Joining Forces for Cancer Treatment: From “TCR versus CAR” to “TCR and CAR”
Abstract
:1. Introduction
2. Part I—TCR versus CAR
2.1. TCR versus CAR: Structure
2.2. TCR versus CAR: Activation upon Stimulation
2.2.1. Antigen Engagement for Initiation of Activation
2.2.2. Formation of the Immunological Synapse
2.3. TCR versus CAR: Signaling Cascade
2.3.1. Proximal Signaling
2.3.2. Downstream Signaling and Outcome
2.3.3. Calcium/NFAT Pathway
2.3.4. Ras/ERK/AP-1 and NF-κB Pathway
2.3.5. PI3K/AKT/mTOR Pathway
2.3.6. Endosomal Trafficking and Lysosomal Degradation
3. Part II—A Change in Perspective: From “TCR versus CAR” to “TCR and CAR”
3.1. Combination of an Endogenous TCR and a CAR
3.2. Combination of a Transgenic TCR and a CAR
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Acknowledgments
Conflicts of Interest
References
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TCR | CAR | ||
---|---|---|---|
Structure | Receptor clustering | One pMHC potentially enough [18,19] | Clustering required [20,21,22] |
ITAM number | 10 ITAMs provided by the CD3 complex [23] | Up to 3 ITAMs per CAR [23] | |
Affinity/ Sensitivity | Lower affinity, higher sensitivity | Higher affinity [24], lower sensitivity [25] | |
Phosph. of CD3 subunits | Phosph. of CD3 ζ, γ, δ, ε [26] | Phosph. of only CD3 ζ [25] | |
Signaling | Phosph. of signaling molecules | Stronger phosph. of ZAP-70, ITAMs and PLCγ1 than in CAR [27,28] | Stronger phosph. of Lck and ERK than in TCR [29] |
Recruitment of signaling molecules | More efficient recruitment of ZAP-70, CD2 and LFA-1 than in CAR [27,28] | Less dependent on LFA-1:ICAM-1 interaction and LAT [21,25,29] | |
Upon increased antigen exposure | Maintain an earlier differentiation phenotype upon strong stimulation [30] | Higher levels of co-inhibitory molecules upon activation [30] | |
IS structure | Classical “bull’s eye” structure [29] or multifocal structures formed by Th2 cells [31] or at the interface with DCs [32] | Non-classical, disorganized IS with multifocal pattern [29] | |
Immunological Synapse | SMACs | Conventional IS consisting of cSMAC, pSMAC and dSMAC [33] | Merged cSMAC and pSMAC, no adhesion molecule ring [21,29] |
Lck | One central Lck cluster [29] | Disorganized Lck patches [29] | |
Duration | Usually slower/weaker effector function [29,30]; longer IS duration, slower off-rate from target [29] | Faster cytotoxic granule secretion and faster resolution of IS [29] | |
Resting state | Constitutive internalization of TCR complex through clathrin-dependent endocytosis (CDE) [34] | Unknown | |
Trafficking | Upon activation | Engaged TCRs: Clathrin- independent endocytosis (CIE) for internalization, recycling or lysosomal degradation [34,35] Bystander TCRs: CDE for internalization and recycling [34,35] | Engagement of antigens induced rapid lysosomal ubiquitination [36] High-affinity CAR T cells demonstrated enhanced trogocytosis [37] |
Combination of Endogenous TCR and CAR | |||||
---|---|---|---|---|---|
CAR | TCR Specificity | TCR Stimulus | Study | Main Result | Citation |
GD2-ζ | EBV- specific TCR | Patients with EBV pre-infection | NCT000 85930 | Prolonged survival and expansion compared to anti-CD3 antibody activation | Pule et al., 2008 [184] Louis et al., 2011 [188] |
CD19-28ζ | EBV- specific TCR | EBV-transformed lymphoblastoid B cell lines | NCT008 40853 | Stimulation of native TCR increased CAR T cell expansion; T cells were donor-derived after allogeneic HSCT (no GVHD) | Cruz et al., 2013 [189] |
GD2-28-OX40ζ | VZV- specific TCR | VZV peptide mix-loaded DCs | In vitro | Exhausted and dysfunctional CAR T cells recovered upon stimulation of native TCR | Tanaka et al., 2017 [185] |
CD19-28ζ | HY- specific TCR | Male bone-marrow-derived cells (HY) | In vivo | Dual stimulation led to exhaustion and apoptosis in CD8+ (not in CD4+) CAR T cells | Yang et al., 2017 [196] |
Her2-28ζ | gp100- specific TCR | Recombinant vaccinia virus encoding gp100 | In vivo | Increased expansion, persistence, tumor infiltration and functionality upon native TCR stimulation | Slaney et al., 2017 [198] |
(1) GD2-ζ (2) GD2-28ζ (3) GD2-BBζ | VZV-/EBV- specific TCR | VZV or EBV peptide mix-loaded DCs | In vitro | TCR stimulation led to increased expansion and functionality in GD2-28ζ (but not in GD2-BBζ) CAR T cells | Omer et al., 2018 [187] |
CD19-28ζ | EBV- specific TCR | Patients with EBV pre-infection | NCT008 40853 | Virus load-dependent increase in CAR T cell expansion | Lapteva et al., 2019 [186] |
EGFRvIII-28-BBζ | Oncolytic VSV or reovirus | Oncolytic virus co-administered with CAR T cell | In vivo | Enhanced trafficking, infiltration and functionality; long-term effects through in vivo reactivation with TCR-directed oncolytic virus | Evgin et al., 2022 [197] |
Combination of Transgenic TCR and CAR | |||||
---|---|---|---|---|---|
CAR | TCR Specificity | CAR/TCR Stimulus | Study | Main Result | Citation |
CSPG4-28ζ (transient) | gp100 (transient) | Target cell line | In vitro | Functionally co- expressed, without reciprocal inhibition | Uslu et al., 2016 [202] |
CSPG4-28ζ (transient) | gp100 (stable) | Target cell line | In vitro | Functionally co- expressed; reduced cytotoxicity compared to TCR T cells | Simon et al., 2019 [203] |
BBζ (lacking scFv) | NY-ESO-1 | TCR-target- expressing cell line | In vitro/ in vivo | Increased proliferation and tumor regression upon single and repeated TCR stimulation | Miyao et al., 2018 [205] |
(1) CD19-28 (2) CD19-BB (3) CD19-28-OX40 (lacking signaling domain) | Survivin | Target cell line | In vitro/ in vivo | Enhanced apoptosis with CD19-BB CAR; CD19-28-OX40 (not CD19-28) increased repeated killing and prolonged tumor control in vivo | Omer et al., 2022 [206] |
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Teppert, K.; Wang, X.; Anders, K.; Evaristo, C.; Lock, D.; Künkele, A. Joining Forces for Cancer Treatment: From “TCR versus CAR” to “TCR and CAR”. Int. J. Mol. Sci. 2022, 23, 14563. https://doi.org/10.3390/ijms232314563
Teppert K, Wang X, Anders K, Evaristo C, Lock D, Künkele A. Joining Forces for Cancer Treatment: From “TCR versus CAR” to “TCR and CAR”. International Journal of Molecular Sciences. 2022; 23(23):14563. https://doi.org/10.3390/ijms232314563
Chicago/Turabian StyleTeppert, Karin, Xueting Wang, Kathleen Anders, César Evaristo, Dominik Lock, and Annette Künkele. 2022. "Joining Forces for Cancer Treatment: From “TCR versus CAR” to “TCR and CAR”" International Journal of Molecular Sciences 23, no. 23: 14563. https://doi.org/10.3390/ijms232314563