Immune Changes Show Response Correlation with VT1021 in Recurrent GBM

Neurons in brain | Image Credit: whitehoune - www.stock.adobe.com

The use of the novel therapeutic VT1021 in patients with recurrent glioblastoma (rGBM) showed durable responses by inhibiting the tumor growth via stimulation of thrombospondin-1, which altered the tumor microenvironment. However, long-term findings showed that patients with a better immune response throughout treatment had better results compared with those who did not exhibit much of an immune response, according to results presented at the 2023 ASCO Annual Meeting.¹

These data from patients with rGBM on the phase 1/2 study (NCT03364400) were presented in a poster session in ASCO by David Peereboom, MD, that showed in 22 evaluable patients with rGBM those with an increase of cytotoxic T cells (CTL) or PD-L1 positive myeloid-derived suppressor cells (MDSCs) correlated with better responses to treatment.

At day 53 of treatment with the cyclic peptide first-in-class agent, patients with either a complete response (CR) or partial response (PR) had a 20% increase in their total CTLs, with the largest increase happening in proliferating CTLS at 66% compared with 63% in their CTL/Treg ratio. Whereas, in patients that either had stable disease (SD) or progressive disease (PD) had no increase or decrease of their CTLs. Further, patients with a CR or PR showed a sustained decrease of PD-L1 positive MDSCs but those with either SD or PD did not exhibit this change.

In an interview with Targeted OncologyTM, Peereboom, director of clinical research at the Cleveland Clinic brain tumor center, discusses the meaning of these findings and where researchers will go next in studying VT1021 for patients with rGBM.

Targeted OncologyTM: Can you provide some background on the poster that discussed the findings of this study?

PEEREBOOM: The poster [discussed] brain tumor patients using a drug called VT1021. It is a drug that inhibits something called thrombospondin, and what that is, is a protein that stimulates the growth of glioma cells. What we found is that the drug stimulates the immune system, and we've 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. So, that gives us an indicator that this drug is doing what we want it to do, and that it's really stimulating the immune system. Hopefully, that's something that we can build on.

What were some of the methods of the study to assess a positive response from patients?

[There are] certain types of lymphocytes [we looked at]. There are good lymphocytes that attack a tumor and there are others that interfere with immune response. What we found is that the ratio of the good lymphocytes to the bad lymphocytes is high in the patients who did well [on the study]. Whereas, in patients who did not have a response, or their tumor progressed, though ratios were not favorable. It gave us a glimpse into what the immune system is doing in response to this treatment.

Please discuss the main findings of the study.

So, what we looked at are different types of T-lymphocytes, which are part of the immune system. Some T-lymphocytes are called cytotoxic T-lymphocytes, or CTLs and others are called T-regs, for T-regulatory cells. So, the cytotoxic T cells, or CTLs, are what we want and with this treatment, there was a higher number of both the CTLs and a subpopulation of [patients with] proliferating CTL. We knew the immune system was getting revved up, so that's a good thing. And at the same time, the patients who had suppression of their T-regs, those were also in the group that did well [on the treatment]. So, [there were patients who] had a complete response, or a partial response, which, in recurrent glioblastoma is unfortunately uncommon. And 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.

What are the next steps for this research?

The next steps are to do a larger study, and the reason we need to do a larger study is to confirm with larger numbers of patients that this treatment is, in fact, affecting them. The other thing we want to do is to look at some of the baseline biomarkers that seemed to be elevated in patients who were destined to do well, so these were [observed] at baseline before they got any treatment. What we found is with the thrombospondin in the peripheral blood, if that was high at baseline those are the patients who had responses. The idea would be, in the next study, is to find the patients who had the high thrombospondin levels and that those would be the patients we would treat. Then, if the thrombospondin levels were not high, we would offer them a different treatment.

What unmet needs still exist in this space?

There is so much unmet need in patients with recurrent glioblastoma. So first, to just to try to stop the progression of their symptoms, stop the progression of their disease, and improve their quality of life. That's a huge unmet need, we really need better drugs. There are people in the scientific labs across the country and across the world who are working on those things, so it's an exciting time to be in the field for sure.

_Reference

_{Chen J, Vincent M, Peereboom D, et al. Immune profiling in patients with glioblastoma treated with VT1021 in a phase I/II expansion study. Presented at: 2023 ASCO Annual Meeting; June 6-11, 2023; Chicago, Illinois. Abstract 2021.}