Oral Presentation 9th Australasian Vaccines & Immunotherapeutics Development Meeting 2022

Enhancing Chimeric Antigen Receptor T cell efficacy against brain tumours with dual-targeting receptors (#30)

Hannah E Hughes-Parry 1 2 , Melinda Iliopoulos 1 , Kathy A Watson 1 , Andrew J Kueh 1 , Marco J Herold 1 2 , Ryan S Cross 1 , Misty R Jenkins 1 2 3
  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. The Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  3. Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia

The heterogeneity of solid tumours is a significant obstacle to the response and long-term remission of patient malignancies following Chimeric Antigen Receptor (CAR) T cell immunotherapy in the clinic. While long-term remission has been achieved against haematological cancers, relapses have frequently occurred several months post-treatment due to antigen escape, and solid tumour responses have been less effective1. Therefore, to improve solid tumour elimination and prevent relapse, CAR T cell immunotherapy may be improved by the targeting of multiple tumour-associated antigens through dual-specific CAR T cells, in which T cells are engineered to express CARs against multiple antigens. Existing studies have observed significant improvements over single-specific CAR T cells2,3; however, few studies have interrogated the underlying biology in immune competent systems.

 

Therefore, we generated dual-targeting CAR T cells using Her2 and EGFRvIII model tumour antigens and assessed their cytotoxic function against different heterogeneous tumour targets in in vitro killing assays. We observed that dual-specific CAR T cells exhibit enhanced killing of heterogeneous tumour cells compared to single-specific and pooled single-specific CAR T cells. This enhanced ability for multi-antigen targeting T cells to eliminate heterogeneous tumours allows for more complete clearance of the entire tumour cell population and may subsequently mitigate opportunities for antigen escape.

 

To further explore the utility of multitargeting tumour antigens in vivo, we used CRISPR technology to generate an immunocompetent mouse model (RHEO), tolerant to human Her2, EGFRvIII and OVA, to evaluate dual-targeted CART cell immunotherapy approaches.

 

Here, we will present this novel RHEO mouse model, and the characterised subcutaneous and intracranial growth of several solid tumour models. We will discuss new approaches to tackling heterogeneous solid tumours, such as glioblastoma, and present unpublished findings on the utility of targeting multiple tumour antigens simultaneously in the context of an intact immune system.

  1. 1. O'Rourke, D.M.; Nasrallah, M.P.; Desai, A.; Melenhorst, J.J.; Mansfield, K.; Morrissette, J.J.D.; Martinez-Lage, M.; Brem, S.; Maloney, E.; Shen, A., et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 2017, 9, doi:10.1126/scitranslmed.aaa0984.
  2. 2. Ruella M, Barrett DM, Kenderian SS, et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. The Journal of Clinical Investigation 2016; 126: 3814-3826.
  3. 3. Hegde M, Corder A, Chow KKH, et al. Combinational Targeting Offsets Antigen Escape and Enhances Effector Functions of Adoptively Transferred T cells in Glioblastoma. Molecular Therapy 2013; 21: 2087-2101.