Figure 4.

Barriers to successful CART immunotherapy in solid tumors. (A) Factors within the tumor microenvironment: Solid tumors contain an abundance of immunosuppressive leukocytes, immune checkpoint molecules, and suppressive cytokines. The tumor cells themselves are highly heterogeneous, preventing the identification of uniformly expressed targets for CAR design; antigen selection is further limited by an inability of CARTs to target intracellularly derived antigens. (B) Barriers to CART migration and entry into tumor sites: In contrast to the disseminated nature of hematologic cancers, solid tumors are often found in isolated locations that are difficult to access, like the brain. (a) following adoptive cancer, CARTs have been shown to preferentially accumulate in organs such as the lungs, liver, and spleen, with limited natural trafficking to tumor sites. (b) downregulated expression of ICAMs and other adhesion molecules on tumor vasculature limits lymphocyte extravasation, (c) reduced release of lymphocyte-attracting chemokines such as CXCL9-11 precludes CART homing to tumor sites, (d) in addition to supporting the growth and persistence of malignant cells, tumor-associated stroma provides both a physical and immunologic barrier to CART immunotherapy, (e) release of angiogenic factors such as VEGF promotes the develop of abnormal, tortuous, high-pressure vasculature that impedes lymphocyte entry.(C) Toxicity secondary to off-target effects: the use of overexpressed self-antigens as CAR targets introduces the risk of significant toxicity associated with CART identification and destruction of normal, healthy cells expressing these antigens.