scholarly journals 480 A first-in-human phase I dose-escalation trial of the B7-H6/CD3 T-cell engager BI 765049 ± ezabenlimab (BI 754091) in patients with advanced solid tumors expressing B7-H6

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A510-A510
Author(s):  
Gerald Falchook ◽  
David Spigel ◽  
Manish Patel ◽  
Babar Bashir ◽  
Susanna Ulahannan ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Primary Objective ◽  
List Type ◽  
Open Label ◽  
Eu Directive ◽  
Dosing Regimens

BackgroundB7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumor types but very little expression can be detected in normal tissues.1 2 BI 765049 is a novel IgG-like bispecific T-cell engager designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent anti-tumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, the treatment with BI 765049 led to target cell apoptosis, local T-cell activation/proliferation and cytokine production in the tumor tissue, with PD-(L)1 upregulation.3 Activation of the PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor.MethodsNCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have failed on, or be ineligible, for standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/in-study fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD and preliminary efficacy of BI 765049 ± ezabenlimab. The trial may assess up to 4 dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in doses); C (BI 765049 + ezabenlimab [q3w]). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ~120 patients enrolled. As of July 2021, patients are being recruited in early dose-escalation cohorts.AcknowledgementsMedical writing support for the development of this abstract, under the direction of the authors, was provided by Becky O’Connor, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim.Trial RegistrationNCT04752215ReferencesBrandt et al. J Exp Med 2009;206:1495–503.Boehringer Ingelheim. Data on file.Hipp et al. AACR Annual Meeting 2021.Ethics ApprovalThe trial will be carried out in compliance with the protocol, the ethical principles laid down in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good Clinical Practice (GCP) and the EU directive 2001/20/EC/EU regulation 536/2014.

HPN217-3001: A Phase 1/2 Open-Label, Multicenter, Dose Escalation and Dose Expansion Study of the Safety, Tolerability, and Pharmacokinetics of HPN217, a Bcma-Targeting T-Cell Engager, in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Henning Schade ◽  
Sumit Madan ◽  
Eva Medvedova ◽  
Rajneesh Nath ◽  
Lisa Knapp ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Ad Hoc ◽  
Phase 1 ◽  
Advisory Board ◽  
Publicly Traded ◽  
Open Label

Background B cell maturation antigen (BCMA) has emerged as a promising target for multiple myeloma (MM) therapies based on its restricted expression profile and functional role in promoting MM cell survival. Some of these BCMA targeting molecules, including CAR-T cells and CD3-based T cell engaging molecules, have demonstrated efficacy against relapsed/refractory MM (R/R MM) in clinical trials. HPN217 is a BCMA -targeting T cell engager with Harpoon's proprietary Tri-specific T cell Activating Construct (TriTAC®) platform, a recombinant polypeptide of ~50kDa containing three humanized antibody-derived binding domains, targeting BCMA (for tumor binding), albumin (for half-life extension) and CD3 (for T cell engagement). It has been engineered to be a small, globular protein to enable efficient exposure in tumor tissue with prolonged half-life and excellent stability under physiological conditions. HPN217 mediates potent target tumor cell killing in a BCMA-specific manner in vitro and in xenograft models in the presence of T cells. Consistent with its mechanism of action (MOA), tumor cell killing is accompanied by T cell activation, cytokine induction, and T cell expansion. HPN217 binds monomerically to CD3 and BCMA, minimizing non-specific T-cell activation. Study Design and Methods HPN217-3001 is an ongoing Phase 1/2, open-label, multicenter, global study of the safety, tolerability, and pharmacokinetics of HPN217 in patients with relapsed and refractory multiple myeloma. The study is divided into 2 parts: Dose Escalation (Part 1) and Expansion (Part 2). Part 1 of the study will determine the Maximum Tolerated Dose (MTD) or the recommended Phase 2 dose (RP2D); Part 2 of the trial will evaluate the safety and efficacy of HPN217 at MTD/RP2D in patients with R/R MM. Patients, who have received at least 3 prior therapies (including proteasome inhibitor, immune modulatory drug, and an anti-CD38 antibody each) and are not candidates for or intolerant to all therapies known to provide clinical benefit in MM, are eligible for enrollment. Prior exposure to a BCMA-targeting agent is permitted in Part 1 but not in Part 2. HPN217 is administered once weekly via IV infusion on Days 1, 8 and 15 during each 21-day cycle at a flat dose. Dose escalation is being performed in serial patient cohorts starting with single patient dose cohorts followed by a conventional 3 + 3 design. Intra-patient dose escalation is permitted. Dose expansion will be initiated once the MTD or a RP2D is established based on safety, preliminary efficacy, PK, and pharmacodynamic data from dose escalation, with a Simon 2-stage design to assess preliminary clinical efficacy of HPN217. Patients may continue weekly HPN217 treatment until disease progression. Primary study endpoints include frequency and severity of treatment-emergent AEs (TEAEs) graded according to NCI CTCAE version 5.0, number and severity of dose limiting toxicities (DLTs) following treatment with HPN217, and PK parameters of HPN217. The study will also evaluate overall response rate (ORR) based on IMWG response criteria, progression-free survival (PFS) and overall survival (OS), duration of response (DOR), immunogenicity of HPN217, and other exploratory endpoints related to the mechanism of action of HPN217. (NCT04184050) Disclosures Madan: Sanofi: Other: Ad hoc advisory board; GSK: Other: Ad hoc advisory board, Speakers Bureau; Karopharm: Speakers Bureau; Amgen: Other: Ad hoc advisory board, Speakers Bureau; Janssen: Other: Ad hoc advisory board, Speakers Bureau; Takeda: Other: Ad hoc advisory board, Speakers Bureau; Celgene/BMS: Other: Ad hoc advisory board, Speakers Bureau. Nath:Harpoon Therapeutics: Consultancy. Knapp:Harpoon Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lemon:Harpoon Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sun:Harpoon Therapeutics: Current Employment, Current equity holder in publicly-traded company.

scholarly journals An Open Label Study of Alpn-101, a First-in-Class Dual CD28/ICOS Antagonist, in Subjects with Steroid-Resistant or Steroid-Refractory Acute Graft Versus Host Disease (aGVHD)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 372-372
Author(s):  
Jing Yang ◽  
Jan L. Hillson ◽  
Kristi L. Manjarrez ◽  
Jennifer R. Wiley ◽  
Gary D. Means ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Objective Response ◽  
Human Study ◽  
Open Label ◽  
Employment Equity ◽  
Free Survival ◽  
Equity Ownership

Background: Cluster of differentiation 28 (CD28) and inducible T cell costimulator (ICOS) provide costimulatory signals required for optimal T cell activation when bound to their respective ligands, CD80 (B7-1) and CD86 (B7-2), and ICOS ligand (ICOSL). CD28 is involved in initiation of the pathogenic process in GVHD and recent studies suggest therapeutic utility of CD28 pathway inhibitors for prophylaxis and treatment. However, CD28 pathway inhibition alone appears insufficient to control established disease in most patients. In this context, it is recognized that following initial activation, CD28 is often down-regulated while ICOS, its most closely related family member, is upregulated, providing additional T cell costimulation that may sustain GVHD including gastrointestinal manifestations (Adom D et al. Blood. 2018; 132:355). In murine models of aGVHD, combined blockade of CD28 and ICOS was significantly superior to isolated blockade of the CD28 or ICOS pathways alone. ALPN-101 is an Fc fusion protein of a human ICOSL variant immunoglobulin domain (vIgDTM) designed to inhibit both the CD28 and ICOS costimulatory pathways. Nonclinical studies of ALPN-101 demonstrate high affinity binding to CD28 and ICOS, potent inhibition of T cell activation, and suppression of disease activity in a human xenogeneic model of GVHD in mice, after only a single dose (Dillon SR et al. Blood. 2018; 132:2037). ALPN-101 is in development as a novel and potentially transformative approach for GVHD. A first-in-human study of ALPN-101 in healthy subjects is ongoing. This clinical study will assess the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN-101 in subjects with aGVHD. Study Design and Methods: Adults with Grade II-IV aGVHD per Mount Sinai Acute GVHD international Consortium (MAGIC) criteria (Harris et al. 2016) that is resistant or refractory to glucocorticoids will receive a single intravenous dose of ALPN-101. This study will be conducted in two parts including dose escalation and dose expansion. Dose escalation will proceed by using an accelerated titration design. Thereafter, a selected dose level(s) will be evaluated in an expansion cohort of 10 subjects; if ≥ 25% (n=3) subjects achieve response, 15 additional subjects will be enrolled (Simon two-stage design). Background Therapy:At the investigator's discretion, subjects may continue therapies administered for prophylaxis, continue or increase glucocorticoids, and/or add another salvage therapy. Responders will be considered for glucocorticoid taper. Endpoints: Safety will be assessed based on the incidence, severity, and seriousness of adverse events. Efficacy endpoints include the objective response rate, duration of response, failure-free survival, event-free survival, non-relapse mortality, malignancy relapse/progression, overall survival, and glucocorticoid use. The incidence and titer of anti-drug antibodies will be assessed. Serum concentrations of ALPN-101 will be measured and PK parameters will be estimated. PD endpoints include target saturation and immunophenotyping of circulating leucocytes, and may include quantification of circulating cytokines, immunoglobulins, acute phase reactants, and soluble forms of the targeted pathway receptor, evaluation of changes in mRNA expression in circulating leucocytes, evaluation of risk alleles, and correlates of response. Disclosures Yang: Alpine immune sciences: Employment, Equity Ownership. Hillson:Alpine Immune Sciences: Employment, Equity Ownership. Manjarrez:Alpine Immune Sciences: Employment, Equity Ownership. Wiley:Alpine Immune Sciences: Employment, Equity Ownership. Means:Alpine Immune Sciences: Employment, Equity Ownership. Dillon:Alpine Immune Sciences: Employment, Equity Ownership. Peng:Alpine Immune Sciences: Employment, Equity Ownership.

scholarly journals Antigen and Checkpoint Receptor Recalibration of T Cell Receptor Signal Strength

2021 ◽  
Author(s):  
Thomas A.E. Elliot ◽  
Emma K. Jennings ◽  
David A.J. Lecky ◽  
Natasha Thawait ◽  
Adriana Flores-Langarica ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Signal Strength ◽  
Cell Receptor ◽  
Receptor Expression ◽  
List Type

SummaryHow T cell receptor (TCR) signal strength modulates T cell function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice as a digital read-out of NFAT pathway activity, we identify the rapid quantitative and qualitative changes that occur in CD4+ T cells in response to a range of TCR signalling strengths. We demonstrate that the time and dose dependent programming of distinct co-inhibitory receptors rapidly re-calibrates T cell activation thresholds. By developing a new in vivo model, we analyse the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 but not anti-Lag3 immunotherapy leads to an increased TCR signal strength. We define a strong TCR signal metric of five genes specifically upregulated by anti-PD1 in T cells (TCR.strong), which can stratify clinical outcomes during anti-PD1 monotherapy in melanoma patients. Our study therefore reveals how analysis of TCR signal strength – and its manipulation – can provide powerful metrics for monitoring outcomes to immunotherapy.Key PointsTCR signal strength-dependent programming of CD4+ T cells revealed over time in vivoInhibitory receptor expression is dynamic, TCR signal strength dependent, and rapidly re-calibrates T cell activation thresholdsPD1 but not Lag3 blockade leads to a unique and increased TCR signal strength signature (coined TCR.strong)TCR.strong metric stratifies melanoma patient survival in response to Nivolumab (anti-PD1) therapy

scholarly journals 265 CD47xPD-L1 bispecific antibodies for cancer therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A287-A287
Author(s):  
Xavier Chauchet ◽  
Elise Pernarrieta ◽  
Nicolas Bosson ◽  
Sébastien Calloud ◽  
Louis Hellequin ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Xenograft Model ◽  
Bispecific Antibodies ◽  
List Type ◽  
Binding Assays ◽  
Anti Tumor Activity

BackgroundPD-1/PD-L1 blockade can significantly improve survival across many types of cancer, but only in a minority of patients. To broaden its therapeutic efficacy, several combination partners are now being evaluated together with PD-1/PD-L1 blockade. Agents blocking CD47/SIRPα innate immune checkpoint are one such example, and co-targeting PD-1/PD-L1 and CD47 with monoclonal antibody (mAb) combinations showed increased antitumor responses in preclinical studies. However, CD47 mAbs are hindered by ubiquitous CD47 expression leading to rapid target-mediated clearance and safety concerns. Consequently, dual-targeting CD47xPD-L1 bispecific antibodies (bsAbs) enabling preferential inhibition of CD47 on PD-L1-positive cells are being tested as an alternative approach. We compare here two distinct bsAbs, based on a common PD-L1 antibody arm, with differing FcgR-enabling effector functions and CD47-binding arm affinities.MethodsAn array of fully human bsAbs associating a high affinity PD-L1 arm to CD47 arms with varying affinities were generated using the κλ-body platform.1 CD47xPD-L1 bsAbs of human IgG1 isotype (CD47 low affinities) or IgG4 isotype (CD47 high affinities) were screened in various binding assays (including to red blood cells (RBC)) and in receptor-blocking assays, and then tested for their Fc-mediated killing and T-cell activation activity (SEA-stimulated PBMC assay). Selected molecules were evaluated in vivo.ResultsBoth bsAb approaches demonstrated strong blockade of PD-1/PD-L1 interaction and significantly enhanced T-cell activation in vitro. CD47lowxPD-L1 IgG1 bsAbs did not bind to RBC and showed PD-L1-guided inhibition of CD47. ADCP and ADCC experiments with a panel of tumor cell lines expressing various target levels showed superior killing activity with CD47lowxPD-L1 IgG1 bsAbs as compared to the anti-PD-L1 IgG1 mAb, avelumab. On the other hand, CD47highxPD-L1 IgG4 bsAbs showed residual RBC binding and PD-L1-independent blocking of CD47/SIRPα. These CD47high IgG4 bsAbs were able to enhance the anti-tumor activity of anti-tumor-associated antigen (TAA) mAbs in vitro (phagocytosis), and in vivo (Raji lymphoma xenograft model). In addition, anti-tumor activity of mouse CD47xPD-L1 bsAbs in a syngeneic MC38 colon carcinoma model was demonstrated.ConclusionsWith the objective of finding the optimal CD47xPD-L1 bsAb design, two approaches targeting CD47 and PD-L1 inhibition were tested. Both the CD47lowxPD-L1 IgG1 bsAbs and CD47highxPD-L1 IgG4 bsAbs were able to mediate enhanced antitumor responses, the former as a standalone treatment, the latter in conjunction with an anti-TAA mAb. To further characterize the CD47lowxPD-L1 and CD47highxPD-L1 bsAbs, lead candidates will be tested in PK and tolerability studies in non-human primates.ReferencesFischer N, Elson G, Magistrelli G, Dheilly E, Fouque N, Laurendon A, et al. Exploiting light chains for the scalable generation and platform purification of native human bispecific IgG. Nat Commun 2015 May;6(1):6113.

scholarly journals PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emily Lee ◽  
Sarah Szvetecz ◽  
Ryan Polli ◽  
Angelo Grauel ◽  
Jayson Chen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Standard Of Care ◽  
Tumor Growth Inhibition ◽  
High Grade ◽  
Ovarian Cancers ◽  
Late Stage Diagnosis ◽  
Anti Tumor Activity

AbstractHigh-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.

406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A431-A431
Author(s):  
Michael Yellin ◽  
Tracey Rawls ◽  
Diane Young ◽  
Philip Golden ◽  
Laura Vitale ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Clinical Activity ◽  
Tumor Types ◽  
Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

scholarly journals Bifunctional iRGD-anti-CD3 enhances antitumor potency of T cells by facilitating tumor infiltration and T-cell activation

2021 ◽  
Vol 9 (5) ◽  
pp. e001925
Author(s):  
Shujuan Zhou ◽  
Fanyan Meng ◽  
Shiyao Du ◽  
Hanqing Qian ◽  
Naiqing Ding ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Confocal Microscope ◽  
Mechanistic Studies ◽  
Tumor Spheroids ◽  
Antitumor Effects ◽  
Transport Pathway

BackgroundPoor infiltration and limited activation of transferred T cells are fundamental factors impeding the development of adoptive cell immunotherapy in solid tumors. A tumor-penetrating peptide iRGD has been widely used to deliver drugs deep into tumor tissues. CD3-targeting bispecific antibodies represent a promising immunotherapy which recruits and activates T cells.MethodsT-cell penetration was demonstrated in tumor spheroids using confocal microscope, and in xenografted tumors by histology and in vivo real-time fluorescence imaging. Activation and cytotoxicity of T cells were assessed by flow cytometry and confocal microscope. Bioluminescence imaging was used to evaluate in vivo antitumor effects, and transmission electron microscopy was used for mechanistic studies.ResultsWe generated a novel bifunctional agent iRGD-anti-CD3 which could immobilize iRGD on the surface of T cells through CD3 engaging. We found that iRGD-anti-CD3 modification not only facilitated T-cell infiltration in 3D tumor spheroids and xenografted tumor nodules but also induced T-cell activation and cytotoxicity against target cancer cells. T cells modified with iRGD-anti-CD3 significantly inhibited tumor growth and prolonged survival in several xenograft mouse models, which was further enhanced by the combination of programmed cell death protein 1 (PD-1) blockade. Mechanistic studies revealed that iRGD-anti-CD3 initiated a transport pathway called vesiculovacuolar organelles in the endothelial cytoplasm to promote T-cell extravasation.ConclusionAltogether, we show that iRGD-anti-CD3 modification is an innovative and bifunctional strategy to overcome major bottlenecks in adoptive cell therapy. Moreover, we demonstrate that combination with PD-1 blockade can further improve antitumor efficacy of iRGD-anti-CD3-modified T cells.

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