Human macrophages engineered to secrete a bispecific T cell engager support antigen-dependent T cell responses to glioblastoma
Open Access
- 1 January 2020
- journal article
- research article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 8 (2), e001202
- https://doi.org/10.1136/jitc-2020-001202
Abstract
Background Targeted and effective treatment options are needed for solid tumors, including glioblastoma (GBM), where survival rates with standard treatments are typically less than 2 years from diagnosis. Solid tumors pose many barriers to immunotherapies, including therapy half-life and persistence, tumor penetrance, and targeting. Therapeutics delivered systemically may not traffic to the tumor site. If cellular therapies or drugs are able to access the tumor site, or can be delivered directly within the tumor, treatments may not persist for the duration necessary to reduce or eliminate tumor burden. An approach that allows durable and titratable local therapeutic protein delivery could improve antitumor efficacy while minimizing toxicities or unwanted on-target, off-tissue effects. Methods In this study, human monocyte-derived macrophages were genetically engineered to secrete a bispecific T cell engager (BiTE) specific to the mutated epidermal growth factor variant III (EGFRvIII) expressed by some GBM tumors. We investigated the ability of lentivirally modified macrophages to secrete a functional BiTE that can bind target tumor antigen and activate T cells. Secreted BiTE protein was assayed in a range of T cell functional assays in vitro and in subcutaneous and intracranial GBM xenograft models. Finally, we tested genetically engineered macrophages (GEMs) secreting BiTE and the proinflammatory cytokine interleukin (IL)-12 to amplify T cell responses in vitro and in vivo. Results Transduced human macrophages secreted a lentivirally encoded functional EGFRvIII-targeted BiTE protein capable of inducing T cell activation, proliferation, degranulation, and killing of antigen-specific tumor cells. Furthermore, BiTE secreting macrophages reduced early tumor burden in both subcutaneous and intracranial mouse models of GBM, a response which was enhanced using macrophages that were dual transduced to secrete both the BiTE protein and single chain IL-12, preventing tumor growth in an aggressive GBM model. Conclusions The ability of macrophages to infiltrate and persist in solid tumor tissue could overcome many of the obstacles associated with systemic delivery of immunotherapies. We have found that human GEMs can locally and constitutively express one or more therapeutic proteins, which may help recruit T cells and transform the immunosuppressive tumor microenvironment to better support antitumor immunity.Funding Information
- Steven Higgins Brain Tumor Fund
- Stand Up To Cancer
- Aldarra Foundation
This publication has 43 references indexed in Scilit:
- Human chimeric antigen receptor macrophages for cancer immunotherapyNature Biotechnology, 2020
- Targeted BiTE Expression by an Oncolytic Vector Augments Therapeutic Efficacy Against Solid TumorsClinical Cancer Research, 2018
- Cancer immunotherapy using checkpoint blockadeScience, 2018
- T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330Blood Cancer Journal, 2015
- Mutational heterogeneity in cancer and the search for new cancer-associated genesNature, 2013
- Specific Recognition and Killing of Glioblastoma Multiforme by Interleukin 13-Zetakine Redirected Cytolytic T CellsCancer Research, 2004
- Extremely potent, rapid and costimulation‐independent cytotoxic T‐cell response against lymphoma cells catalyzed by a single‐chain bispecific antibodyInternational Journal of Cancer, 2002
- Induction of antitumor immunity by direct intratumoral injection of a recombinant adenovirus vector expressing interleukin-12Cancer Gene Therapy, 1999
- Bioactive murine and human interleukin-12 fusion proteins which retain antitumor activity in vivoNature Biotechnology, 1997
- The molecular control of cell division, differentiation commitment and maturation in haemopoietic cellsNature, 1989