An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like affinity to maintain antigen specificity

Maus, Marcela V.; Plotkin, Jason; Jakka, Gopinadh; Stewart‐Jones, Guillaume; Rivière, Isabelle; Merghoub, Taha; Wolchok, Jedd D.; Renner, Christoph; Sadelain, Michel

doi:10.1038/mto.2016.23

Cited by 79 publications

(75 citation statements)

References 46 publications

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“…Given that CAR-T cells experience constant antigen stimulation in vivo , we analysed their adaptation phenotype. To do this, we utilised the previously described T1 CAR (65) fused to the cytoplasmic tail of the ζ-chain (1 st generation CAR) that also recognises the NY-ESO-1 157−165 peptide on HLA-A2 in a similar orientation to the TCR (K D = 4 nM (66)). These CAR-T cells were first stimulated with a titration of 9V pMHC before being transferred for a second stimulation on the same titration of 9V (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Alternatively, leukocyte cones were purchased from National Health Services Blood and Transplant service. Only HLA-A2 - peripheral blood or leukocyte cones were used due to the cross-reactivity of the high-affinity receptors used in this project which leads to fratricide of HLA-A2 + T cells (65, 66, 80). CD8 + T cells were isolated directly from blood using the CD8 + T Cell Enrichment Cocktail (StemCell Technologies) and density gradient centrifugation according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

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Perfect adaptation of CD8⁺ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation

Trendel

Krüger

Gaglione

et al. 2019

Preprint

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Maintaining and limiting T cell responses to constant antigen stimulation is critical to control pathogens and maintain self-tolerance, respectively. Antigen recognition by T cell receptors (TCRs) induces signalling that activates T cells to produce cytokines and also leads to the downregulation of surface TCRs. In other systems, receptor downregulation can induce perfect adaptation to constant stimulation by a mechanism known as statedependent inactivation that requires complete downregulation of the receptor or the ligand. However, this is not the case for the TCR, and therefore, precisely how TCR downregulation maintains or limits T cell responses is controversial. Here, we observed that in vitro expanded primary human T cells exhibit perfect adaptation in cytokine production to constant antigen stimulation across a 100,000-fold variation in affinity with partial TCR downregulation. By directly fitting a mechanistic model to the data, we show that TCR downregulation produces imperfect adaptation, but when coupled to a switch produces perfect adaptation in cytokine production. A prediction of the model is that pMHC-induced TCR signalling continues after adaptation and this is confirmed by showing that, while costimulation cannot prevent adaptation, CD28 and 4-1BB signalling reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We show that adaptation also applied to 1st generation chimeric antigen receptor (CAR)-T cells but is partially avoided in 2nd generation CARs. These findings highlight that even partial TCR downregulation can limit T cell responses by producing perfect adaptation rendering T cells dependent on costimulation for sustained responses.Introduction 1 T cell activation is critical to initiate and maintain adaptive immunity. It proceeds by the recognition of peptide 2 major-histocompatibility complex (pMHC) antigens by T cells using their T cell receptors (TCRs). TCR/pMHC 3 binding induces signalling pathways that can activate T cells to directly kill cancerous or infected cells and to se-4 crete a range of cytokines (1). When T cells are confronted with persistent or constant pMHC antigens, maintaining 5 responses to foreign or altered-self pMHC (in chronic infections and cancers (2)) can be just as important as lim-6 iting responses to self pMHC (e.g. adaptive tolerance (3)). Like other surface receptors, the TCR is downregulated 7 from the surface of T cells upon recognition of pMHC ligands (4). Precisely how TCR downregulation controls T 8 cell responses to constant pMHC antigen stimulation remains controversial. 9In other cellular systems, receptor downregulation can induce biological adaptation to constant ligand stimulation 10 (5). Adaptation is defined by the ability of a system to display transient responses that return to baseline when 11 presented with constant input stimulation. The process is known as perfect (or near-perfect) when the baselines 12 before and after stimulation are similar and is imperfect otherwise. Systematic network searches have identified...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Perfect adaptation of CD8⁺ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation

Trendel

Krüger

Gaglione

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…This approach therefore requires amassing a vast collection of validated TCRs, or high-throughput efforts to rapidly derive TCRs for personalized therapy 87 . Notably, CARs specific for HLA–peptide complexes offer an alternative, antibody-based approach to target neoantigens 88–92 .…”

Section: Identification Of New Targets For Engineered T Cellsmentioning

confidence: 99%

Therapeutic T cell engineering

Sadelain¹,

Rivière²,

Riddell³

2017

Nature

Self Cite

716

534

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Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimaeric antigen receptors (CARs) are a class of synthetic receptors that reprogram lymphocyte specificity and function. CARs targeting CD19 have demonstrated remarkable potency in B cell malignancies. Engineered T cells are applicable in principle to many cancers, pending further progress to identify suitable target antigens, overcome immunosuppressive tumour microenvironments, reduce toxicities, and prevent antigen escape. Advances in the selection of optimal T cells, genetic engineering, and cell manufacturing are poised to broaden T-cell-based therapies and foster new applications in infectious diseases and autoimmunity.

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“…ese are T lymphocytes that have been modified ex vivo and able to recognize their molecular target irrespective of antigen presentation by the molecules of major histocompatibility complex [52,206]. Structure of CAR-T cells makes them able to exhibit both activity of antibodies and toxicity of T lymphocytes [207].…”

Section: Immunotherapy In Egfr VIII -Positive Tumorsmentioning

confidence: 99%

EGFR^vIII: An Oncogene with Ambiguous Role

Rutkowska

Stoczyńska-Fidelus

Janik

et al. 2019

Journal of Oncology

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Epidermal growth factor receptor variant III (EGFRvIII) seems to constitute the perfect therapeutic target for glioblastoma (GB), as it is specifically present on up to 28–30% of GB cells. In case of other tumor types, expression and possible role of this oncogene still remain controversial. In spite of EGFRvIII mechanism of action being crucial for the design of small active anticancer molecules and immunotherapies, i.e., CAR-T technology, it is yet to be precisely defined. EGFRvIII is known to be resistant to degradation, but it is still unclear whether it heterodimerizes with EGF-activated wild-type EGFR (EGFRWT) or homodimerizes (including covalent homodimerization). Constitutive kinase activity of this mutated receptor is relatively low, and some researchers even claim that a nuclear, but not a membrane function, is crucial for its activity. Based on the analyses of recurrent tumors that are often lacking EGFRvIII expression despite its initial presence in corresponding primary foci, this oncogene is suggested to play a marginal role during later stages of carcinogenesis, while even in primary tumors EGFRvIII expression is detected only in a small percentage of tumor cells, undermining the rationality of EGFRvIII-targeting therapies. On the other hand, EGFRvIII-positive cells are resistant to apoptosis, more invasive, and characterized with enhanced proliferation rate. Moreover, expression of this oncogenic receptor was also postulated to be a marker of cancer stem cells. Opinions regarding the role that EGFRvIII plays in tumorigenesis and for tumor aggressiveness are clearly contradictory and, therefore, it is crucial not only to determine its mechanism of action, but also to unambiguously define its role at early and advanced cancer stages.

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An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like affinity to maintain antigen specificity

Cited by 79 publications

References 46 publications

Perfect adaptation of CD8⁺ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation

Perfect adaptation of CD8⁺ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation

Therapeutic T cell engineering

EGFR^vIII: An Oncogene with Ambiguous Role

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An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like affinity to maintain antigen specificity

Cited by 79 publications

References 46 publications

Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation

Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation

Therapeutic T cell engineering

EGFRvIII: An Oncogene with Ambiguous Role

Contact Info

Product

Resources

About

Perfect adaptation of CD8⁺ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation

Perfect adaptation of CD8⁺ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation

EGFR^vIII: An Oncogene with Ambiguous Role