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Clinical Trial
. 2023 Jan 25;3(1):130-139.
doi: 10.1158/2767-9764.CRC-22-0420. eCollection 2023 Jan.

A Phase I Trial of VEGF-A Inhibition Combined with PD-L1 Blockade for Recurrent Glioblastoma

Daniel Chiu #  1 , Jingjing Qi #  2 , Tin Htwe Thin  3 , Monica Garcia-Barros  3 , Brian Lee  2 , Mary Hahn  1 , John Mandeli  4 , Puneet Belani  5 , Kambiz Nael  6 , Omid Rashidipour  3 , Saadi Ghatan  2   7 , Constantinos G Hadjipanayis  7 , Raymund L Yong  7 , Isabelle M Germano  7 , Rachel Brody  3 , Nadejda M Tsankova  3 , Sacha Gnjatic  2 , Seunghee Kim-Schulze  2 , Adília Hormigo  8
Affiliations
Clinical Trial

A Phase I Trial of VEGF-A Inhibition Combined with PD-L1 Blockade for Recurrent Glioblastoma

Daniel Chiu et al. Cancer Res Commun. .

Abstract

Purpose: The treatment of glioblastoma (GBM) poses challenges. The use of immune checkpoint inhibition (ICI) has been disappointing as GBM is characterized by low mutational burden and low T-cell infiltration. The combination of ICI with other treatment modalities may improve efficacy.

Patient and methods: Patients with recurrent GBM were treated with avelumab, a human IgG1 antibody directed against PD-L1 (part A), or avelumab within a week after laser interstitial thermal therapy (LITT) and continuation of avelumab (part B). Bevacizumab was allowed to be combined with ICI to spare steroid use. The primary objective was to characterize the tolerability and safety of the regimens. The secondary objectives included overall survival, progression-free survival (PFS), signatures of plasma analytes, and immune cells.

Results: A total of 12 patients (median age 64; range, 37-73) enrolled, five in part A and seven in part B. Two serious adverse events occurred in the same patient, LITT treated, not leading to death. The median survival from enrollment was 13 months [95% confidence interval (CI), 4-16 months] with no differences for part A or B. The median PFS was 3 months (95% CI, 1.5-4.5 months). The decrease in MICA/MICB, γδT cells, and CD4+ T cell EMRA correlated with prolonged survival.

Conclusions: Avelumab was generally well tolerated. Adding bevacizumab to ICI may be beneficial by lowering cytokine and immune cell expression. The development of this combinatorial treatment warrants further investigation. Exploring the modulation of adaptive and innate immune cells and plasma analytes as biomarker signatures may instruct future studies in this dismal refractory disease.

Significance: Our phase I of PD-L1 inhibition combined with LITT and using bevacizumab to spare steroids had a good safety profile for recurrent GBM. Developing combinatory treatment may help outcomes. In addition, we found significant immune modulation of cytokines and immune cells by bevacizumab, which may enhance the effect of ICI.

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Conflict of interest statement

K. Nael reports other from Olea Medical outside the submitted work. C.G. Hadjipanayis reports personal fees from Stryker Corp, Hemerion, and Synaptive Medical outside the submitted work. S. Gnjatic reports grants from EMD Serono during the conduct of the study; grants from Bristol-Myers Squibb, Genentech, Boehringer-Ingelheim, Takeda, and Regeneron outside the submitted work; in addition, S. Gnjatic has a patent to multiplex IHC to characterize tumors and treatment responses issued. A. Hormigo reports grants from EMD Serono, Inc. (CrossRef Funder ID:10.13039/100004755), an affiliate of Merck KGaA, as part of an alliance between Merck and Pfizer during the conduct of the study; grants from National Brain Tumor Society, Cancer Research Institute, V Foundation, Novocure, and personal fees from TargTex outside the submitted work. No disclosures were reported by the other authors.

Figures

FIGURE 1
FIGURE 1
Disease course, response to treatment, and outcomes. A, Shows treatments received by patients with recurrent glioblastoma, the duration of the treatments to closing the study with the key within the plot showing all symbols and color coding, and each bar representing a patient. B, Shows the percent change of tumor growth or reduction from baseline at enrollment and through the treatment. C, Indicates survival (left) and PFS (right) Kaplan–Meier curves.
FIGURE 2
FIGURE 2
Chromogenic multiplex expression analysis of different biomarkers in formalin-fixed paraffin-embedded tissue of a patient's tumor with a survival of 13 months (34364) and another 3.5 months (34368) after treatment and quantitative analysis using Halo image analysis platform. A, Representative field for chromogenic multiplex for D45(brown)/Ki67(purple)/CD3(teal)/CD163(yellow) for case 34364 (left) and 34368 (right) tissues. Color deconvolution for each marker was obtained using HALO image analysis, and quantitative analysis for Ki67 and CD163 is shown in E (CD45 and CD3 color deconvolution and HALO quantification is shown in Supplementary Fig. S2). B, Representative field for chromogenic multiplex for PD- L1 (brown)/CD8 (purple) with their respective deconvolution images and quantification on E. C, Representative field for CD31 IHC in brown with image deconvolution with quantitative analysis in E. D, Representative field for CD68 IHC in yellow with image deconvolution with quantitative analysis in E.
FIGURE 3
FIGURE 3
Treatment effect of combining bevacizumab with avelumab. A, Kaplan–Meier curves showing overall survival of patients treated with bevacizumab (blue) versus those never treated with bevacizumab (red). B, Difference of cytokine NPX comparing baseline, avelumab treated and avelumab combined with bevacizumab. C, Differentially expressed CD4+ T cells EMRA and γδT cells in patients’ samples treated with avelumab alone (red) combined with bevacizumab (green).
See this image and copyright information in PMC

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