CAR T cells targeting abnormal N-glycans for the treatment of refractory/metastatic solid cancers

Treatment of non-resectable recurrent/metastatic solid cancers is currently palliative only. Available systemic treatments fail to eradicate disease and typically delay disease progression by only months, with patients quickly becoming refractory. Thus, the prognosis remains abysmal for patients with advanced solid tumors and there is an urgent unmet need for novel mechanisms of action and additional paradigm shifting therapeutic options.

Directing the immune system to attack and kill cancer cells by genetically engineering a patients own T cells (i.e. chimeric antigen receptor T cells or CAR T cells) has markedly reduced tumor burden in B cell related cancers by targeting a cell-surface antigen with antibodies. However, high-affinity antibodies required to maximize CAR T cell killing detect low antigen expression in normal tissue, risking ‘on-target, off-cancer’ toxicity. This compels identification of cancer-restricted cell surface protein antigens, which are rare, and has been a major barrier to development of CAR T cells for solid cancers. 

Tumor Associated Carbohydrate Antigens are the most abundant and widespread cancer antigens known, but are poorly targetable by antibodies. Here we developed a pan-cancer CAR T cell using a novel class of glycan-targeting immunotherapeutics termed ‘Glycan-dependent T cell Recruiter’ (GlyTR). GlyTR therapeutics utilize ‘velcro-like’ binding to target and kill cells with high but not low target-expression. We find that the GlyTR1 CAR T cells trigger target-density dependent T cell mediated pan-cancer killing of diverse solid cancers when cultured together, including triple negative breast cancer, glioblastoma, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer and colon cancer.  In mouse models, we also observe robust killing of ovarian cancer. However, additional improvements are being pursued before finalizing the design and moving GlyTR1 CAR T cells into the clinic. 

Treatment of non-resectable recurrent/metastatic solid cancers is currently palliative only. Available systemic treatments fail to eradicate disease and typically delay disease progression by only months, with patients quickly becoming refractory. Thus, the prognosis remains abysmal for patients with advanced solid tumors and there is an urgent unmet need for novel mechanisms of action and additional paradigm shifting therapeutic options.

Directing the immune system to attack and kill cancer cells by genetically engineering a patients own T cells (i.e. chimeric antigen receptor T cells or CAR T cells) has markedly reduced tumor burden in B cell related cancers by targeting a cell-surface antigen with antibodies. However, high-affinity antibodies required to maximize CAR T cell killing detect low antigen expression in normal tissue, risking ‘on-target, off-cancer’ toxicity. This compels identification of cancer-restricted cell surface protein antigens, which are rare, and has been a major barrier to development of CAR T cells for solid cancers. 

Tumor Associated Carbohydrate Antigens are the most abundant and widespread cancer antigens known, but are poorly targetable by antibodies. Here we developed a pan-cancer CAR T cell using a novel class of glycan-targeting immunotherapeutics termed ‘Glycan-dependent T cell Recruiter’ (GlyTR). GlyTR therapeutics utilize ‘velcro-like’ binding to target and kill cells with high but not low target-expression. We find that the GlyTR1 CAR T cells trigger target-density dependent T cell mediated pan-cancer killing of diverse solid cancers when cultured together, including triple negative breast cancer, glioblastoma, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer and colon cancer.  In mouse models, we also observe robust killing of breast and ovarian cancers. However, additional improvements are being pursued before moving GlyTR1 CAR T cells into the clinic.