3 results found
Symington J, Perryman R, Morse S, et al., 2022, TMIC-31. ADI-PEG20 RESTORES IMMUNITY IN THE TUMOR MICROENVIRONMENT AND ERADICATES GBM TUMORS IN MICE WHEN COMBINED WITH RADIATION, Neuro-Oncology, Vol: 24, Pages: vii278-vii278, ISSN: 1522-8517
<jats:title>Abstract</jats:title> <jats:p>Glioblastoma (GBM) is a primary brain tumour with poor prognosis and limited treatment options. We previously demonstrated that arginine deprivation by ADI-PEG20 is effective in GBM tumors which are auxotrophic for arginine. We also reported that ADI-PEG20 has efficacy in arginine non-auxotrophic GBM when combined with radiation in the presence of an immune competent environment. Here, we present detailed mechanistic insight into our latter findings using multiplex Imaging Mass Cytometry (Fluidigm) and Spatial Transcriptomics (10x Genomics) of tumor samples treated with ADI-PEG20. ADI-PEG20 enhanced the expression on MHC class II on infiltrating CD11c+ dendritic cells and these cells colocalised specifically with CD4+ T cells. We also observed changes in the expression of PD-1/PD-L1 with ADI-PEG20 and this was further enhanced when ADI-PEG20 was combined with radiation. Moreover, combination therapy increased the expression of chemokines involved in immune cell recruitment and activation. Our findings demonstrate that arginine deprivation restores immune function in the tumor microenvironment of arginine non-auxotrophic GBM tumors and suggests that combinations with immunotherapies will further enhance efficacy for GBM tumors.</jats:p>
Symington J, Perryman R, Morse S, et al., 2022, ADI-PEG20 RESTORES IMMUNITY IN THE TUMOR MICROENVIRONMENT AND ERADICATES GBM TUMORS IN MICE WHEN COMBINED WITH RADIATION, 27th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO), Publisher: OXFORD UNIV PRESS INC, Pages: 278-278, ISSN: 1522-8517
Hajji N, Garcia-Revilla J, Sarmiento Soto M, et al., 2022, Arginine deprivation alters microglia polarity and synergises with radiation to eradicate non arginine auxotrophic glioblastoma tumors, Journal of Clinical Investigation, Vol: 132, Pages: 1-19, ISSN: 0021-9738
New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine depleting agent ADI-PEG20 in a non-arginine auxotrophic cellular background (Arginine Succinate Synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response with extended disease-free survival in an orthotopic immune competent model of GBM with no significant toxicity. ADI-PEG20 not only enhances the cellular sensitivity of Arginine succinate synthetase 1 positive GBM to ionising radiation by elevated production of nitric oxide (NO) and hence generation of cytotoxic peroxynitrites, but also promotes glioma-associated macrophages/microglia infiltration into tumors and turns their classical anti-inflammatory (pro-tumor) phenotype into a pro-inflammatory (anti-tumor) phenotype. Our results provide an effective, well-tolerated and simple strategy to improve GBM treatment which merits consideration for early evaluation in clinical trials.
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