A First-In-Human Phase I, Open Label, Safety and Tolerability Study of Escalating Multiple Doses of Intratumoral MQ710, a Multi-Transgene Expressing Modified Vaccinia Virus Ankara-Based Virotherapy, Alone and in Combination With the Systemic Checkpoint Inhibitor Pembrolizumab in Solid Tumors

Participants of this study will have a diagnosis of a solid tumor cancer that has come back to its original location or spread beyond its original location (advanced), came back (relapsed) or worsened (refractory) after standard treatments, or no standard treatments are available for the participants' cancer. The purpose of this study if to find the highest dose of MQ710 that causes few or mild side effects in participants with a solid tumor cancer diagnosis.

Start Date04 May 2023

Sponsor / Collaborator

Memorial Sloan Kettering Cancer Center

100 Clinical Results associated with OX40L x Flt3L

100 Translational Medicine associated with OX40L x Flt3L

0 Patents (Medical) associated with OX40L x Flt3L

Literatures (Medical) associated with OX40L x Flt3L

07 Aug 2023·Journal of Experimental Medicine

OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs

Article

Author: Mazo, Gregory ; Liu, Shuaitong ; Wang, Jiahu ; Merghoub, Taha ; Zhang, Tuo ; Choi, John ; Rice, Charles M. ; Xiang, Jenny Zhaoying ; Yang, Ning ; Yan, Wei ; Rossi, Anthony ; Deng, Liang ; Tan, Adrian ; Wang, Yi ; Luna, Joseph M. ; Wolchok, Jedd D. ; Tariq, Shanza Baseer

Effective depletion of immune suppressive regulatory T cells (Tregs) in the tumor microenvironment without triggering systemic autoimmunity is an important strategy for cancer immunotherapy. Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus with a long history of human use. Here, we report rational engineering of an immune-activating recombinant MVA (rMVA, MVA∆E5R-Flt3L-OX40L) with deletion of the vaccinia E5R gene (encoding an inhibitor of the DNA sensor cyclic GMP-AMP synthase, cGAS) and expression of two membrane-anchored transgenes, Flt3L and OX40L. Intratumoral (IT) delivery of rMVA (MVA∆E5R-Flt3L-OX40L) generates potent antitumor immunity, dependent on CD8+ T cells, the cGAS/STING-mediated cytosolic DNA-sensing pathway, and type I IFN signaling. Remarkably, IT rMVA (MVA∆E5R-Flt3L-OX40L) depletes OX40hi regulatory T cells via OX40L/OX40 interaction and IFNAR signaling. Single-cell RNA-seq analyses of tumors treated with rMVA showed the depletion of OX40hiCCR8hi Tregs and expansion of IFN-responsive Tregs. Taken together, our study provides a proof-of-concept for depleting and reprogramming intratumoral Tregs via an immune-activating rMVA.

01 Oct 2020·Cell ReportsQ1 · BIOLOGY

Dendritic Cells and Microglia Have Non-redundant Functions in the Inflamed Brain with Protective Effects of Type 1 cDCs

Q1 · BIOLOGY

ArticleOA

Author: Justicia, Carles ; Cugota, Roger ; Miró-Mur, Francesc ; Planas, Anna M ; Cano, Eva ; Gelderblom, Mathias ; Brait, Vanessa H ; Salas-Perdomo, Angélica ; Del Fresno, Carlos ; Gallizioli, Mattia ; Pedragosa, Jordi ; Magnus, Tim ; Arbaizar-Rovirosa, Maria ; Otxoa-de-Amezaga, Amaia ; Bonfill-Teixidor, Ester ; Ruiz-Jaén, Francisca ; Sancho, David

Brain CD11c⁺ cells share features with microglia and dendritic cells (DCs). Sterile inflammation increases brain CD11c⁺ cells, but their phenotype, origin, and functions remain largely unknown. We report that, after cerebral ischemia, microglia attract DCs to the inflamed brain, and astroglia produce Flt3 ligand, supporting development and expansion of CD11c⁺ cells. CD11c⁺ cells in the inflamed brain are a complex population derived from proliferating microglia and infiltrating DCs, including a major subset of OX40L⁺ conventional cDC2, and also cDC1, plasmacytoid, and monocyte-derived DCs. Despite sharing certain morphological features and markers, CD11c⁺ microglia and DCs display differential expression of pattern recognition receptors and chemokine receptors. DCs excel CD11c^- and CD11c⁺ microglia in the capacity to present antigen through MHCI and MHCII. Of note, cDC1s protect from brain injury after ischemia. We thus reveal aspects of the dynamics and functions of brain DCs in the regulation of inflammation and immunity.

01 May 2003·ImmunityQ1 · MEDICINE

CD4+CD3− Accessory Cells Costimulate Primed CD4 T Cells through OX40 and CD30 at Sites Where T Cells Collaborate with B Cells

Q1 · MEDICINE

Article

Author: Margaret D Goodall ; Chandra Raykundalia ; Lucy S.K Walker ; Peter J.L Lane ; Mi-Yeon Kim ; Helen E Wiggett ; Fabrina M.C Gaspal ; Fiona M McConnell ; Adam Gulbranson-Judge

In this report we identify an accessory cell that interacts with primed and memory T cells at sites where they collaborate with B cells. These cells are distinguished from conventional dendritic cells by their lack of response to Flt3 ligand and their inability to process antigen. Unlike dendritic cells, the CD4(+)CD3(-) cells have little CD80 or CD86 expression but do express high levels of the TNF ligands, OX40 ligand and CD30 ligand. We show that Th2-primed cells express the receptors for these TNF ligands and preferentially survive when cocultured with these cells. Furthermore, we show that the preferential survival of OX40(+) T cells and support of memory T cell help for B cells are linked to their association with CD4(+)CD3(-) cells in vivo.

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