Selective T-Cell Therapy Shows Activity in Treatment-Resistant Cancers

A protein designed to engage a small subset of T cells may show antitumor activity against treatment-resistant cancers without the severe side effects associated with less selective approaches, according to the results from an early study by researchers at the National Institutes of Health, Mass General Brigham and Memorial Sloan Kettering. The study was published last week in Nature Medicine.

“Patients whose tumors are advanced — particularly tumors that don’t respond well to immunotherapy — often have their backs against a wall. Few options remain once you reach that point, but these results highlight a more precise means of stimulating anti-tumor immunity that could provide another solution,” said co-corresponding author James Gulley, MD, PhD.

The protein investigated in this study is invikafusp alfa (invika), a first-in-class bispecific treatment that selectively targets Vβ6/Vβ10 T-cell subsets. Other T-cell–activating therapies can stimulate a broad range of T cells, potentially triggering widespread immune activation and serious side effects. Vβ6/Vβ10 T cells are enriched among tumor-infiltrating lymphocytes across many different cancers, allowing invika to restrict T-cell activation while targeting a population enriched in tumors.

Researchers recruited patients with a wide variety of cancers, most of whom had not responded well to immune checkpoint blockade. In the phase 1 portion of the START-001 trial, they studied varying doses of invika to evaluate the drug’s safety and determine the optimal dose. Several participants experienced flu-like side effects, though these were generally manageable.

The recommended phase 2 dose was 0.08 mg/kg intravenously every 2 weeks. Across both phases, 27 patients were treated at the optimal biological doses of 0.08 or 0.12 mg/kg. Of these, 16 (59.3%) did not experience disease progression. Four (14.8%) had reductions of more than 30% in the size of target tumors.

The researchers found that the drug expanded the targeted T-cell populations without significant expansion of other populations. The four tumor responses were associated with the largest shifts in the targeted populations, although immune activity did not always produce a measurable clinical response.

“It’s new and exciting to see activity in patients whose cancers had stopped responding to immunotherapy — a group of people with very few options left,” said co-first author Nicholas Tschernia, MD, in an NIH press release.