Chimeric Antigen Receptors T Cell Therapy in Solid Tumor: Challenges and Clinical Applications

Abstract

Adoptive cellular immunotherapy (ACT) employing engineered T lymphocytes expressing chimeric antigen receptors (CARs) has demonstrated promising antitumor effects in advanced hematologic cancers, such as relapsed or refractory acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma, supporting the translation of ACT to non-hematological malignancies. Although CAR T cell therapy has made remarkable strides in the treatment of patients with certain hematological cancers, in solid tumors success has been limited likely due to heterogeneous antigen expression, immunosuppressive networks in the tumor microenvironment limiting CAR T cell function and persistence, and suboptimal trafficking to solid tumors. Here, we outline specific approaches to overcome barriers to CAR T cell effectiveness in the context of the tumor microenvironment and offer our perspective on how expanding the use of CAR T cells in solid tumors may require modifications in CAR T cell design. We anticipate these modifications will further expand CAR T cell therapy in clinical practice.

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

“…Additional problems include T cell homing to the site of the disease, penetration of T cells into solid masses, overcoming immunosuppressive tumour microenvironment (TME) and limited CAR T cell persistence after infusion [23]. Multiple strategies for improving CAR T cell therapy efficacy against solid tumours have been extensively reviewed recently and are summarised in Table 1 [22][23][24][25][26].…”

The application of prostate specific membrane antigen in CART‑cell therapy for treatment of prostate carcinoma (Review)

“…While engineered CART-cells have seen effective improvements in the treatment of hematological cancer, its application in solid tumors has proven to be difficult. The impediment surrounding the success of CART-cell therapy against solid tumors may be due to the following factors: i) The lack of a unique tumor-associated antigen in the majority of different types of cancer; ii) inefficient trafficking of CART-cells to tumor sites; iii) heterogeneous expression of the targeted antigen(s) leading to outgrowth of antigen-negative tumor variants; iv) inadequate supply of growth factors (including IL-2); v) the presence of immunosuppressive agents; and vi) the metabolically hostile tumor microenvironment (23).…”

“…The survival rate or time period of infused modified T-cells (including CART) determines its efficiency in fighting and killing cancerous tumors. While first-generation CARs have a poor persistence rate, the second and third generations have been demonstrated to exhibit higher persistence rates (23,61). Activation of CAR with two or more co-stimulatory domains has been reported to enhance the persistence of infused CART-cells.…”

“…The homing potential of CART-cells to target sites is called trafficking, an essential requirement for T-cell-tumor eradication. Homing of CART-cells has been observed to be enhanced by transducing T-cells with the chemokine receptor expressing gene IL-8Rβ which recognizes chemokine ligand 1 expressed in melanomas (23).…”

“…Nonetheless, while the use of CART-cell therapy is advanced in hematological malignancies, it is also presenting potential in solid tumors, though at a limited rate. The delay over the years has been as a result of the difficulty of immune cells targeting and penetrating tumors and cancerous cells, as well as overcoming the metabolically hostile tumor microenvironment (23,24).…”