ASCO 2020 – Gene-engineered T-cell therapy is safe, partially effective in epithelial cancers


  • Daniela Ovadia — Agenzia Zoe
  • Oncology Conference reports
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Takeaway

  • E7 T-cell receptor (TCR)-T cells demonstrated safety and clinical activity in the treatment of highly refractory metastatic human papillomavirus (HPV)-16+ cancers.
  • In most patients with disease response, the authors saw a durable, complete regression of 1 or more tumors.
  • Treatment resistance appears to be driven by tumor-intrinsic, immune-related gene defects, especially if related to antigen processing and presentation.

Why this matters

  • T cells genetically engineered with an antigen receptor (involving chimeric antigen receptor or TCR) are successful in treating B-cell malignancies and associated with encouraging results in melanoma and synovial cell sarcoma.
  • It is not known if this type of treatment can be applied effectively to epithelial cancers, which account for 80%-90% of human malignancies.

Study design

  • Phase 1 clinical trial including 12 patients with metastatic HPV-16+ epithelial cancers, previously treated with a median of 4 (range, 3-7) anticancer agents, including programmed cell death protein 1 (PD-1) inhibitors.
  • All were treated with a 1-time infusion of genetically engineered T cells expressing a TCR targeting an HLA-A*02:01-restricted epitope of HPV-16 E7 (E7 TCR-T cells).
  • A lymphocyte-depleting conditioning regimen was administered before cell infusion, and high-dose systemic aldesleukin was administered after cell infusion.
  • Funding: NIH; Kite Pharma.

Key results

  • 6 patients (including 4 who previously received PD-1-based therapy) demonstrated objective clinical responses, including regression of bulky tumors and complete elimination of some tumors.
  • Responses occurred in patients with vulvar, anal, head and neck, and cervical cancer, with a duration ranging from 3 to 9 months.
  • Sustained, high-level presence of E7 TCR-T cells in peripheral blood was observed and correlated with cell dose but not with clinical response.
  • Infused T-cell characteristics did not correlate strongly with response.
    • Of the 4 resistant tumors studied:
      • 3 demonstrated genetic defects in HLA-A*02:01 or B2M (necessary components of the target complex).
      • 1 demonstrated copy loss with decreased expression of antigen presentation and interferon response molecules.
  • None of the 3 sensitive tumors studied showed these genetic defects.

Limitations

  • Included only 12 patients; enrollment is ongoing.

Expert commentary

  • “We learnt that T cells therapies are feasible in patients with solid tumors and that higher doses of preparative regimen and T cells are required compared to lymphoma," said panel discussant Marcela Maus of Harvard Medical School. "Toxicities are mainly related to the chemotherapy regimen. Responses are more frequent in synovial cell sarcoma than in other types of cancer. This could depend on the heterogeneity of antigen expression, the loss of HLA-expression, the number of targets per cell and the tumor microenvironment. We don’t know if the mechanisms of resistance are different across tumor histologies, and predictive biomarkers of response in solid tumors remain to be determined.”