Beyond TIGIT, the DNAM-1 axis includes the novel inhibitory receptor 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 bi-specific T-cell engager (BiTE).

In addition, CD4+ and CD8+ T cells more frequently expressed TIGIT and CD137, suggesting that CD112/TIGIT and CD137L/CD137 interactions may suppress T-cell activity against CD34+ MM cells. Furthermore, our finding of higher FcRH5 expression on CD34+ MM cells is encouraging for future research into the efficacy of FcRH5-targeted therapy in MM.

P1, N=141, Recruiting, GlaxoSmithKline | Trial completion date: Oct 2026 --> Sep 2028 | Trial primary completion date: Oct 2026 --> Sep 2028

P1/2, N=140, Not yet recruiting, Biotheus Inc.

P1/2, N=48, Completed, Compugen Ltd | Active, not recruiting --> Completed | N=100 --> 48

P1, N=121, Completed, Compugen Ltd | Active, not recruiting --> Completed | Trial completion date: May 2024 --> Jan 2024

P2, N=16, Not yet recruiting, Fujian Cancer Hospital; Fujian Cancer Hospital

Additionally, our in silico data (n = 671) show that poor prognosis AML patients rather displayed a CD86low CD112/CD155high phenotype, whereas patients with a better outcome rather exhibited a CD86high CD112/CD155low phenotype. Collectively, our data evidence that the complex CR ligand expression profile on AML blasts may be one explanation for the intrinsic NK cell exhaustion observed in AML patients which might be overcome with adoptive NK-92 transfer in combination with TIGIT-blockade.

CD112 expression was found to be negatively associated with anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) treatment outcomes in patients. CD112 may act as a possible prognostic marker in immune therapy and may stimulate tumor growth by upregulating the EMT pathway.

P1, N=19, Completed, Atridia Pty Ltd. | Active, not recruiting --> Completed | N=50 --> 19 | Trial completion date: Sep 2025 --> Feb 2024 | Trial primary completion date: Jul 2025 --> Jul 2023

Moreover, comprehensive comparisons of the binding capacities between co-receptors and ligands provide innovative insights into the intra-axis immunoregulatory mechanism. Taken together, these findings broaden our understanding of immune recognition and regulation mediated by nectin/Necl co-receptors and provide a rationale for the development of immunotherapeutic strategies targeting the nectin/Necl axis.

These data uncover PVRL2 as a distinct inhibitor of the antitumor immune response with functions beyond that of its known receptor PVRIG. Moreover, the data provide a strong rationale for combinatorial targeting of PVRL2 and TIGIT for cancer immunotherapy.

P1, N=50, Active, not recruiting, Atridia Pty Ltd. | Recruiting --> Active, not recruiting

P1/2, N=100, Active, not recruiting, Compugen Ltd | Trial completion date: Dec 2023 --> Aug 2024 | Trial primary completion date: Dec 2023 --> May 2024

P1, N=140, Active, not recruiting, Compugen Ltd | Phase classification: P1a/1b --> P1 | Trial completion date: Dec 2023 --> May 2024 | Trial primary completion date: Dec 2023 --> Feb 2024

P1, N=38, Recruiting, Hefei TG ImmunoPharma Co., Ltd. | Withdrawn --> Recruiting | Trial completion date: Jun 2023 --> Sep 2027 | Trial primary completion date: Jun 2023 --> Sep 2027

P1, N=0, Withdrawn, Hefei TG ImmunoPharma Co., Ltd. | N=38 --> 0 | Trial completion date: Sep 2026 --> Jun 2023 | Recruiting --> Withdrawn | Trial primary completion date: May 2026 --> Jun 2023

In conclusion, the modification of the DNAM-1/CD112 axis in NK cells may be an effective novel immunotherapy for AML. Furthermore, these results suggest the potential of the expression levels of these molecules as prognostic markers in AML.

These findings suggest the role of BATF and CD112 not only as a role in T cell exhaustion, but in effector differentiation program in CLL, which warrants further studies in future.

P1, N=38, Recruiting, Hefei TG ImmunoPharma Co., Ltd. | Not yet recruiting --> Recruiting

Integration of all available spatial and immune checkpoint expression parameters revealed a superior predictive performance for overall survival (area under the curve, 0.65; 95% CI, 0.60-0.70) compared with the commonly used CD8 tumor-infiltrating lymphocyte density (area under the curve, 0.57; 95% CI, 0.53-0.61; P < .001). Cytotoxic T cells with elevated CD112R and PD-1 expression levels are orchestrated in T cell nests of colorectal cancer and predict favorable patient outcomes, and the spatial nonredundancy underlies fundamental differences between both inhibitory immune checkpoints that provide a rationale for dual anti-CD112R/PD-1 immune checkpoint therapy.

P1a/1b, N=140, Active, not recruiting, Compugen Ltd | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2022 --> Dec 2023

P1/2, N=100, Active, not recruiting, Compugen Ltd | Recruiting --> Active, not recruiting | Trial primary completion date: Jan 2023 --> Dec 2023

These results suggest that patients with PVRIG High tumors might be good candidates for immune therapy involving ICIs, notably ICIs targeting the TIGIT/DNAM-1 axis. Further functional and clinical validation is urgently required.

Previously, we have shown the JAK1/2 inhibitor ruxolitinib has beneficial effects for treating multiple myeloma (MM) patients...Specifically, we examined the anti-proliferative effects of pacritinib alone and in combination with dexamethasone, pomalidomide or bortezomib using these 3 MM cell lines and 1 patient's fresh MM BMMCs...We also show the anti-MM effects of pacritinib both alone and in combination with other anti-MM drugs. Pacritinib can be potentially beneficial for treating myeloma patients due to its inhibitory role on PVRIG and TIGIT expression which may enhance tumor cell killing by CD8+ T cells.

M002 successfully infects, replicates in, produces mIL-12, and kills QGP-1 cells. Furthermore, in an established PDX in vivo model, M002 treatment delayed tumor growth and increased animal survival. These data provide preclinical data supporting translation of oncolytic virotherapy for pediatric giNET tumors to the clinical setting.

NK-92 DNAM-1 cells show enhanced anti-AML activity compared with WT NK-92 cells. High expression of DNAM-1 may overcome inhibitory activity by TIGIT. Modification of the DNAM-1/TIGIT/CD155/CD112 axis in NK cells may constitute an effective novel immune therapy for AML.

The co-culture results of BMSCs and NK cells demonstrated that BMSCs regulate NK cells through the TIGIT/CD155 interaction, indicating that NK cells play a vital role in MDS progression. BMSCs regulate the function of NK cells via TIGIT/CD155. Video Abstract.

Conclusions Our findings show that the combination of HSV-1 rQNestin34.5v2 virotherapy with anti-TIGIT checkpoint blockade immunotherapy represents a promising strategy to overcome primary resistance to immune checkpoint inhibitors in GBM. Ethics Approval All animal experiments and procedures described in this study were approved by Brigham and Women's Institutional Animal Care and Use Committee.

Conclusions This study confirmed that NK cell cytotoxicity plays an important role in the anti-tumor activity of M6223 and demonstrated the additive effect of avelumab and M6223 in enhancing NK cell activation, especially in CD155+ human leukocyte antigen (HLA) class I-deficient target tumors. Currently, M6223 plus avelumab is being studied as first-line maintenance therapy for advanced UC in the phase 2 JAVELIN Bladder Medley umbrella trial ( NCT05327530 ).

M002 successfully infects, replicates within, and kills QGP-1 cells. Furthermore, in an established PDX in vivo model, M002 treatment delayed tumor growth and increased animal survival. These data provide preclinical data supporting translation of oncolytic virotherapy for pediatric giNET tumors to the clinical setting.

Furthermore, both LA-N-5 and SMS-KCNR cells pretreated with Nutlin-3a were significantly more susceptible to DNAM-1-engineered NK cells than NK cells transfected with the empty vector. Our results provide a proof-of-concept suggesting that the combined use of DNAM-1-chimeric receptor-engineered NK cells and Nutlin-3a may represent a novel therapeutic approach for the treatment of solid tumors, such as NB, carrying dysfunctional p53.

P1/2, N=100, Recruiting, Compugen Ltd | Trial primary completion date: Aug 2022 --> Jan 2023

Patients will receive IV GSK'859A/EOS-448 + dostarlimab + GSK'608 (dose escalation) q3w for ≤35 cycles or 2 years or until disease progression, consent withdrawal, intolerability, or death. Part 1 endpoints are safety and tolerability (primary) and efficacy and pharmacokinetics (secondary).

Secondary endpoints include PFS (RECIST v1.1; BICR) in pts with PD-L1 TC ≥1%, overall survival, objective response rate and duration of response (RECIST v1.1; BICR), safety/tolerability, and pt-reported outcomes. Enrolment is ongoing.

Results and Discussions Together, these data will provide the necessary evidence for a rational-based combination immunotherapy. Conclusion Eventually, this might pave the way towards clinical benefit for PDAC patients, who are in dire need of new treatment options.

Patients who received prior docetaxel or have known molecular alterations with therapeutic options available (eg, EGFR, ALK, ROS1) are excluded. Part 1 primary endpoints are safety and tolerability, and secondary endpoints are efficacy and pharmacokinetics. Four patients have been treated at the starting dose (Figure) as of March 1, 2022.

Synergistic effect was obtained when NTX-1088 was combined with the anti-CD112R mAb, NTX-2R13...Furthermore, NTX-1088 in combination with pembrolizumab, was superior to the combination of pembrolizumab with tiragolumab...This is a step change in antitumor immune activation that provides a remarkable and differentiated addition to the armamentarium available to patients and their treating oncologists. An IND will be open during 2Q2022.

Our anti-TIGIT × PVRIG biAb, a fully human bispecific antibody, either alone or in combination with anti-PD-1 mAb promotes immune cell activation both in vitro and in vivo, supporting its clinical development for the treatment of human cancers. The molecule is currently under GLP-toxicity evaluation in NHP, and a first-in-human study is expected to begin in 2022.

The current phase 3 study (KeyVibe-003; ClinicalTrials.gov, NCT04738487) is comparing first-line treatment with MK-7684A, a co-formulation of vibostolimab plus pembrolizumab, versus pembrolizumab monotherapy in patients with PD-L1-positive metastatic NSCLC. This randomized, multicenter, double-blind study is enrolling adults with pathologically confirmed, previously untreated, metastatic NSCLC with PD-L1 TPS ≥1% (centrally confirmed). N/A

Integration of all available spatial and immune checkpoint expression parameters (AUC: 0.65) revealed a superior predictive performance for overall survival compared to the commonly used CD8+ TILs density (AUC 0.57, p<0.001). Cytotoxic T-cells with elevated CD112R and PD-1 expression levels are orchestrated in T-cells-nests of colorectal cancer, predict favorable patient’s outcome and the spatial non-redundancy underlies fundamental differences of both inhibitory immune checkpoints that provide a rationale for dual anti-CD112R/ PD-1 immune checkpoint therapy.