Tumor-Associated Antigen Cytotoxic T Cells in Relapsed or Refractory Solid Tumors
In a phase I trial reported in the Journal of Clinical Oncology, Hont et al found that treatment of relapsed or refractory solid tumors with ex vivo expanded autologous multiantigen-associated specific cytotoxic T cells—or, tumor-associated antigen cytotoxic T cells—was safe and showed evidence of antitumor activity.
As stated by the investigators, three target tumor-associated antigens uniquely expressed or overexpressed on malignant cells were selected with the aim of producing tumor-associated antigen T cells that preferentially target tumor cells with reduced risk of damage to healthy tissues. The tumor-associated antigen T cells selected target Wilms tumor gene 1 (WT1), preferentially expressed antigen of melanoma (PRAME), and survivin.
Study Details
In the dose-escalation trial, a total of 15 evaluable patients with tumors reported in the literature to express one or more of the target antigens and who received no lymphodepleting chemotherapy before infusion received tumor-associated antigen T cells generated from autologous peripheral blood and infused at dose levels of 1, 2, and 4 x 107 cells/m2. Patients were eligible for up to eight infusions administered 4 to 7 weeks apart. Dose-limiting toxicity was assessed for up to 45 days after infusion. Of the 15 patients, 14 were 3 to 27 years old, and 1 was 53 years old.
Dose-Limiting Toxicity
Patients received a median of two infusions (range = 1–8), with a total of 44 treatment cycles administered. No dose-limiting toxicities and no infusion-related reactions were observed. Adverse events considered related to treatment consisted of grade 1 fatigue and grade 1 myalgia and occurred in one patient each. The recommended dose for further study in patients with solid tumors was 4 x 107 cells/m2.
Responses
Among the 15 evaluable patients, 11 (73%) with stable disease or better at day 45 postinfusion were considered responders. Six responders had not had disease progression at a median follow-up of 13.9 months (range = 4.1–19.9 months) after treatment.
Median progression-free survival was 9.3 months at the highest dose level (n = 8) vs 2.8 months at the lower two dose levels combined (n = 7). Progression-free survival at 6 and 12 months in patients receiving the highest dose was numerically better than that with the treatment course immediately prior to tumor-associated antigen T-cell treatment (73% and 58% vs 38% and 25%).
Of 11 responding patients, 10 exhibited increased specificity for the three target tumor-associated antigens. Tumor samples available from nine patients—including two nonresponders and seven responders—expressed the targeted tumor-associated antigens in all samples (WT1 n = 5; PRAME n = 8; survivin n = 8). Antigen spreading and a reduction in circulating tumor-associated antigens were observed after tumor-associated antigen T-cell infusion.
The investigators concluded, “[Tumor-associated antigen T cells] safely induced disease stabilization, prolonged time to progression, and were associated with antigen spreading and a reduction in circulating tumor-associated antigen DNA levels in patients with relapsed [or] refractory solid tumors without lymphodepleting chemotherapy before infusion. [Tumor-associated antigen T cells] are a promising new treatment approach for patients with solid tumors.”
Holly J. Meany, MD, of the Center for Cancer and Immunology Research, Children’s National Health System, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Children’s National Health System Heroes Gala, Children’s National Health System Board of Visitors, Hyundai Hope on Wheels Young Investigator Grant to Support Pediatric Cancer Research, Children’s Research Institute Bioinformatics Unit, Clinical and Translational Science Institute, and National Institutes of Health National Center for Advancing Translational Sciences. For full disclosures of the study authors, visit jco.ascopubs.org.
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