T-cell receptor therapy / Regeneron - LARVOL DELTA

A Novel Approach To Preclinical Safety Assessment Of TCRs, Pairing Quantitative Immunopeptidomics With Cell-Based Functional Assays, Identified a Development-Limiting Risk Of Cardiotoxicity f or a PRAME TCR (ASGCT 2025) - "Background: T cell receptor (TCR)-engineered T cells (TCR-T) are a promising modality for the treatment of solid tumors... By pairing in vitro co-culture data with quantitative immunopeptidomics, we elucidated the threshold of reactivity to LRP1 peptide for a PRAMETCR. Comparing the threshold of reactivity with the observed peptide copy number in normal and diseased tissues identified a potential high risk of cardiotoxicity presented by this OT reactivity. Standard in vitro models did not reveal this risk because they did not present physiologically relevant LRP1 copy numbers."

IO biomarker • Preclinical • Cardiovascular • Coronary Artery Disease • Oncology • Peripheral Arterial Disease • Solid Tumor • HLA-A • IFNG • LRP1 • PRAME

COMET, a novel TCR-enabled architecture, combines the sensitivity and intracellular targetability of a TCR with the ease of engineering of a CAR (ASGCT 2025) - "However, it is widely accepted that T cell receptors (TCRs) are superior in reacting to antigens with lower surface density compared to CARs...In conclusion, our data demonstrate that the COMET architecture enables COMET-T cells to target either surface or intracellular antigens with significantly enhanced in vitro and in vivo potency compared to 2nd Generation CAR-T cells, which may lead to more successful solid-tumor immunotherapies in the clinic. Disease Focus of Abstract:Cancer Solid Tumors"

Oncology • Solid Tumor • CD4 • IL2

CAR T cells based on fully human T cell receptor-mimetic antibodies exhibit potent antitumor activity in vivo. (PubMed, Sci Transl Med) - "Here, we provide a comprehensive strategy for generating fully human TCRm antibodies across multiple HLA alleles, beginning with pHLA target discovery and validation and culminating in the engineering of TCRm-based chimeric antigen receptor T cells with potent antitumor activity. By incorporating mass spectrometry, bioinformatic predictions, HLA-humanized mice, antibody screening, and cryo-electron microscopy, we have established a pipeline to identify additional pHLA complex-specific antibodies with therapeutic potential."

Journal • Preclinical • Oncology

Neoadjuvant Cemiplimab for Stage II-IV Cutaneous Squamous Cell Carcinoma: 2-Year Follow-up and Biomarker Analyses (EADO-WCM 2025) - P2 | "Tumour tissue collected pretreatment and at Day 22 ± 3 (after the first dose of cemiplimab) was analysed via flow cytometry and bulk RNA/T-cell receptor (TCR) sequencing. Conclusions At 2 years of follow-up, patients with resectable stage II–IV CSCC treated with neoadjuvant cemiplimab had encouraging EFS, DFS and OS rates. Neoadjuvant cemiplimab enhances T-cell responses, with increased clonal abundance in responders."

Biomarker • Clinical • IO biomarker • Non-melanoma Skin Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • CD4 • CD8 • IFNG • PD-1

RESET: A reversible TCR-coupled antigen receptor with superior targeting sensitivity and pharmacologically controlled anti-tumor activity. (PubMed, Mol Ther) - "Here, we describe a novel receptor architecture called RESET (rapamycin-enabled, switchable endogenous T-cell receptor) that combines: (i) cell surface antigen targeting; (ii) small-molecule regulation; and (iii) the signaling proficiency and inherent sensitivity of native T-cell receptors. Pharmacological control then increases safety through toggling T-cell activation between active and resting states and may mitigate T-cell exhaustion caused by continuous antigen exposure. This convergence of drug-regulated targeting and natural immune receptor signal transduction may better replicate the kinetics and physiology of a classical T-cell response and potentiate more successful and safer immunotherapies."

IO biomarker • Journal • Oncology

A CD38xCD28 Costimulatory Bispecific Antibody Demonstrates Potent Preclinical Combinatorial Activity with a BCMAxCD3 T Cell-Engager (ASH 2024) - "In RRMM, linvoseltamab activates T cells by engaging the T cell receptor (TCR)/CD3 complex in the presence of BCMA-expressing MM tumor cells leading to tumor cell killing...CD28-targeting bsAbs, including REGN5668 (MUC16xCD28) and REGN5837 (CD22xCD28), are an emerging class of therapeutics capable of providing targeted costimulation and enhancing T cell effector function in combination with CD3-targeted bsAbs...Based on these promising preclinical results, a Phase 1 clinical trial is planned to evaluate the safety, tolerability, and preliminary efficacy of the CD38xCD28 bsAb REGN7945 and the BCMAxCD3 bsAb linvoseltamab in patients with RRMM. This innovative approach, leveraging the combinatorial potential of CD38xCD28 costimulation with linvoseltamab's targeted cytolytic activity, represents a novel therapeutic strategy with the potential to improve RRMM treatment outcomes."

Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • CD28

T Cell Receptor (TCR) Sequencing and Transcriptional Profiling in Adult Celiac Disease Patients Undergoing Gluten Challenge (clinicaltrials.gov) - P=N/A | N=24 | Completed | Sponsor: Regeneron Pharmaceuticals | Recruiting ➔ Completed | Trial completion date: Sep 2024 ➔ May 2024 | Trial primary completion date: Sep 2024 ➔ May 2024

Trial completion • Trial completion date • Trial primary completion date • Celiac Disease • Immunology

The Role of Sarcoidosis-Specific T-Cell Receptors and Environmental Antigens in Sarcoidosis Pathogenesis (ATS 2024) - "There is no abstract associated with this presentation."

Immunology • Sarcoidosis

Designing meaningful continuous representations of T cell receptor sequences with deep generative models. (PubMed, Nat Commun) - "We thoroughly quantify these properties of the representations, providing a framework for future protein representation learning in low dimensions. The continuity of TCR-VALID representations allows fast and accurate TCR clustering and is benchmarked against other state-of-the-art TCR clustering tools and pre-trained language models."

Journal

VelociT mice genetically humanized for the T cell receptor, MHCI/II and CD4/CD8 serve as a promising platform for studying HLA-restricted T cell responses in multiple inflammatory settings. (IMMUNOLOGY 2024) - "Finally, we successfully established an allogeneic skin graft mouse model by showing that VelociT recipient mice rejected Balb/c donor skin grafts. This work established VelociT mice as a platform for investigation of T cell–mediated immunity in different disease settings including autoimmunity, antitumor responses, and allo-immunity."

Preclinical • CNS Disorders • Immunology • Multiple Sclerosis • Oncology • Transplant Rejection • CD4 • CD8

Dual-receptor T cell platform with Ab-TCR and costimulatory receptor achieves specificity and potency against AML. (PubMed, Blood) - "One approach to overcome this hurdle is dual targeting by an antibody-T cell receptor (AbTCR) and a chimeric costimulatory signaling receptor (CSR) to two different antigens, in which both antigens are found together on the cancer cells, but not together on normal cells...By use of a AbTCR receptor comprising a newly developed TCR mimic monoclonal antibody (mAb) against the WT1 RMFPNAPYL (RMF) epitope/HLA-A2 complex, ESK2, and a secondary CSR comprising a scFv directed to CD33 linked to a truncated CD28 costimulatory fragment, this unique platform confers specific T cell cytotoxicity to the AML cells, while sparing healthy hematopoietic cells, including CD33+ myelomonocytic normal cells. These data suggest that this new platform, named AbTCR-CSR, through the combination of a AbTCR CAR and CSR could be an effective strategy to reduce toxicity and improve specificity and clinical outcomes in adoptive T cell therapy in AML."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Wilms Tumor • CD33 • WT1

A Family’s Challenging Story Of Ataxia Telangiectasia (ACAAI 2023) - "The diagnosis is clinical, but screening for severe combined immunodeficiency (SCID) revealing low levels of T-Cell Receptor Excision Circles (TRECs) provides a clue...These siblings contribute to data that low TRECs and T cell lymphopenia may have high sensitivity as screening tools. The ethical sequela of this knowledge is what to do with it as society is divided on how individuals confront uncurable diseases."

IO biomarker • Ataxia • Genetic Disorders • Immunology • Movement Disorders • Oncology • Preventive care • Primary Immunodeficiency • ATM

A Case Of Ataxia-Telangiectasia With Compound Heterozygous AT Mutations Discovered On Abnormal Newborn Screen (ACAAI 2023) - "Supported by Sanofi and Regeneron Introduction A patient who presented with low T-cell receptor excision circles (TRECs) on newborn screening (NBS) was diagnosed with AT due to compound heterozygous variants in ATM...Subsequently, the patient started subcutaneous immunoglobulin therapy and sulfamethoxazole-trimethoprim for Pneumocystis jirovecii prophylaxis...Discussion Early diagnosis of AT, which can be picked up with low TREC on NBS, can lead to implementation of supportive care reducing infection-related morbidity and mortality. While the c.8339T>C, p.Leu2780Pro variant was classified as a VUS, studies assessing ATM function in DNA DSB repair identified it as pathogenic, which in conjunction with the second pathogenic variant on the other allele resulted in a compound heterozygous (biallelic) defect in ATM causing a clinical and immunological phenotype."

Clinical • IO biomarker • Ataxia • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Movement Disorders • Primary Immunodeficiency • Septic Shock • CD4 • CD8

The Course of Purine Nucleoside Phosphorylase Deficiency-Severe Combined Immunodeficiency Without Hematopoietic Stem Cell Transplant (ACAAI 2023) - "Case Description A male infant was born at full term with a normal T-cell receptor excision circle (TREC) evaluation...Discussion PNP-SCID is a rare and lethal condition that may result in delayed diagnosis due its low incidence and varied presentation. HSCT is the only potential curative treatment."

IO biomarker • Bone Marrow Transplantation • Cardiovascular • CNS Disorders • Dermatology • Diffuse Large B Cell Lymphoma • Genetic Disorders • Hematological Malignancies • Herpes Zoster • Immunology • Infectious Disease • Ischemic stroke • Keratitis • Lymphoma • Non-Hodgkin’s Lymphoma • Ocular Inflammation • Oncology • Ophthalmology • Primary Immunodeficiency • Rare Diseases • Respiratory Diseases • Transplantation • Varicella Zoster • Vasculitis • CD4

T Cell Receptor (TCR) Sequencing and Transcriptional Profiling in Adult Celiac Disease Patients Undergoing Gluten Challenge (clinicaltrials.gov) - P=N/A | N=20 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Trial completion date: Dec 2023 ➔ Sep 2024 | Trial primary completion date: Dec 2023 ➔ Sep 2024

IO biomarker • Trial completion date • Trial primary completion date • Celiac Disease • Immunology

T Cell Receptor (TCR) Sequencing and Transcriptional Profiling in Adult Celiac Disease Patients Undergoing Gluten Challenge (clinicaltrials.gov) - P=N/A | N=20 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Trial completion date: Aug 2023 ➔ Dec 2023 | Trial primary completion date: Aug 2023 ➔ Dec 2023

IO biomarker • Trial completion date • Trial primary completion date • Celiac Disease • Immunology

Comprehensive biophysical characterization of AAV-AAVR interaction uncovers serotype- and pH-dependent interaction. (PubMed, J Pharm Biomed Anal) - "These data indicate that for certain serotypes, AAVR may play a prominent role in trafficking AAV to the Golgi rather than acting as a host cell receptor. Information obtained from these combinatorial biophysical methods can be used to engineer future generations of AAVs to have better transduction efficiency."

Journal • Gene Therapies

T Cell Receptor (TCR) Sequencing and Transcriptional Profiling in Adult Celiac Disease Patients Undergoing Gluten Challenge (clinicaltrials.gov) - P=N/A | N=20 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Trial completion date: Jan 2023 ➔ Aug 2023 | Trial primary completion date: Jan 2023 ➔ Aug 2023

IO biomarker • Trial completion date • Trial primary completion date • Celiac Disease • Immunology

Structural analysis of cancer-relevant TCR-CD3 and peptide-MHC complexes by cryoEM. (PubMed, Nat Commun) - "The recognition of antigenic peptide-MHC (pMHC) molecules by T-cell receptors (TCR) initiates the T-cell mediated immune response...We also determined cryoEM structures of pMHCs containing MAGEA4 (230-239) peptide and the closely related MAGEA8 (232-241) peptide in the absence of TCR, which provided a structural explanation for the MAGEA4 preference displayed by the TCRs. These findings provide insights into the TCR recognition of a clinically relevant cancer antigen and demonstrate the utility of cryoEM for high-resolution structural analysis of TCR-pMHC interactions."

Journal • Oncology • MAGEA4

Spontaneous tumor regression mediated by human T cells in a humanized immune system mouse model. (PubMed, Commun Biol) - "Single-cell RNAseq analysis indicated activation of CD8+ T cells in regressing Raji tumors as well as clonal expansion of specific T cell receptors (TCRs). Cloning of TCRs from Raji-infiltrating T cells into a Jurkat reporter cell line showed reactivity specific for Raji tumor cells. Overall, we report a platform for studying in vivo human T cell tumor immunity by highlighting spontaneous Raji tumor regression, clonal TCR expansion, and T cell memory in HIS mice."

Journal • Preclinical • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD4 • CD8

TCR-T and CAR-T cells targeting HLA-A2/MAGEA4 demonstrate differential tumor control, reflecting co-stimulatory signaling requirements (AACR 2023) - "Surface-accessible pHLA complexes may be targeted with engineered T cell receptors or TCR mimetic antibodies reformatted to chimeric antigen receptors (CARs)...However, stimulating 41BB signaling pathways in the MAGE-A4 TCR T cells augmented long-term cytotoxicity. These data demonstrate that tumor-specific pHLA complexes can be potently targeted by both TCR and CAR-T cells, and that co-stimulatory signaling is necessary to mediate durable anti-tumor activity."

CAR T-Cell Therapy • IO biomarker • Hematological Malignancies • Oncology • Solid Tumor • MAGEA4

A Quantitative Systems Pharmacology Modeling Framework for Evaluation of Cytokine Release Mediated By Intravenous Odronextamab Monotherapy in Patients with B-Cell Non-Hodgkin Lymphoma (ASH 2022) - P1 | "Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity, independent of T-cell receptor-mediated recognition. The model was also able to predict the CD8+ T-cell and B-cell profiles over time following IV odronextamab split-dosing regimen.Conclusion This QSP model was developed to address the safety concern related to CRS following treatment with odronextamab. The work demonstrated that the QSP modeling is a powerful tool that enabled optimization of odronextamab step-up dosing to minimize the risk of higher grade (i.e. Grade 2 and 3) CRS in lymphoma patients treated with odronextamab."

Clinical • Monotherapy • Hematological Malignancies • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD8 • IL6

Evaluate Dynamics of IL-6 Release during Step-up Dosing of Subcutaneous Administration of Odronextamab Via a Quantitative Systems Pharmacology Modeling Approach (ASH 2022) - P1 | "Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, eliciting T-cell-mediated cytotoxicity independent of T-cell receptor-mediated recognition. The selected step-up regimen for SC odronextamab allows adequate step-up to effective therapeutic doses while simplifying and improving overall convenience. The simulations suggest that no split dosing is necessary for SC administration, which may further reduce overall hospital resource burden and requirements for in-patient monitoring."

Hematological Malignancies • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20 • IL6

Optimization of Intravenous Odronextamab Step-up Regimen for Reducing the Risk of High-Grade Cytokine Release Syndrome (ASH 2022) - P1 | "Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity, independent of T-cell receptor-mediated recognition. This indicates that the same therapeutic levels are achieved with both regimens, which is beneficial for the treatment of disease.Conclusion This optimized odronextamab dosing regimen was associated with lower risk of CRS and lower levels of baseline cytokine levels compared with the original regimen. The drug exposure was lower in the first cycle when the risk of CRS is greater, but it was comparable to that of the original regimen after the full dose of treatment was received, ensuring that odronextamab dose levels required for efficacy are maintained."

Cytokine release syndrome • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • IL6

Modeling and Simulation in Support of Odronextamab Subcutaneous Dose Selection for Adult Patients with Indolent or Aggressive Non-Hodgkin Lymphoma (ASH 2022) - P1, P2 | "Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, eliciting T-cell-mediated cytotoxicity independent of T-cell receptor-mediated recognition. Simulated IL-6 profiles, obtained using the SC QSP model, showed the peak IL-6 values during Cycle 1 with the proposed SC step-up dosing regimen (2/26/100 mg) would not exceed those of 0.7/4/20 mg IV.Conclusion SC administration of odronextamab may be simpler and more convenient than IV dosing. PK and IL-6 modeling and simulation analyses enabled the identification of SC regimens for clinical evaluation, which may improve the tolerability while preserving the efficacy for the treatment of patients with B-cell NHL."

Clinical • Hematological Malignancies • Indolent Lymphoma • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20 • IL6