High-affinity T cell receptors for adoptive cell transfer

Isser, Ariel; Schneck, Jonathan P.

doi:10.1172/jci125471

Cited by 2 publications

(2 citation statements)

References 25 publications

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“…Although the safety of engineered T cell therapy will ultimately depend on the degree of preferential expression of the target tumor antigen versus healthy tissue, the strategy of catch bond engineering to maintain physiological affinity yet strong agonist signaling responses may help to reduce the chance of unwanted cross-reactivity with other pMHCs for clinically directed TCRs. Enhancing the efficacy of clinical TCRs has generally involved affinity maturation ( 15 , 17 , 41 , 42 ). However, some affinity-matured TCRs have displayed off-target toxicity ( 17 , 43 ).…”

Section: Discussionmentioning

confidence: 99%

Tuning T cell receptor sensitivity through catch bond engineering

Xiang

Kolawole

Chan

et al. 2022

Science

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Adoptive cell therapy using engineered T cell receptors (TCRs) is a promising approach for targeting cancer antigens, but tumor-reactive TCRs are often weakly responsive to their target ligands, peptide–major histocompatibility complexes (pMHCs). Affinity-matured TCRs can enhance the efficacy of TCR–T cell therapy but can also cross-react with off-target antigens, resulting in organ immunopathology. We developed an alternative strategy to isolate TCR mutants that exhibited high activation signals coupled with low-affinity pMHC binding through the acquisition of catch bonds. Engineered analogs of a tumor antigen MAGE-A3–specific TCR maintained physiological affinities while exhibiting enhanced target killing potency and undetectable cross-reactivity, compared with a high-affinity clinically tested TCR that exhibited lethal cross-reactivity with a cardiac antigen. Catch bond engineering is a biophysically based strategy to tune high-sensitivity TCRs for T cell therapy with reduced potential for adverse cross-reactivity.

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Section: Discussionmentioning

confidence: 99%

Tuning T cell receptor sensitivity through catch bond engineering

Xiang

Kolawole

Chan

et al. 2022

Science

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“…Murine TCRs (mTCRs) are less likely to form unexpected mixed TCRs with endogenous human TCR chains in T cells and, therefore, may enhance antitumor activity (32)(33)(34). Moreover, mTCRs lack tolerance to human TAAs; therefore, it is possible to isolate high-affinity TCRs from mice (35). mTCRs specific for MAGE, CEA, gp100, and p53 have been isolated from HLA-transgenic mice and are undergoing clinical trials (8,36,37).…”

Section: Introductionmentioning

confidence: 99%

Identification of NY-ESO-1157–165 Specific Murine T Cell Receptors With Distinct Recognition Pattern for Tumor Immunotherapy

et al. 2021

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New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a promising target for T-cell receptor-engineered T cell (TCR-T) therapy, and targeting the human leukocyte antigen (HLA)-A2 restricted NY-ESO-1157−165 epitope has yielded remarkable clinical benefits in the treatment of multiple advanced malignancies. Herein, we report the identification of two NY-ESO-1157−165 epitope-specific murine TCRs obtained from HLA-A*0201 transgenic mice. NY-ESO-1157−165 specific TCRs were isolated after vaccinating HLA-A2 transgenic mice with epitope peptides. HZ6 and HZ8 TCRs could specifically bind to NY-ESO-1157−165/HLA-A2 and were capable of cytokine secretion with engineered Jurkat T cells and primary T cells upon recognition with K562 target cells expressing the single-chain trimer (SCT) of NY-ESO-1157−165/HLA-A2. The reactivity profiles of the HZ6 and HZ8 TCRs were found to be distinct from one another when co-cultured with K562 target cells carrying alanine-substituted NY-ESO-1157−165 SCTs. The binding characterization revealed that the recognition pattern of the HZ6 TCR to NY-ESO-1157−165/HLA-A2 was substantially different from the widely used 1G4 TCR. These findings would broaden the understanding of immunogenicity of the NY-ESO-1157−165, and the two identified TCRs may serve as promising candidates for the future development of TCR-T therapy for tumors.

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High-affinity T cell receptors for adoptive cell transfer

Cited by 2 publications

References 25 publications

Tuning T cell receptor sensitivity through catch bond engineering

Tuning T cell receptor sensitivity through catch bond engineering

Identification of NY-ESO-1157–165 Specific Murine T Cell Receptors With Distinct Recognition Pattern for Tumor Immunotherapy

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