Figure 1. A designer adoptive T-cell therapy for solid cancers.

T-lymphocytes expressing conventional TCRs (TILs, TCR_gm) or CARs at different stages of activation and differentiation are required to kill primary and metastatic cancers and to persist in cancer patients. Fully activated, tumouricidal T-cells expressing inflammation-associated homing molecules migrate from tumour blood vessels into primary cancers and sites of metastases (including sentinel lymph nodes) where they kill cancer cells. Tumouricidal T-cells migrating to non-cancerous tissues are unable to exert anti-cancer activity and are ineffective. Central memory T-cells expressing conventional TCRs, but not CARs, are re-activated by endogenously processed and presented tumour-derived antigens in tumour-draining lymph nodes before being redistributed to cancerous tissue. Central memory T-cells receive survival signals during normal recirculation through lymphoid organs. Recruitment of T-cells into non-inflamed cancers is promoted by patient conditioning which sensitizes the normally anergic tumour blood vessels to inflammatory mediators, increases the expression of homing-associated molecules and promotes recruitment of tumouricidal T-cells. Maturation of tumour blood vessels by activated T-cells in already inflamed tumours, promotes the development of HEV which recruit central memory T-cells into the tumour and shift the site of T-cell activation to cancerous tissues which avoids the loss of tumouricidal T-cells to non-cancerous tissues during their redistribution from the normal LN site of priming. γ-chain cytokines generate central memory and effector T-cells during T-cell expansion prior to adoptive transfer to cancer patients.