Adoptive T Cell Therapies: A Comparison of T Cell Receptors and Chimeric Antigen Receptors

Harris, Daniel T.; Kranz, David M.

doi:10.1016/j.tips.2015.11.004

Cited by 219 publications

(197 citation statements)

References 99 publications

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“…Reductions in sensitivity were observed with both first generation (CD3ζ signaling domain only) and second generation (CD28/CD3ζ signaling domains) CARs. These sensitivity values were observed even in the absence of the CD8 co-receptor, indicating that the TCR/CD3 machinery itself accounts for the differences (10, 12). Mathematical modeling suggested that the CAR result could be explained by either a 1000-fold reduction in the kinetic proofreading rate (k p ) or by a 100-fold reduction in the activation rate (i.e.…”

Section: Introductionmentioning

confidence: 93%

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Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains

Harris

Hager

Smith

et al. 2018

The Journal of Immunology

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135

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Adoptive T cell therapies have achieved significant clinical responses, especially in hematopoietic cancers. Two types of receptor systems have been used to redirect the activity of T cells, normal heterodimeric T-cell receptors (TCRs) or synthetic chimeric antigen receptors (CARs). TCRs recognize peptide-HLA complexes whereas CARs typically use an antibody-derived scFv (single-chain fragments variable) that recognizes cancer-associated cell-surface antigens. While both receptors mediate diverse effector functions, a quantitative comparison of the sensitivity and signaling capacity of TCRs and CARs has been limited due to their differences in affinities and ligands. Here we describe their direct comparison by using TCRs that could be formatted either as conventional αβ heterodimers, or as scFv constructs linked to CD3ζ and CD28 signaling domains or to CD3ζ only. Two high-affinity TCRs (KD values of approximately 50 and 250 nM) against MART1/HLA-A2 or WT1/HLA-A2 were used, allowing MART1 or WT1 peptide titrations to easily assess the impact of antigen density. Although CARs were expressed at higher surface levels than TCRs, they were 10 to 100-fold less sensitive, even in the absence of the CD8 co-receptor. Mathematical modeling demonstrated that lower CAR sensitivity could be attributed to less efficient signaling kinetics. Furthermore, reduced cytokine secretion observed at high antigen density for both TCRs and CARs suggested a role for negative regulators in both systems. Interestingly, at high antigen density, CARs also mediated greater maximal release of some cytokines, such as IL-2 and IL-6. These results have implications for next-generation design of receptors used in adoptive T cell therapies.

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Section: Introductionmentioning

confidence: 93%

“…While TCR and CAR formats have some elements in common, the mechanistic details of signaling through CARs are less studied than TCRs (9, 10). The αβ TCR heterodimer assembles in a precisely controlled stoichiometry with the signaling machinery consisting of six CD3 subunits (CD3εγ, CD3εδ, CD3ζζ) (11).…”

Section: Introductionmentioning

confidence: 99%

Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains

Harris

Hager

Smith

et al. 2018

The Journal of Immunology

Self Cite

135

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show abstract

“…This method has been proven safe and effective for the induction of tumor remission in patients with neuroblastoma (93) and hematological malignancies (94). To date, the most successful CARs were those specific for CD19 on B cell malignances (92). Several research centres have confirmed the compelling efficacy of CARs against acute and chronic B-cell malignancies (95).…”

Section: Antigen-specific Tcr Gene Transductionmentioning

confidence: 99%

“…Furthermore, CARs can induce activity even against low-density antigens. The CAR density, antigenbinding domain affinity still need to be optimized to match the antigen density of tumor and tissue (92). However, risk also exits because both on-target and off-target recognition of normal tissue occur in engineered T cells.…”

Section: Antigen-specific Tcr Gene Transductionmentioning

confidence: 99%

αβ T-cell receptor bias in disease and therapy (Review)

Wang

et al. 2016

International Journal of Oncology

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Abstract.The diversity and specificity of T cell receptors (TCR), the characteristics of T-cell surface marker, are central to the adaptive immunity. TCR variability is required for successful immunization coverage because this structural foundation is indispensable for the valid identification of short antigen peptides (derived from degraded antigens) that are presented by major histocompatibility molecules on the surfaces of antigen-presenting cells. Despite the vast T-cell repertoire, biased αβ TCR has become a common theme in immunology. To date, numerous examples of TCR bias have been observed in various diseases. Immunotherapy strategies that are based on αβ T cell responses are also emerged as a prominent component of clinical treatment. In the present review, we briefly summarize the current knowledge regarding basic structural information and the molecular mechanisms underlying TCR diversity. Moreover, we outline the role of TCR repertoire bias in some diseases, and its application for therapeutic interventions, as these play significant roles in disease progression, even with patients with a good prognosis.

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“…However, similar to DLI, graft-versus-host disease (GVHD) is a potential concerning side effect following alloCAR T-cell infusion. Furthermore, TCR and CAR share the same immune-tyrosine activation motifs (ITAMs) that become phosphorylated upon ligand binding [7]. The interaction between the TCR and CAR signal pathways on allogeneic T cells can lead to signaling overload [2], affecting cell expansion, persistence, exhaustion, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsed/refractory acute lymphoblastic leukemia

Wang

Wei

et al. 2018

Bone Marrow Transplant

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The source of CAR T cells can be autologous (autoCAR) or allogeneic (alloCAR). The latter is seen in patients with a history of allogeneic hematopoietic stem cell transplantation, and can be either donor-derived (DD-alloCAR) or recipientderived (RD-alloCAR). While autoCAR is activated by CAR only, alloCAR receives activation signals from both T-cell receptor (TCR) and CAR. As a result, the biological differences could impact clinical outcomes. We retrospectively reviewed 31 patients: 17 received autoCAR, 11 received RD-alloCAR, and 3 received DD-alloCAR. After a median followup of 9 months, CR rate was 88.2% (95% CI 63.6-98.5%) in autoCAR and 100% (95% CI 71.5-100%) in RD-alloCAR. The median peak expansion in the autoCAR was significantly higher than the RD-alloCAR group (p = 0.007). RD-alloCAR group had significantly less patients with severe CRS (Grade ≥ 3) than the autoCAR group (p = 0.049). Acute graft-versushost disease (GVHD) occurred in 2 (18.2%) of RD-alloCAR patients and 1 (33.3%) of DD-alloCAR patients. Univariate subgroup analysis of alloCAR group showed the presence of cGVHD at the time of T-cell collection was significantly associated with less than 6-month relapses (p = 0.022). RD-alloCAR patients with or without cGVHD at PBMC collection did not differ regarding the peak CAR T-cell expansion, CRS grades and OS.

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Adoptive T Cell Therapies: A Comparison of T Cell Receptors and Chimeric Antigen Receptors

Cited by 219 publications

References 99 publications

Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains

Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains

αβ T-cell receptor bias in disease and therapy (Review)

A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsed/refractory acute lymphoblastic leukemia

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