CAR T Cells in Solid Tumors: Blueprints for Building Effective Therapies

Abstract

Genetic redirection of T lymphocytes with chimeric antigen receptors (CARs) has soared from treating cancers preclinically to FDA approval for hematologic malignancies and commercial-grade production scale in under 30 years. To date, solid tumors are less susceptible to CAR therapies and instead have been treated more successfully with immune checkpoint blockade or tumor-infiltrating lymphocyte therapy. Here, we discuss the current challenges in treating solid tumors with CAR T cells, and the obstacles within the host and tumor microenvironment hindering their efficacy. We present a novel three-pronged approach for enhancing the efficacy of CAR T cells whereby a single infusion product can synergize the power of an optimal CAR construct, a highly potent T cell subset, and rejuvenate the endogenous immune response to conquer therapeutically-resistant solid tumors.

Identification of human CD4+T cell populations with distinct antitumor activity

“…CAR T cells are therapeutic in many patients with hematological malignancies but have been less effective thus far against solid tumors, owing in part to the oppressive tumor microenvironment and poor persistence. Many efforts for overcoming these obstacles include modulating T cell trafficking, targeting, cytokine delivery, co-stimulation, and improving cell persistence among other strategies reviewed previously ( 10 ). CD4 + T cells help cytotoxic CD8 + T cells and when CAR engineered, have the ability to improve longevity of responses against hematological malignancies ( 11, 12 ).…”

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Some of the co-inhibitory ligands such as PD-L1 are known to be upregulated by solid tumors including myeloma, ovarian, breast and renal cancers [213]. Thus, blocking such pathways using antibodies (immune checkpoint inhibitors) may lead to "rejuvenation" of existing T cells and impressive anti-tumor functions [1,214] and to the clinical implementation of novel T-cell engineering treatments (reviewed in [215]). …”

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].…”