Unlike the situation in hematologic malignancies, there are some obstacles to be overcome in solid tumor treatment.
The first obstacle is target antigen heterogeneity resulting from the variability of the expression of the antigen on the cells within a given tumor. Using immunohistochemistry for expression of tumor antigen to screen patient tumors is an approach to address this problem. The subjects are enrolled only if the percentage of tumor-associated antigens-expressing tumor cells exceeds number of cells that stain and a certain threshold in the intensity. Another method is to augment the CAR T cell’s ability to kill tumor cells by introducing activating cytokines to improve CAR function 20.
The second obstacle is trafficking. To target the tumor antigen, a CAR must successfully target and infiltrate the solid tumor. However, there is often a mismatch between the chemokine receptors on the CAR and the chemokines secreted by the tumors. To overcome this problem, one approach is to design CAR T cells that coexpress better-matched chemokine receptors 21. Local instillation of CARs is another method to address the poor trafficking after intravenous injection 22.
The last obstacle is the hostile tumor microenvironment (TME). There is a still purely physical barrier caused by stroma when the T cells arrive in the tumor. This barrier can be countered by using of FAP CAR T cells which can reduce tumor fibroblast numbers 23 or using CARs which secrete an enzyme to degrade the matrix 24. Moreover, there is also a metabolic barrier that the TME which is hypoxia is inhospitable and stressful to T cells 25. There are some tumor-derived soluble factors (e.g. Prostaglandin E2 and Adenosine 26) which have immunosuppressive function. This problem can be addressed by using antigen-specific CARs that can simultaneous interrupt these factors signaling 27. The cytokine transforming growth factor ? (TGF?), has direct negative effects on the functions of T cell effector. It was demonstrated that using soluble receptors to antibodies which can achieve systemic blockade of TGF? worked well in augmenting adoptive T cell therapy 28.
By overcoming these challenges, CAR T cell therapy can be a powerful technique to treat cancers and bring hope to many patients.