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Table 1. Types of adoptive T cell therapies. Summary of T cell therapeutic strategies, mechanistic action, benefits and
limitations
Modified T-cell Description Mechanism Benefits Limitations
product
TILs Natural T lymphocytes Recognition of TAA Extensive intracellular and Restricted to MHC-I complex
extracted from autologous via MHC-I complex by extracellular TAA specificity Isolation and expansion complexities
tumor biopsy and ex vivo conditioned TCRs and recognition Low frequency of antigenic peptides
cytokine fortification expressed by specialized cells
CTLs Enhanced and expanded in ex Via MHC-I complex, Highly advantageous of Restricted to MHC-I complex.
vivo isolated circulating tumor- enriched TCRs recognize helper T cells and APC Limited efficacy in non-viral tumor-
specific T cells extracted from processed TAAs augmentation of persistent specific antigenic peptides
the patients’ peripheral blood anti-tumor activity and Low affinity of TAA TCR. Low
using APCs prolonged survival in vivo. frequency of TAA specific cells
Specific to viral or non-viral
antigenic peptides
TCRs T lymphocytes modified to Recognition of tumor Augmented specificity in Restricted to MHC-I complex and
express a tgTCR with optimal antigenic peptides by targeting extracellular or HLA-A2 patients
specificity towards TAAs tgTCR presented on intracellular TAAs tgTCR genetic mis-match with
MHC-I molecules native TCR
CARs Engineered T cells expressing CAR extracellular domain Highly specific modified T Cytokine release syndrome largely
an antibody-binding scFv recognizes and binds to cells with reliable production due to persistent T cell proliferation
exodomain fused with a CD3z specific TAAs in a MCH- and unrestricted to any and subsequent cytokine secretion
chain intracellular domain via a independent manner MHC complexes
transmembrane domain

TILs: tumor infiltrating lymphocytes; CTLs: cytotoxic T lymphocytes; TCR: T cell receptor; CARs: chimeric antigen receptors; IL-2:
interleukin-2; TAA: tumor-associated antigens; MHC-I: major histocompatibility complex I; APCs: antigen presenting cells; tgTCR:
transgenic TCR; HLA: human leukocyte antigen; scFv: single-chain variable fragment

[13]
and subsequently execute T cell activation . T cells can also be engineered to express TCRs and the abil-
ity to genetically clone, and affinity optimize TCRs can substantially increase their potential in recognizing
tumor-specific antigens [14,15] . Lastly, CARs are genetically engineered surface receptors composed of extracel-
lular antigen-binding domains fused to intracellular T cell signaling domains of the T-cell receptor. These
modified T-cells expressing tumor-targeted CARs redirect antineoplastic specificity towards cancer cells
without MHC restriction. CARs have advanced the furthest in clinical development with their recent FDA
approval and their use showing remarkable clinical outcomes for patients with hematological malignan-
cies [14-19] .

CARs consist of an extracellular recognition domain that can bind specifically to a target molecule ex-
pressed on the surface of tumor cells, and an intracellular signaling domain that provides an activation sig-
nal upon target binding, linked via a transmembrane spacer/hinge domain. The extracellular domain is usu-
ally comprised of an antibody single-chain variable fragment (scFv) [20,21] . Interestingly, ligands of cell-surface
receptors are also alternative molecules being used at multiple institutions [22,23] . The transmembrane spacer
domain is important in conferring stability, flexibility and spacial orientation for CAR-antigen immunologi-
cal synapse formation. Once the extracellular domain binds to a tumor-specific antigen, it will communicate
and activate the intracellular domain, which directly initiates CAR-T cell cytolytic activity, cytokine produc-
tion and proliferation . The intracellular domain usually incorporates a region of the TCR CD3z chain to
[24]
provide the primary activating signal. Most CAR designs also incorporate one or more domains from co-
stimulatory receptors, such as CD28, CD134 (OX40), and/or CD137 (4-1BB) to provide the secondary signal
for the optimal activation of downstream signaling cascades [25,26] .

Over the past two decades, CAR-T cell designs have dramatically improved in their ability to mediate
anti-tumor activity. The first-generation CARs only included a CD3z signaling domain, and although
these first-generation CARs were sufficient to redirect T cell cytotoxic activity, they exhibited suboptimal
persistence and in vivo killing potential. By contrast, second generation CARs include the addition of a
costimulatory signaling domain (i.e., CD28, CD134, CD137) to enhance the signal function of the CD3z