Labiano et al. showed that in mice with diffuse midline glioma (DMG), intratumoral co-administration of the Delta-24-RGD oncolytic virus and agonist CD40 antibodies extended survival and induced complete responses in 40% of mice, with protection from rechallenge that was dependent on local and resident immune memory. No signs of toxicity were observed. Mechanistically, treatment induced TME remodeling towards a pro-inflammatory landscape. Macrophage and microglia mediated recruitment of mature, cross-presenting cDC1s that supported the accumulation of activated and proliferating CD4+ and CD8+ TILs in tumors.
Contributed by Lauren Hitchings
ABSTRACT: Diffuse midline glioma (DMG) is a devastating pediatric brain tumor. The oncolytic adenovirus Delta-24-RGD has shown promising efficacy and safety in DMG patients but is not yet curative. Thus, we hypothesized that activating dendritic cells (DCs) through the CD40 costimulatory receptor could increase antigen presentation and enhance the anti-tumor effect of the virus, resulting in long-term responses. This study shows that the intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody is well tolerated and induces long-term anti-tumor immunity, including complete responses (up to 40%) in DMG preclinical models. Mechanistic studies revealed that this therapy increased tumor-proliferating T lymphocytes and proinflammatory myeloid cells, including mature DCs with superior tumor antigen uptake capacity. Moreover, the lack of cross-presenting DCs and the prevention of DC recruitment into the tumor abolish the Delta-24-RGD+anti-CD40 anti-DMG effect. This approach shows potential for combining virotherapy with activating antigen-presenting cells in these challenging tumors.
Author Info: (1) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pampl
Author Info: (1) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. Electronic address: slalminana@unav.es. (2) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (3) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (4) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (5) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (6) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (7) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (8) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (9) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (10) Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA. (11) Bioinformatics Platform, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. (12) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (13) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (14) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (15) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (16) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (17) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (18) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (19) Jack Martin Fund Division of Pediatric Hematology-oncology, Mount Sinai, New York, NY, USA. (20) Dpt. Of NeuroOncology, UT MD Anderson Cancer Center, Houston, TX, USA. (21) Dpt. Of NeuroOncology, UT MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (23) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (24) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. Electronic address: mmalonso@unav.es.
