Favorable Immune Profile Linked to VT1021 Treatment Response in rGBM

David Peereboom, MD

Cleveland Clinic

Patients with recurrent glioblastoma (rGBM) who responded to VT1021, a therapeutic cyclic peptide, had beneficial and sustained changes to immune markers associated with response, according to analysis of a phase 1/2 trial.¹

In 22 evaluable patients with rGBM, those who had a complete response (CR) or partial response (PR) had an increase in total and proliferating cytotoxic T-cells (CTLs) and higher CTL/Treg ratio as well as a decrease in PD-L1–positive myeloid-derived suppressor cells (MDSCs). These changes were not observed in those who had stable disease (SD) or progressive disease (PD).

“What we found is that some of the immune stimulation occurred in patients who responded well to treatment and did not occur in patients who did not have a response,” said David M. Peereboom, MD, in an interview with Targeted Oncology. “That gives us an indicator that this drug is doing what we want it to do, and it’s stimulating the immune system, and hopefully that’s something we can build on.”

VT1021 has been shown to inhibit tumor growth by stimulating the protein thrombospondin-1, with responses observed in a phase 1/2 dose expansion study (NCT03364400) in solid tumors. In 22 evaluable patients with rGBM, there were 3 CRs and 1 PR, plus 6 patients with SD.

Patients received VT1021 at a dose of 11.8 mg/kg twice weekly, for an average study duration of over 120 days.

Peereboom, a professor of medicine at Case Western Reserve University and a neuro-oncologist at the Cleveland Clinic, said the efficacy in this dose expansion cohort was favorable. “There were patients with CR [or] PR, which in rGBM unfortunately is pretty uncommon. We also have 1 patient who’s been treated for almost 1000 days and has no disease left, so we’re very encouraged by that.”

Peripheral blood samples were collected, and immune cell profiles were analyzed by flow cytometry in order to interpret the immune activity of the drug. Peereboom presented the results of the immune profiling in a poster session at the 2023 American Society of Clinical Oncology Annual Meeting.

At day 53 of treatment, patients with CR/PR had 20% increase in total CTLs as a percentage of total T cells, rising from 33.79% pre-treatment to 40.42% 6 hours after treatment. These patients had a 66% increase in proliferating CTLs from 1.37% of total T cells pre-treatment to 2.28% 6 hours after treatment. There was a 63% increase in the ratio of CTL to Treg cells, from 7.85 pre-treatment to 12.81 after 6 hours. No change or decrease in these CTL parameters was observed in patients with an SD or PD. The change from day 1 pre-treatment to 6 hours after treatment was not significant.

Additionally, investigators observed a sustained decrease in PD-L1–positive MDSCs after VT1021 treatment in responders. The day 1 pre-treatment percentage of PD-L1+ MDSCs out of all MDSCs was 95.96%, whereas at day 53 it was 92.66% before treatment and 88.06% 6 hours after treatment. This decrease was not observed among patients with SD or PD.

Moreover, a sustained increase and induction of thrombospondin-1 was correlated with response to VT1021, and the levels of thrombospondin-1 correlated to the CTL profile in a time course manner. According to Peereboom, the findings suggest baseline thrombospondin-1 could be potentially used as a predictive biomarker.

“If that was high at baseline, those are the patients who had response,” he explained. “The idea would be that in the next study, to find the patients who had the high thrombospondin levels, and those would be the patients who we would treat. If the thrombospondin levels were not high, then we would offer them a different treatment.”

Based on the efficacy results, VT1021 is being investigated in the phase 2/3 GBM AGILE adaptive platform trial (NCT03970447), which is matching patients with rGBM to effective therapies based on subtypes.

The investigators noted that though the immune profile findings are positive and consistent with the mechanism of action of VT1021, this is a small sample size and lacks a control arm.

“We need to do larger studies to actually confirm with larger numbers of patients that this treatment is in fact effective,” said Peereboom.

_Reference:

_{1. Chen JJ, Vincent M, Peereboom DM, et al. Immune profiling in patients with glioblastoma treated with VT1021 in a phase I/II expansion study. J Clin Oncol. 2023;41(suppl_16):2021. doi:10.1200/JCO.2023.41.16_suppl.2021}