Developing Novel Immunotherapies for Paediatric Diffuse Midline Glioma

Primary supervisor: Richard Vile, King’s College London

Secondary supervisor: John Marshall, Queen Mary University of London

Project

Pediatric high grade gliomas and Diffuse Midline Glioma (DMG), previously diffuse intrinsic pontine glioma (DIPG) in particular, manifest as aggressive diseases with a two year median survival of less than 10%. Brainstem-located tumors are not surgically re-sectable due to their precarious neuroanatomical location and diffusely infiltrative nature. Although radiotherapy improves quality of life, it is not curative. Chimeric antigen receptor (CAR) T cells have been remarkably successful in the hematologic setting, but identification of truly tumor specific antigens for many solid tumor indications has limited broad translation. Two CAR target antigens have been described to be highly expressed in Diffuse Midline Glioma H3 K27M-mutant tumors: the checkpoint molecule B7H3 and the disialoganglioside and oncofetal antigen GD2 and our group plan to initiate a clinical trial of anti-B7-H3 CAR T cells for DMG in the coming year. However, as neither B7-H3 nor GD2 are exclusively restricted to neoplastic tissue, safety concerns exist with respect to on-target, off-tumor toxicity. Our group has conducted extensive preclinical characterization of multiple oncolytic viruses as immunotherapeutic agents for the treatment of cancer. In this respect, we have shown that delivery of the Conditionally Replication Competent adenovirus CRAd-657-CD40L provides a significant therapeutic advantage in multiple tumour models, including glioma, as a monotherapy and promotes cross priming of endogenous T cells against glioma associated antigens. As a result, we have recently initiated a clinical trial of CRAd-657-CD40L as a monotherapy. Pre-clinically, we have shown that CRAd-657-CD40L can potentiate CAR T cell therapy against tumours through a variety of mechanisms including both CAR T cell activation and endogenous T cell activation. In this proposal, we will leverage the tumour tropism of CRAd-657-CD40L to co-deliver a CAR target for DMG along with CD40L. The goal of this proposal is to develop a dual therapy approach which combines both direct tumor cell viral oncolysis and CAR T cytolysis, enhanced CAR T cell recruitment/activation by virus-mediated inflammation, and importantly, CD40L-mediated mobilization of endogenous antigen presenting cells, B cells and T cells. We will engineer an oncolytic vector to deliver titratable levels of CD40L using the E. coli DHFR destabilizing domain, and an intracellularly truncated signaling-dead EGFRvIII molecule to be used in conjunction with safety tested EGFRvIII CAR T cells. The safety and efficacy of the OV-CAR T approach will be evaluated in a genetically engineered immunocompetent model of DMG. This project will provide novel insight into how CD40L can mobilize an endogenous B cell and T cell response and support CAR T therapy. This studentship will, therefore, capitalize on the properties of designer oncolytic viruses to enable the use of CAR T cell therapy in paediatric high-grade glioma, and in particular apply existing safety tested immunotherapies to a devastating and urgent unmet clinical need.

Candidate background

This project would suit candidates with a background in cancer biology, tumour immunology, virology, molecular biology and /or cell biology

Potential placements

1. Michael Barry, Mayo Clinic (US)
2. Alan Melcher, ICR
3. Drs. Lopez & Cockle, Evelina, KCL

References

1. Wongthida P, Schuelke MR, Driscoll CB, Kottke T, Thompson JM, Tonne J, Stone C, Huff AL, Wetmore C, Davies JA, Parker AL, Evgin L, Vile RG. Ad-CD40L mobilizes CD4 T cells for the treatment of brainstem tumors. Neuro Oncol. 2020 Dec 18;22(12):1757-1770. doi: 10.1093/neuonc/noaa126. PMID: 32459315; PMCID: PMC7746943.
2. Schuelke MR, Gundelach JH, Coffey M, West E, Scott K, Johnson DR, Samson A, Melcher A, Vile RG, Bram RJ. Phase I trial of sargramostim/pelareorep therapy in pediatric patients with recurrent or refractory high-grade brain tumors. Neurooncol Adv. 2022 Jun 17;4(1):vdac085. doi: 10.1093/noajnl/vdac085. PMID: 35821679; PMCID: PMC9268737.
3. Liseth O, Appleton E, Kendall B, Thompson J, Sangsuwannukul T, Tonne J, Diaz RM, Evgin L, Patrikeev A, Sarbia N, Foo S, Harrington K, Ono M, Melcher A, Vile R. Engagement of the TCR against an oncolytic virus generates a population of effector CAR T cells with potent antitumor activity. Sci Adv. 2026 Jun 5;12(23):eaef5331. doi: 10.1126/sciadv.aef5331. Epub 2026 Jun 5. PMID: 42247513; PMCID: PMC13240226.
4. Evgin L, Kottke T, Tonne J, Thompson J, Huff AL, van Vloten J, Moore M, Michael J, Driscoll C, Pulido J, Swanson E, Kennedy R, Coffey M, Loghmani H, Sanchez-Perez L, Olivier G, Harrington K, Pandha H, Melcher A, Diaz RM, Vile RG. Oncolytic virus-mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice. Sci Transl Med. 2022 Apr 13;14(640):eabn2231. doi: 10.1126/scitranslmed.abn2231. Epub 2022 Apr 13. PMID: 35417192; PMCID: PMC9297825.
5. Appleton E, Chiocca EA, Ungerechts G, Melcher A, Vile R. Oncolytic viruses as anticancer agents: clinical progress and remaining challenges. Lancet. 2025 Sep 20;406(10509):1295-1312. doi: 10.1016/S0140-6736(25)01206-1. PMID: 40975614.