Co-blocking TIGIT and PVRIG using a novel bispecific antibody enhances anti-tumor immunityLin, Lin, Fu
et alMol Cancer Ther (2025)
Abstract: TIGIT and PVRIG are immune checkpoints co-expressed on activated T and NK cells, contributing to tumor immune evasion. Simultaneous blockade of these pathways may enhance therapeutic efficacy, positioning them as promising dual targets for cancer immunotherapy. This study aimed to develop a bispecific antibody (BsAb) to co-target TIGIT and PVRIG. Expression of TIGIT and PVRIG was assessed on tumor-infiltrating lymphocytes (TILs) from patients with various cancers, including non-small cell lung cancer (n=63) and colorectal cancer (n=26). The BsAb was engineered by fusing anti-PVRIG nanobodies to the N terminus of anti-TIGIT antibodies. Functional characterization of the BsAb was performed in vitro and in vivo, including assessments of T and NK cell activation and cytotoxicity. Pharmacokinetics and safety profiles were evaluated in cynomolgus monkeys. Statistical analyses were conducted using the Student's t-test. The results showed that the BsAb effectively blocked TIGIT and PVRIG from binding their respective ligands, CD155 and CD112, leading to significant increases in T cell activation (2.8-fold, p<0.05) and NK cell cytotoxicity (1.8-fold, p<0.05). In vivo, the BsAb demonstrated potent anti-tumor activity, both as a monotherapy and in combination with anti-PD-1 or anti-PD-L1, in humanized PBMC and transgenic mouse models. Pharmacokinetic studies in cynomolgus monkeys revealed a favorable profile, with no dose-limiting toxicities observed after four repeated doses of 200 mg/kg. These findings provide compelling preclinical evidence for the therapeutic potential of targeting the TIGIT-PVRIG axis with a bispecific antibody. This approach shows promise for enhancing anti-tumor immunity and warrants further investigation in clinical trials.
The inhibitory receptor PVRIG is dominantly expressed in the bone marrow of patients with multiple myeloma and its blockade enhances T-cell engager's immune activationFrenkel, Alteber, Xu
et alExp Hematol (2025) 143, 104696
Abstract: Therapeutic advances in treating patients with multiple myeloma (MM), including novel immunotherapies, have improved the disease control, but it remains incurable. Although traditional immune check point inhibitors have shown limited clinical benefit, targeting alternative immune-inhibitory pathways may offer a novel way to address relapsed disease. Blockade of the immune regulator TIGIT was shown to enhance antitumor immunity in preclinical MM models. Beyond TIGIT, the DNAM-1 axis includes the novel inhibitory receptor PVR related immunoglobulin (PVRIG). In this study we evaluated the expression of DNAM-1 axis receptors and the function of PVRIG in bone marrow of individuals with MM, specifically highlighting PVRIG blockade as a potential therapeutic opportunity in combination with bispecific T-cell engager (BiTE).Copyright © 2024 International Society for Experimental Hematology. All rights reserved.
Examining the evidence for immune checkpoint therapy in high-grade serous ovarian cancerConnor, Lyons, Kilgallon
et alHeliyon (2024) 10 (20), e38888
Abstract: The 5-year survival rate for ovarian cancer has remained relatively static over the past number of years, which can be attributed in part to the lack of new therapeutic strategies to target this disease. Although numerous other cancer types have benefited from the success of immune checkpoint inhibitors, their use in clinical trials targeting ovarian cancer has shown limited efficacy. Most clinical trials have focused on PD-1/PD-L1 immune checkpoint blockade, either as a monotherapy or in combination with chemotherapies, however inhibiting other pathways may potentially be more efficacious in treating ovarian cancer. For example, drugs targeting some emerging immune checkpoints (such as LAG-3, TIM-3, TIGIT and PVRIG), are entering into clinical trials, which could show improved success for ovarian cancer patients. Similarly, predictive biomarkers that have been approved for use with immune checkpoint inhibitors, such as PD-L1 expression, are limited, as only the presence or absence of PD-L1 is assessed. However, the development of next generation predictive biomarkers, which assesses density and location of tumour infiltrating lymphocytes, could be more beneficial for this heterogenous cancer. In this review we discuss the use of immune checkpoint inhibitors in ovarian cancer, with a focus on high-grade serous disease, and delve into what the future may hold for immunotherapy in this cancer type.© 2024 Published by Elsevier Ltd.
Effect of NK cell receptor genetic variation on allogeneic stem cell transplantation outcome and in vitro NK cell cytotoxicityNihtilä, Penna, Salmenniemi
et alSci Rep (2024) 14 (1), 26988
Abstract: Natural killer (NK) cells recognize and may kill malignant cells via their cell surface receptors. Killer cell immunoglobulin-like receptor (KIR) genotypes of donors have been reported to adjust the risk of relapse after allogeneic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia. To test whether non-KIR NK cell receptors have a similar effect, we screened 1,638 genetic polymorphisms in 21 non-KIR NK cell receptor genes for their associations with relapse and graft-versus-host disease (GVHD) after HSCT in 1,491 HSCT donors (from Finland, the UK, Spain, and Poland), divided into a discovery and replication cohort. Eleven polymorphisms regulating or located in CD226, CD244, FCGR3A, KLRD1, NCR3, and PVRIG were associated with the risks for relapse and GVHD. These associations could not be confirmed in the replication cohort. Blood donor NK cells carrying alleles showing genetic protection for relapse had a higher in vitro NK cell killing activity than non-carriers whereas those with alleles genetically protective for GVHD had lower cytotoxicity, potentially indicating functional effects. Taken together, these results show no robust effects of genetic variation in the tested non-KIR NK cell receptors on the outcome of HSCT.© 2024. The Author(s).
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