WT1, PRAME, survivin (multiple tumor-associated antigens)

Class

Off-the-shelf allogeneic multi-tumor-associated-antigen-specific T-cell therapy (non-genetically engineered, antigen-primed T cells)

Pathway

T-cell receptor-mediated recognition and killing of leukemic cells presenting the targeted tumor-associated antigens

WT1, PRAME, and survivin are proteins that are markedly overexpressed inside many leukemic and other malignant cells while remaining largely absent, or expressed at very low levels, in most healthy adult tissue. Because they are intracellular, they cannot be reached by antibodies; instead, fragments of these proteins are displayed on the cell surface bound to major histocompatibility complex (MHC) molecules, where they can be recognized by the T-cell receptor (TCR) of cytotoxic T lymphocytes. This mechanism uses T cells that have been primed and expanded, outside the body, to recognize all three antigens simultaneously, rather than engineering them with an artificial receptor. Because the product is manufactured from a donor rather than the patient (allogeneic, "off-the-shelf"), it can potentially be produced in advance and used across multiple recipients, in contrast to therapies that must be custom-made for each individual. Targeting several tumor-associated antigens at once addresses a central vulnerability of single-antigen therapies: if a cancer cell reduces or loses expression of one target, cells still displaying the other two remain vulnerable to attack. This class of approach is being explored primarily in blood cancers such as leukemias, where these antigens are frequently and consistently overexpressed on malignant blasts.