Development of a universal antigen as a target for chimeric antigen receptor therapy – ICARE

Chimeric antigen receptor (CAR) cell therapy represents a ground-breaking advancement in cellular immunotherapy, showcasing remarkable clinical efficacy in hematological cancers. However, its broader application is hindered by several challenges, with the primary obstacle being the low specificity of target antigens for diseased cells, which often leads to significant toxicity in healthy tissues. The ideal target antigen should exhibit restricted and homogenous expression within targeted cells, a criterion rarely met in practice. To address this limitation, the ICARE project endeavors to engineer a novel antigen, tailored to meet these stringent criteria, thereby enhancing the efficacy of CAR therapies across various diseases. Initially focusing on glioblastoma, an aggressive solid cancer with limited treatment modalities, our project aims to demonstrate proof of concept. However, our long-term vision extends to the potential application of this strategy across diverse pathologies. To achieve this, we will design a foreign antigen distinct from any human proteins, ensuring specificity and safety. In our pursuit of specific targeting of glioblastoma cells, we will harness brain-directed adeno-associated viruses as vectors to deliver the foreign antigen transgene into recipient cells. Importantly, the use of a hypoxia-regulated promoter will ensure antigen expression exclusively within the highly hypoxic tumor microenvironment, enhancing specificity and minimizing off-target effects. Additionally, the use of a tissue-specific promoter will further restrict expression to the target tissue. Furthermore, we will develop CAR-macrophages to effectively target and eliminate cells expressing the foreign antigen. Given the prevalence of macrophages among immune cells infiltrating diseased tissues, particularly in cancer, CAR-macrophages offer a promising approach to overcome the limitations associated with T lymphocytes. Moreover, recognizing the challenge of achieving complete tumor coverage with a single antigen delivery vehicle, CAR-macrophages are positioned to play a pivotal role. By ingesting tumor cells and presenting antigens to T cells, CAR-macrophages can reinvigorate the endogenous anti-tumor immune response, thereby eliminating both foreign antigen-expressing variants and those lacking foreign antigen expression. By addressing the challenges of antigen specificity and CAR lymphocyte efficacy in solid tissues, the ICARE project seeks to pave the way for broader applications of CAR therapies beyond hematological malignancies. Through innovative strategies and multidisciplinary, we aspire to revolutionize cellular immunotherapy and unlock new avenues for the treatment of various diseases.