasive option for any patient with a tumor expressing a TP53 mutation, including those with inoperable cancers. “Our results indicate that an obstacle to performing adoptive cell therapy, which is the need to resect tumors with surgical procedures to obtain T cells, may not be necessary,” said study author Steven A. Rosenberg, MD, PhD, Chief of the Surgery Branch at the National Cancer Institute Center for Cancer Research, in a statement. “In theory, we could do a blood draw and then identify and expand reactive T cells using techniques similar to those used in this study. These findings bring us closer to the practical application of targeting common cancer mutations, such as those in p53.”
Dr. Rosenberg, of the National Cancer Institute, is the corresponding author of this study.
Disclosure: Funding for this study was provided by the National Cancer Institute. For full disclosures of the study authors, visit clincancerres.aacrjournals.org.
