Relationship of p53 overexpression on cancers and recognition by anti-p53 T cell receptor-transduced T cells.

Tumor suppressor p53 is reported to be an attractive immunotherapy target because it is mutated in approximately half of human cancers, resulting in inactivation and often an accumulation of the protein in the tumor cells. Only low amounts of protein are detectable in normal tissues. The differential display of antigen in normal versus tumor tissues has been reported to create an opportunity to target p53 by immunotherapy. We sought to determine the relationship between p53 expression and its recognition by cognate T cells in human tumors including common epithelial malignancies. Inasmuch as nonsense or missense p53 mutations may disrupt processing and presentation, we studied tumors with either identified wild-type or mutated p53, based on our gene-sequencing studies or published data. T cells transduced with a high-affinity, p53(264-272)-reactive T cell receptor (TCR) derived from HLA-A2.1 transgenic mice recognized a wide panel of human tumor lines. There was no significant correlation between p53 expression in tumors and recognition by the anti-p53 TCR-transduced T cells. This conclusion was based on the study of 48 cell lines and is in contrast to several prior studies that used only a limited number of selected cell lines. A panel of normal cells was evaluated for recognition, and some of these populations were capable of stimulating anti-p53 T cells, albeit at low levels. These studies raise doubts concerning the suitability of targeting p53 in the immunotherapy of cancer patients.

Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis.

The inhibitory receptor CTLA4 has a key role in peripheral tolerance of T cells for both normal and tumor-associated antigens. Murine experiments suggested that blockade of CTLA4 might have antitumor activity and a clinical experience with the blocking antibody ipilimumab in patients with metastatic melanoma did show durable tumor regressions in some patients. Therefore, a phase II study of ipilimumab was conducted in patients with metastatic renal cell cancer with a primary end point of response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Two sequential cohorts received either 3 mg/kg followed by 1 mg/kg or all doses at 3 mg/kg every 3 weeks (with no intention of comparing cohort response rates). Major toxicities were enteritis and endocrine deficiencies of presumed autoimmune origin. One of 21 patients receiving the lower dose had a partial response. Five of 40 patients at the higher dose had partial responses (95% confidence interval for cohort response rate 4% to 27%) and responses were seen in patients who had previously not responded to IL-2. Thirty-three percent of patients experienced a grade III or IV immune-mediated toxicity. There was a highly significant association between autoimmune events (AEs) and tumor regression (response rate=30% with AE, 0% without AE). CTLA4 blockade with ipilimumab induces cancer regression in some patients with metastatic clear cell renal cancer, even if they have not responded to other immunotherapies. These regressions are highly associated with other immune-mediated events of presumed autoimmune origin by mechanisms as yet undefined.