508MO - Spatial remodeling of the immune tumor microenvironment after radiotherapy and CXCL12 inhibition in glioblastoma in the phase I/II GLORIA trial

Background

Radiotherapy (RT) causes upregulation of CXCL12, a chemokine facilitating recruitment of tumor-associated macrophage (TAM) precursors promoting neovasculogenesis and the formation of an immunosuppressive tumor microenvironment (TME). Here, we report an in-depth analysis of the immune TME (iTME) in patients of the multicentric phase 1/2 GLORIA trial (NCT04121455) which combines RT and CXCL12 inhibition with the RNA-Spiegelmer NOX-A12.

Methods

We analyzed tumor tissue of 10 GLORIA patients with newly diagnosed, incompletely resected (n=8) or biopsied (n=2) GBM with ECOG≤2 lacking MGMT promoter methylation. All patients received standard RT and escalating dose levels of continuous (24/7) i.v. infusions of NOX-A12. Two patients underwent re-surgery, whereas one was diagnosed with pseudoprogression (PsP) and one with recurrence. To characterize the iTME, we used highly multiplexed immunofluorescence (mIF) imaging. As a comparison to the GLORIA cohort, we investigated the pre/post-therapeutic iTME of reference patients receiving standard-of-care (n=7) treatment.

Results

In all samples analyzed, CXCL12 co-localized with endothelial cells. Unlike in the reference cohort, matched pre-/post-treatment tissue analysis of the patient with PsP revealed endothelial and gliomal CXCL12 depletion following treatment with NOX-A12, confirming the mode of action of the drug. Both post-treatment GLORIA samples showed intralesional clustering of activated CD8⁺ T cells. In the non-responder diagnosed with recurrence, a pro-tumorigenic spatial rearrangement of the iTME was observed, characterized by a presence of M2-like TAMs in the proximity of the perivascular T cell clusters, confirmed by nearest neighbor analysis. None of the reference patients showed similar alterations of the iTME.

Conclusions

m IF of matched pre-/post-therapy tissue samples from the ongoing GLORIA trial supports the proposed modes of action of RT and NOX-A12 counteracting vasculogenesis and modulating the iTME reflected through its spatial rearrangement. This opens up the question of a targetable, compartment-specific role of CXCL12 to be further assessed.

Clinical trial identification

NCT04121455.

Editorial acknowledgement

Legal entity responsible for the study

TME Pharma.

Funding

TME Pharma.

Disclosure

S. Leonardelli: Financial Interests, Personal, Funding, Travel Reimbursemen: TME Pharma; Financial Interests, Personal, Advisory Role: AlphaSights Ltd; Financial Interests, Institutional, Funding: TME Pharma. J.P. Layer: Other, Personal, Full or part-time Employment: MVZ Venusberg gGmgh; Financial Interests, Personal, Stocks/Shares: BioNtech, Siemens Healthineers, Bayer, TME Pharma; Financial Interests, Institutional, Funding: TME Pharma; Financial Interests, Personal, Funding, Travel reimbursement: TME Pharma; Financial Interests, Personal, Advisory Role: Siemens Healthineers. C. Schaub: Financial Interests, Personal, Stocks/Shares: Bayer. E. Sperk: Financial Interests, Personal, Financially compensated role, + Travel expenses: Zeiss Meditech. M. Glas: Financial Interests, Personal, Financially compensated role: Novocure, Roche, Novartis, AbbVie, Seagan, TME Pharma, Daiichi Sankyo Pharmaceutical, Merck; Financial Interests, Personal, Advisory Role: Novocure, Seagan, AAA HealthCare; Financial Interests, Personal, Research Funding: Novocure; Financial Interests, Personal, Funding, Travel Reimbursement: Novocure. C. Seidel: Financial Interests, Personal, Advisory Role: Seagen; Financial Interests, Personal, Financially compensated role: Seagen . U. Herrlinger: Financial Interests, Personal, Advisory Role: Janssen, Bayer; Financial Interests, Personal, Speaker’s Bureau: Medac. F.A. Giordano: Financial Interests, Personal, Advisory Role: Cureteq, Carl Zeiss Meditec, Targeted Medical Education, Inc.; Financial Interests, Personal, Funding: Carl Zeiss Meditec, TME Pharma; Financial Interests, Personal, Expert Testimony: Carl Zeiss Meditec; Financial Interests, Personal, Royalties, Patent: US10857388B2; Financial Interests, Personal, Other: Federal Joint Committee (G-BA); Financial Interests, Personal, Stocks/Shares: TME Pharma; Financial Interests, Personal, Financially compensated role: AstraZeneca, Carl Zeiss Meditec, Medac, TME Pharma, Cureteq; Financial Interests, Personal and Institutional, Research Funding: Carl Zeiss Meditec, TME Pharma. M. Hölzel: Financial Interests, Personal, Financially compensated role: Bristol Myers Squibb, Novartis; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Novartis; Financial Interests, Personal and Institutional, Research Funding: TME Pharma; Financial Interests, Personal, Funding, Travel reimbursement: TME Pharma. All other authors have declared no conflicts of interest.