Limitations in the Design of Chimeric Antigen Receptors for Cancer Therapy

Abstract

Cancer therapy has entered a new era, transitioning from unspecific chemotherapeutic agents to increasingly specific immune-based therapeutic strategies. Among these, chimeric antigen receptor (CAR) T cells have shown unparalleled therapeutic potential in treating refractory hematological malignancies. In contrast, solid tumors pose a much greater challenge to CAR T cell therapy, which has yet to be overcome. As this novel therapeutic modality matures, increasing effort is being invested to determine the optimal structure and properties of CARs to facilitate the transition from empirical testing to the rational design of CAR T cells. In this review, we highlight how individual CAR domains contribute to the success and failure of this promising treatment modality and provide an insight into the most notable advances in the field of CAR T cell engineering.

Predicting the Efficacy and Safety of TACTICs (Tumor Angiogenesis-Specific CAR-T Cells Impacting Cancers) Therapy for Soft Tissue Sarcoma Patients

“…In this study, we first examined the specifications and transport conditions for the final development of a promising anti-VEGFR2 CAR-T cells candidate, in preparation for a future FIH study using TACTICs therapy. CAR-T cells generated via viral vectors are expected to have long-term anti-tumor effects due to persistent CAR expression; of note, CD137-derived STD are often incorporated into the second-generation CAR constructs to improve the in vivo persistence of CAR-T cells [ 22 , 23 ]. On the other hand, in CAR-T cells generated via mRNA-EP, memory differentiation and long-term survival of the transfected T cell are not as important, since they lose their CAR-mediated antigen specificity with time.…”

Latest evidence on immunotherapy for cholangiocarcinoma (Review)

“…Despite the toxicity profile and huge expense of CAR T cells, the clinical efficacy of CAR T cells in the treatment of refractory hematological malignancies is satisfactory. In the past few years, it has been discovered that improved second-generation CARs, which usually comprise an antibody-derived single-chain variable fragment linked with intracellular signaling molecules, are able to activate T-cell effector functions ( 26 ). CD28- and 4-1BB-derived domains are the most commonly used costimulatory domains.…”

“…CD28- and 4-1BB-derived domains are the most commonly used costimulatory domains. 4-1BB-containing CAR T cells are thought to have superior persistence, but the protein phosphorylation changes of signaling intermediates induced by CD28-CAR T cells are stronger and faster ( 26 ). Third-generation CAR T cells containing both CD28 and 4-1BB costimulatory domains have been demonstrated to be safe and effective at every dose level tested ( 27 ).…”

T Cell Activation Machinery: Form and Function in Natural and Engineered Immune Receptors

“…While the FDA approval of two such “second-generation” designs in late 2017 (tisagenlecleucel/Kymriah ® and axicabtagene ciloleucel/Yescarta ® ) for B cell malignancies has kept much of the effort to develop new CAR-T cell therapies focused on similar single-chain designs, many alterations have been investigated that can modulate their performance, and approaches are being developed that seek to improve safety and/or efficacy by incorporating lessons from the now-substantial body of knowledge around natural immune receptor structure, assembly, activation and regulation. The sections that follow are not intended to provide exhaustive coverage of the CAR design space (see detailed recent reviews [ 128 , 129 , 130 , 131 , 132 , 133 , 134 ]), and we will not focus heavily on the large number of completed or ongoing clinical trials (see detailed recent reviews [ 5 , 6 , 135 , 136 ]). Rather, we discuss what is known about single-chain CAR structure and function with reference to the above overview of natural immune receptors, identifying similarities and contrasts to highlight what we view as key benefits and liabilities of different features and domain configurations (summarized in Figure 2 ).…”