Making CAR T Cells a Solid Option for Solid Tumors

Abstract

Adoptive cell therapy with chimeric antigen receptor (CAR) T cells aims to redirect the patient's own immune system to selectively attack cancer cells. To do so, CAR T cells are endowed with specific antigen recognition moieties fused to signaling and costimulatory domains. While this approach has shown great success for the treatment of B cell malignancies, response rates among patients with solid cancers are less favorable. The major challenges for CAR T cell immunotherapy in solid cancers are the identification of unique tumor target antigens, as well as improving CAR T cell trafficking to and expansion at the tumor site. This review focuses on combinatorial antigen targeting, regional delivery and approaches to improve CAR T cell persistence in the face of a hostile tumor microenvironment.

Keywords: CAR-T cells; cancer; cell engineering; immunotherapy; solid tumors; toxicity.

Figure 1

Evolution of CAR design. The basic CAR set up consists of an antigen binding moiety (e.g., scFv based) and a spacer on the extracellular side, a transmembrane domain and domains for T cell activation on the intracellular side. While 1st generation CARs (A) contain only a CD3ζ chain for T cell activation, 2nd (B), and 3rd (C) generation CARs have one or two costimulatory domains incorporated, respectively.

Figure 2

Major hurdles to the efficiency of CAR T cells in solid cancers. (A) Heterogeneous expression of tumor associated antigens (TAA) on solid cancers as well as overlapping expression on healthy tissues makes it difficult to find suitable targets of CAR T cells therapy. (B) After intravenous application CAR T cells need to traffic to the tumor site, extravasate the circulation, and penetrate the tumor. (C) The term tumor microenvironment describes the interplay between the tumor cells themselves and the surrounding blood vessels, stromal cells, immune cells, as well as the extracellular matrix. CAR T cell migration and expansion are inhibited by the immunosuppressive environment of solid cancers.

Figure 3

Combinatorial antigen targeting for solid cancers. (A) For “OR” gate/ tandem CAR T cells the presence of one antigen is sufficient to trigger effector function, while concurrent expression of both antigens leads to synergistical improvement of activation. (B+C) “AND” gate CAR T cells require the presence of either target antigens to efficiently activate. (B) The split CAR approach taken by Kloss and colleagues uses a 1st generation CAR that recognizes antigen 1 combined with a chimeric costimulatory receptor (CCR) that provides the necessary costimulation upon encounter of antigen 2. (C) In the synthetic Notch (synNotch) approach reported by Roybal and colleagues sensing of antigen 1 by a synNotch transcriptional receptor (synNotch rec.) induces expression of a CAR that is specific for antigen 2. (D) Universal CAR T cells can target a variety of different antigens since their antigen specificity comes from the administration of soluble adaptors.