Optimizing T‐cell receptor avidity with somatic hypermutation

Bassan, David; Gozlan, Yosi Meir; Sharbi‐Yunger, Adi; Tzehoval, Esther; Eisenbach, Lea

doi:10.1002/ijc.32612

Cited by 8 publications

(10 citation statements)

References 49 publications

(220 reference statements)

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“…Also, more targeted methods for the mutagenesis of CDR regions have been described, including alanine-scanning to identify key amino acids in the interaction of TCRs with pHLA [ 34 ] and structure-based designs [ 35 , 36 ] to predict affinity-enhancing point mutations. Recently, high-affinity TCRs have also been created by somatic hypermutation in host cells transduced with activation-induced cytidine deaminase [ 37 ]. Besides the genetic engineering of TCR regions directly interacting with pHLA, Thomas et al [ 38 ] described amino acid replacements in framework regions of the α and β chain, thereby creating TCRs with improved cell surface expression and enhanced effector functions.…”

Section: Discussionmentioning

confidence: 99%

An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML

Lee

Koutsoumpli

Reijmers

et al. 2021

Cancers

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Acute myeloid leukemia (AML) is a hematological malignancy caused by clonal expansion of myeloid progenitor cells. Most patients with AML respond to chemotherapy, but relapses often occur and infer a very poor prognosis. Thirty to thirty-five percent of AMLs carry a four base pair insertion in the nucleophosmin 1 gene (NPM1) with a C-terminal alternative reading frame of 11 amino acids. We previously identified various neopeptides from the alternative reading frame of mutant NPM1 (dNPM1) on primary AML and isolated an HLA-A*02:01-restricted T-cell receptor (TCR) that enables human T-cells to kill AML cells upon retroviral gene transfer. Here, we isolated T-cells recognizing the dNPM1 peptide AVEEVSLRK presented in HLA-A*11:01. The TCR cloned from a T-cell clone recognizing HLA-A*11:01+ primary AML cells conferred in vitro recognition and lysis of AML upon transfer to CD8 cells, but failed to induce an anti-tumor effect in immunodeficient NSG mice engrafted with dNPM1 OCI-AML3 cells. In conclusion, our data show that AVEEVSLRK is a dNPM1 neoantigen on HLA-A*11:01+ primary AMLs. CD8 cells transduced with an HLA-A*11:01-restricted TCR for dNPM1 were reactive against AML in vitro. The absence of reactivity in a preclinical mouse model requires further preclinical testing to predict the potential efficacy of this TCR in clinical development.

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Section: Discussionmentioning

confidence: 99%

An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML

Lee

Koutsoumpli

Reijmers

et al. 2021

Cancers

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“…The RMA‐S 12 and EL4 13 lymphoma cell lines were cultured in complete RPMI (Gibco, Waltham, MA), supplemented with 10% heat‐inactivated FBS (Gibco), 40 μg/mL gentamycin sulfate (Biological Industries, Kibbutz Beit‐Haemek, Israel) and 50 μM 2‐mercaptoethanol (Merck KGaA, Darmstadt, Germany). RMA‐S (RRID:CVCL_2180) cells were obtained 25 years ago from Prof. Klas Kärre (Stockholm, Sweden).…”

Section: Methodsmentioning

confidence: 99%

On the development of a neoantigen vaccine for the prevention of Lynch Syndrome

Solomon

Alteber

Bassan

et al. 2022

Intl Journal of Cancer

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Lynch Syndrome (LS) is an autosomal dominant genetic condition that causes a high risk of colorectal cancer. The hallmark of LS is genetic instability as a result of mismatch repair (MMR) deficiency, particularly in repetitive low complexity regions called microsatellites (MS). MLH1−/− mice deficient in MMR are prone to developing tumors in the colon, upon oral administration of dextran sodium sulfate (DSS), at a rate of more than 70%. Using this LS mouse model, we found a novel tumor neo‐antigen from a deletion mutation of the coding MS in the SENP6 gene that prevented tumorigenesis or hindered tumor growth rate in immunized mice. This was accomplished via high throughput exome sequencing of DSS‐induced colorectal tumors in the MLH1−/− mice and predicting the most highly immunogenic mutant gene products processed and presented as antigens in C57BL/6 MHC‐I molecules. Throughout our study, we were able to prove the validity of the vaccine by analyzing the colorectal tumors in immunized DSS‐treated mice using either our epitope, called Sp6D1, or an unrelated peptide as a negative control. Tumors developed in this context were found to be antigenic and Sp6D1‐specific CD8+ tumor infiltrating lymphocytes were detected by flow cytometry and cytotoxic T lymphocytes (CTL) killing assays. Additionally, immunohistochemistry showed that tumor‐adjacent tertiary lymphoid organs were a potentially significant source of CD8+ lymphocytes. Altogether, our results indicate that there may be a protective effect to patients carrying LS mutations through the induction of a peptide‐specific CTL response from the use of neoepitope vaccination.

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“…As few as one or two amino acid changes in the complementarity determining regions can increase the affinity of TCRs ( 8 , 65 , 114 , 123 ), evident by slower TCR off rates ( 124 ). High throughput methods such as phage ( 124 , 125 ), yeast ( 126 , 127 ), and T cell display libraries ( 128 , 129 ), along with somatic hypermutation ( 130 ), and in-vitro T cell differentiation ( 131 ) have been employed to generate high affinity TCRs, sometimes in conjunction with available structure data ( 132 ). While increasing TCR affinity has been shown to increase the effectiveness of the T cell ( 65 , 74 , 123 ), TCRs whose affinities are too high can become less effective ( 115 ) and are at higher risk for cross reactivity ( 74 , 115 , 123 ).…”

Section: Generation Of Therapeutic T Cellsmentioning

confidence: 99%

Empirical and Rational Design of T Cell Receptor-Based Immunotherapies

et al. 2021

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The use of T cells reactive with intracellular tumor-associated or tumor-specific antigens has been a promising strategy for cancer immunotherapies in the past three decades, but the approach has been constrained by a limited understanding of the T cell receptor’s (TCR) complex functions and specificities. Newer TCR and T cell-based approaches are in development, including engineered adoptive T cells with enhanced TCR affinities, TCR mimic antibodies, and T cell-redirecting bispecific agents. These new therapeutic modalities are exciting opportunities by which TCR recognition can be further exploited for therapeutic benefit. In this review we summarize the development of TCR-based therapeutic strategies and focus on balancing efficacy and potency versus specificity, and hence, possible toxicity, of these powerful therapeutic modalities.

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Optimizing T‐cell receptor avidity with somatic hypermutation

Cited by 8 publications

References 49 publications

An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML

An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML

On the development of a neoantigen vaccine for the prevention of Lynch Syndrome

Empirical and Rational Design of T Cell Receptor-Based Immunotherapies

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