CAR T Cell Therapy: A Game Changer in Cancer Treatment

Abstract

The development of novel targeted therapies with acceptable safety profiles is critical to successful cancer outcomes with better survival rates. Immunotherapy offers promising opportunities with the potential to induce sustained remissions in patients with refractory disease. Recent dramatic clinical responses in trials with gene modified T cells expressing chimeric antigen receptors (CARs) in B-cell malignancies have generated great enthusiasm. This therapy might pave the way for a potential paradigm shift in the way we treat refractory or relapsed cancers. CARs are genetically engineered receptors that combine the specific binding domains from a tumor targeting antibody with T cell signaling domains to allow specifically targeted antibody redirected T cell activation. Despite current successes in hematological cancers, we are only in the beginning of exploring the powerful potential of CAR redirected T cells in the control and elimination of resistant, metastatic, or recurrent nonhematological cancers. This review discusses the application of the CAR T cell therapy, its challenges, and strategies for successful clinical and commercial translation.

Figure 1

Elements involved in TCR and CAR recognition and activation. The TCR is disulfide-linked heterodimer consisting of one α and one β chain expressed in complex with invariant CD3 chains (γ, δ, ζ, and ε). The TCR recognizes intracellular or extracellular proteins presented as peptides by MHC molecules. Costimulation of CD28 through its ligands, CD80/CD86, is required for optimal activation and production of interleukin-2 (IL-2) and other cytokines. While most hematological tumors express costimulatory molecules, solid tumor cells as well as antigen presenting cells in the tumor microenvironment usually lack such molecules. CARs recognize surface antigens in an MHC unrestricted manner. CARs are fusion proteins between single-chain variable fragments (scFv) from a monoclonal antibody and one or more T cell receptor intracellular signaling domains. Various hinges and transmembrane (TM) domains are used to link the recognition and the signaling molecules [5]. While first generation CARs signaled through the CD3ζ chain only, second generation CARs include a signaling domain from a costimulatory molecule, for example, CD28 (illustrated), 4-1BB, OX40, CD27, or ICOS.

Figure 2

Open clinical studies investigating the safety and efficiency of adoptive T cell therapy (ATC) in cancer registered in https://clinicaltrials.gov/ as of December 2015 (search terms: “intervention: T cells”, indication: “cancer”). More than 200 protocols are registered, and about 40% of these address the use of CAR T cells, of which 65% are studied in trials for hematological malignancies. The use of unmodified/minimally manipulated/nongene modified T cells (based on the endogenous T cell repertoire) isolated from PMBC and from tumor (TILs) constitutes a similar fraction (16% virus/antigen specific + 15% TIL + 10% DLI/minimally manipulated) to CAR T cells. TCR gene modified T cells make-up about 11% of the studies. The term armored T cells refers to the adoptive transfer of T cells that have been precoated ex vivo with bispecific antibodies targeting CD3 and tumor associated antigen, like CD19 [6].

Figure 3

Example of manufacturing and delivery pipeline of CAR T cell therapies [7, 8]. Peripheral blood mononuclear cells (PBMCs) are harvested from the patient (or a T cell donor) (a) and transferred to a good manufacturing practice (GMP) facility, where the T cells are isolated and activated in the presence of magnetic beads conjugated with CD3 and CD28 antibodies (b) and subsequently genetically engineered by viral transduction to express the CAR (c). The activated T cells are expanded ex vivo for a period, typically 10–14 days, to reach a therapeutic relevant number (d) before magnetic bead removal (e) and formulation, either for freezing or for adoptive transfer (f). The patient undergoes a conditional chemotherapy prior to infusion of the CAR T cells (g).