anti-TIGIT Monoclonal Antibody Research Articles

Immune restoration by TIGIT blockade is insufficient to control chronic SIV infection.

TIGIT is a negative immune checkpoint receptor associated with T cell exhaustion in cancer and HIV. TIGIT upregulation in virus-specific CD8+ T cells and NK cells during HIV/SIV infection results in dysfunctional effector capabilities. In vitro studies targeting TIGIT on CD8+ T cells suggest TIGIT blockade as a viable strategy to restore SIV-specific T cell responses. Here, we extend these studies in vivo using TIGIT blockage in nonhuman primates in an effort to reverse T cell and NK cell exhaustion in the setting of SIV infection. We demonstrate that in vivo administration of a humanized anti-TIGIT monoclonal antibody (mAb) is well tolerated in both cynomolgus macaques and rhesus macaques. Despite sustained plasma concentrations of anti-TIGIT mAb, we observed no consistent improvement in NK or T cell cytolytic capacity. TIGIT blockade minimally enhanced T cell proliferation and virus-specific T cell responses in both magnitude and breadth though plasma viral loads in treated animals remained stable indicating that anti-TIGIT mAb treatment alone was insufficient to increase anti-SIV CD8+ T cell function. The enhancement of virus-specific T cell proliferative responses observed in vitro with single or dual blockade of TIGIT and/or PD-1 highlights TIGIT as a potential target to reverse T cell dysfunction. Our studies, however, reveal that targeting the TIGIT pathway alone may be insufficient in the setting of viremia and that combining immune checkpoint blockade with other immunotherapeutics may be a future path forward for improved viral control or elimination of HIV.IMPORTANCEUpregulation of the immune checkpoint receptor TIGIT is associated with HIV-mediated T cell dysfunction and correlates with HIV disease progression. Compelling evidence exists for targeting immune checkpoint receptor pathways that would potentially enhance immunity and refocus effector cell efforts toward viral clearance. In this report, we investigate TIGIT blockade as an immunotherapeutic approach to reverse immune exhaustion during chronic SIV/SHIV infection in a nonhuman primate model of HIV infection. We show that interfering with the TIGIT signaling axis alone is insufficient to improve viral control despite modest improvement in T cell immunity. Our data substantiate the use of targeting multiple immune checkpoint receptors to promote synergy and ultimately eliminate HIV-infected cells.

A randomized phase II trial of atezolizumab with or without tiragolumab before and after definitive chemoradiation for unresectable stage III non-small cell lung cancer (NSCLC; AFT-57).

TPS8123 Background: A minority of patients with unresectable stage III non-small cell lung cancer (NSCLC) may be cured by chemoradiotherapy (CRT). Adjuvant checkpoint inhibition through PD-L1 blockade after CRT improved survival compared to placebo in the PACIFIC trial (median progression-free survival (mPFS) 16.9 vs 5.6 months (mo), median overall survival (mOS) 47.5 vs 29.1 mo), but overall survival at 5 years remains below 50% (Spigel D, et al J Clin Oncol 2022, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9015199/ . Only patients completing CRT without progression and with good performance status were eligible for this approach. Neoadjuvant checkpoint inhibition would allow more patients the opportunity to benefit from immunotherapy and may attenuate tumor-related immunosuppression via depletion of regulatory T cells and clonal expansion of effector T cells, thereby improving tumor immunogenicity. Neoadjuvant atezolizumab had favorable outcomes compared to historic PACIFIC data in the phase II single arm trial, AFT-16 (mPFS 30 mo and mOS not reached). Whether combination immunotherapy therapy before CRT will improve outcomes in this setting is the question posed in the AFT-57 trial. Methods: This phase II randomized Alliance Foundation Trials study (AFT-57) will evaluate safety and efficacy of atezolizumab with or without the anti-TIGIT monoclonal antibody, tiragolumab, before and after definitive CRT with concurrent atezolizumab. The primary endpoint is PFS in the two experimental arms with a goal to select the most promising regimen for further study. AFT-57 will randomly assign 158 patients with stage III NSCLC (AJCC v8), Eastern Cooperative Oncology Group performance status 0-1, no active autoimmune disease and no underlying organ dysfunction to 2 cycles of neoadjuvant atezolizumab (1200 mg intravenously [IV] every 21 days) with or without tiragolumab (600 mg IV). Non-progressing patients will receive carboplatin and paclitaxel weekly with atezolizumab 1200 mg IV every 21 days concurrent with 60 Gray involved field thoracic radiation in 30 daily fractions (Monday - Friday) followed by atezolizumab with or without tiragolumab on the same schedule as the neoadjuvant doses, with a plan to complete one year of therapy. A pilot cohort of 20 patients for whom tiragolumab will be combined with atezolizumab during chemoradiotherapy is planned toward the end of accrual. Correlative science includes tissue and blood-based immune-related biomarkers at baseline and during therapy. This trial utilizes the Alliance Participant Engagement Portal, a patient-facing site designed to provide information and resources to Alliance clinical trial participants. The trial was activated on 12/7/23 with the first patient screened 1/19/24. Clinical trial information: NCT05798663 .

Abstract 5303: A novel TIGIT and 4-1BB bispecific antibody, ABL112, exhibits potent in vitro and in vivo antitumor activity through dual immune modulation

Abstract T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an immune checkpoint molecule responsible for delivering inhibitory signals that suppress immune activation. Due to its inhibitory role in the immune response, TIGIT has emerged as a potential therapeutic target for various malignancies, with several clinical trials exploring the use of anti-TIGIT blocking antibodies with anti-PD-(L)1 therapies. Recent reports have indicated elevated expression of 4-1BB within intra-tumoral Tregs. Therefore, we hypothesized that a dual targeting approach involving both TIGIT and 4-1BB could effectively enhance intra-tumoral immunity. ABL112, a First-in-Class bispecific antibody targeting TIGIT and 4-1BB, demonstrated the induction of T cell activation by blocking the TIGIT signaling and TIGIT dependent 4-1BB clustering. By having intact Fc, ABL112 bound to FcγRI and its crosslinking with 4-1BB also induced 4-1BB activation. ABL112 selectively depleted Treg cells but not other T cells in vitro, potentially through antibody-dependent cell-mediated cytotoxicity. ABL112 demonstrated superior efficacy in tumor regression compared to anti-TIGIT monoclonal antibody across various mouse tumor models. Additionally, combining ABL112 with pembrolizumab significantly inhibited tumor growth better than combining anti-TIGIT monoclonal antibody with pembrolizumab. According to immune cell depletion assay, ABL112-mediated tumor suppressive activity was predominantly driven by CD8+ T cells, with a partial tumor reduction by CD4+ T cell or NK cell depletion. Mice with complete remission (CR) were further protected from the tumor re-challenge after 3 months of cessation of ABL112 treatment, and the proportion of tumor-specific memory T cells in the blood increased, suggesting long-term immunological memory has been established. In conclusion, ABL112 exhibited potent in vitro and in vivo anti-tumor activity through multiple mode of action including TIGIT inhibition and 4-1BB activation. These results strongly suggest that ABL112 is an innovative and promising therapeutic option with the combination of anti-PD-(L)1 therapies for cancer patients. Citation Format: Wonjun Son, Yangsoon Lee, Yelim Park, Jonghwa Won. A novel TIGIT and 4-1BB bispecific antibody, ABL112, exhibits potent in vitro and in vivo antitumor activity through dual immune modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5303.

Pharmacokinetics (PK) of Tiragolumab in First-in-Human Study in Patients with Mixed Solid Tumors (GO30103).

Tiragolumab is a first-in-class, fully human IgG1/kappa anti-TIGIT monoclonal antibody that blocks the binding of TIGIT to CD155 (the poliovirus receptor). We summarize the pharmacokinetics (PK) data from the phase1a/1b GO30103 study of Q3W (every 3weeks) sequential dosing of tiragolumab (2, 8, 30, 100, 400, 600, or 1200mg) followed by atezolizumab (1200mg), Q4W (every 4weeks) sequential dosing (tiragolumab 840mg followed by atezolizumab 1680mg), and Q4W co-infusion (tiragolumab 840mg plus atezolizumab 1680mg). Serum samples were collected at multiple time points following tiragolumab and atezolizumab intravenous infusion in patients with solid tumors for PK and immunogenicity assessment. The serum PK profile of tiragolumab appeared to be biphasic, with a rapid distribution phase followed by a slower elimination phase when administered alone or in combination with atezolizumab. In phase1a, across doses of tiragolumab ranging from 2 to 1200mg (cycle1), the geometric mean (GM), coefficient of variation (CV%), serum tiragolumab Cmax ranged from 0.682 to 270µg/mL (18.6% to 36.5%) and Cmin ranged from 0.0125 to 75.3µg/mL (0.0% to 24.2%). The GM systemic exposure (area under the plasma drug concentration-time curve, AUC0-21) ranged from 310 to 2670µgday/mL (20.5% to 27.0%); interindividual variability in AUC0-21 ranged from 20.5% to 43.9%. Tiragolumab exposure increased in an approximately dose-proportional manner when administered alone or with atezolizumab at doses ≥100mg. Postbaseline, 4/207 patients (1.9%) were positive for treatment-emergent antidrug antibodies (ADA) against tiragolumab, each at a single time point. Tiragolumab combined with atezolizumab demonstrated desirable PK properties, with no drug-drug interactions or immunogenicity liability. There were no meaningful differences in tiragolumab or atezolizumab exposure between the Q4W co-infusion and sequential dosing cohorts. ClinicalTrials.gov: NCT02794571 (date of registration June 6, 2016).

Nonfucosylation of an anti-TIGIT antibody enhances FcγR engagement, driving innate immune activation and antitumor activity.

TIGIT is an immune checkpoint receptor expressed on activated and memory T cells, immunosuppressive T regulatory cells, and natural killer (NK) cells. TIGIT has emerged as an attractive target for antitumor therapies, due to its proposed immunosuppressive effects on lymphocyte function and T cell activation. We generated an anti-TIGIT monoclonal antibody (mAb) that binds with high affinity to human, non-human primate, and murine TIGIT and through multiple experimental methodologies demonstrated that checkpoint blockade alone is insufficient for antitumor activity. Generating anti-TIGIT mAbs with various Fc backbones we show that muting the Fc-Fcγ receptor (FcγR) interaction failed to drive antitumor activity, while mAbs with Fc functional backbones demonstrate substantial antitumor activity, mediated through activation of antigen-presenting cells (APCs), T cell priming, and NK-mediated depletion of suppressive Tregs and exhausted T cells. Further, nonfucosylation of the Fc backbone resulted in enhanced immune responses and antitumor activity relative to the intact IgG1 backbone. The improved activity correlated with the biased FcγR interaction profile of the nonfucosylated anti-TIGIT mAb, which supports that FcγRIIIa binding with decreased FcγRIIb binding favorably activates APCs and enhances tumor-specific CD8+ T cell responses. The anti-TIGIT mAbs with intact FcγR interacting backbones also demonstrated synergistic enhancement of other standard antitumor treatments, including anti-PD-1 treatment and a model monomethyl auristatin E antibody-drug conjugate. These findings highlight the importance of the anti-TIGIT mAb's Fc backbone to its antitumor activity and the extent to which this activity can be enhanced through nonfucosylation of the backbone.

AdvanTIG-105: a phase I dose escalation study of the anti-TIGIT monoclonal antibody ociperlimab in combination with tislelizumab in patients with advanced solid tumors

BackgroundOciperlimab, a novel, humanized monoclonal antibody (mAb), binds to T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) with high affinity and specificity. Tislelizumab is an anti-programmed cell...

AdvanTIG-105: Phase 1b dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy (chemo) in patients (pts) with stage IV gastric/gastroesophageal adenocarcinoma (GC/GEJC).

31 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 8.1 months (95% CI: 4.5, not evaluable [NE]). Median PFS was 8.2 months (95% CI: 5.8, NE). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n=27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP <5% (n=28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

KEYVIBE-010: Adjuvant coformulated vibostolimab with pembrolizumab versus adjuvant pembrolizumab in patients with high-risk stage II-IV melanoma.

TPS9611 Background: Pembrolizumab is an anti−PD-1 monoclonal antibody that has been shown to significantly improve recurrence-free survival and distant metastasis-free survival when used as adjuvant therapy in patients with high-risk resected melanoma (Long GV, et al. Lancet Oncol. 2022;23:1378-88; Eggermont AMM, et al. Lancet Oncol. 2021;22:643-54). Combining pembrolizumab with other therapies may further improve outcomes in this setting. Vibostolimab is an anti-TIGIT monoclonal antibody that showed antitumor activity and manageable safety when used in combination with pembrolizumab in patients with advanced solid tumors in the phase 1 KEYVIBE-001 study (Niu J, et al. Ann Oncol. 2022;33:169-80). The randomized, double-blind, phase 3 KEYVIBE-010 study (NCT05665595) is designed to evaluate the efficacy and safety of adjuvant coformulated vibostolimab and pembrolizumab (MK-7684A) versus pembrolizumab alone in patients with resected high-risk stage IIB-IV melanoma. Methods: Eligible patients are ≥12 years of age (weighing ≥40 kg if < 18 years), with surgically resected stage IIB or IIC (pathologic or clinical), III, or IV cutaneous melanoma per AJCC 8th edition guidelines, and an Eastern Cooperative Oncology Group performance status of 0 or 1 (Lansky play-performance scale ≥70 if < 16 years; Karnofsky performance status ≥70 if ≥16 to < 18 years). Patients must not have received any prior systemic therapy beyond complete resection and no more than 12 weeks can have elapsed between final surgical resection and randomization. Patients with ocular, mucosal, or conjunctival melanoma, and prior allogeneic tissue/solid organ transplant are excluded. Patients will be stratified by risk. Approximately 1560 patients will be randomly assigned 1:1 to receive intravenous coformulated vibostolimab 200 mg with pembrolizumab 200 mg or pembrolizumab 200 mg (2 mg/kg up to a maximum of 200 mg for adolescents) every 3 weeks. Treatment will continue for 17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. The primary end point is recurrence-free survival by investigator review. Secondary end points are distant metastasis-free survival by investigator review, overall survival, safety and tolerability, and quality of life. Hazard ratios and 95% confidence intervals will be estimated using a stratified Cox regression model with the Efron method of handling ties, with treatment as a covariate. Between-treatment differences will be evaluated using a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05665595 .

AdvanTIG-105: A phase 1b dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy (chemo) in patients (pts) with stage IV gastric/gastroesophageal adenocarcinoma (GC/GEJC).

4028 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 4.6 months (95% CI: 3.9, 7.1). Median PFS was 8.2 months (95% CI: 5.8, not evaluable). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n = 27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP < 5% (n = 28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

Abstract 6361: A preclinical model of acquired anti-PD-1 resistance is responsive to SEA-TGT, an effector-function enhanced anti-TIGIT monoclonal antibody

Abstract Immune checkpoint inhibitors, including monoclonal antibodies targeting the PD-1/PD-L1 axis, induce robust antitumor immunity in a subset of patients with various cancers. Despite continued success of these therapies, some patients experience limited efficacy owing to clinically complex and unresolved mechanisms of primary and acquired immunotherapy resistance. To begin to understand the mechanisms of acquired resistance to anti-PD-1 blockade, we developed a syngeneic murine CT26 colorectal tumor model that is resistant to anti-PD-1 therapy. To achieve this, CT26 tumors were subjected to successive rounds of increasing levels of anti-PD-1 therapy. When tumors grew out, they were cultured in vitro and then re-implanted and re-treated for three rounds until PD-1 resistance was achieved. To characterize the underlying drivers of acquired resistance across the generation of the model, wild type and anti-PD-1 resistant tumors and cultured cell lines were evaluated by flow cytometric immunophenotyping and RNA-sequencing analysis. To assess how observed changes in the tumor microenvironment impact response to various therapeutics, the resistant tumors were treated with anti-PD-1 therapy or SEA-TGT, a nonfucosylated anti-TIGIT mAb with enhanced Fc-function that drives activity through multiple modes of action. As expected, treatment with anti-PD-1 monotherapy was ineffective, however, treatment with SEA-TGT demonstrated potent anti-tumor activity. These data are consistent with responsiveness to anti-TIGIT agents in other in vivo models of PD-1 resistance and/or PD-1 refractory response, indicating that the factors driving resistance to anti-PD-1 therapy can be different than those driving response to other known checkpoint molecules such as TIGIT. Thus, investigational agents such as SEA-TGT may have the potential to be efficacious in tumors that are primary or secondarily resistant to anti-PD-1 therapy. We have initiated a phase 1 study (NCT04254107) evaluating the safety, tolerability, and activity of SEA-TGT monotherapy and in combination with anti-PD-1 therapy in patients with advanced malignancies. Citation Format: David R. Gruber, Weiping Zeng, Bob Thurman, Brian P. O'Connor, Shyra J. Gardai, Alyson J. Smith. A preclinical model of acquired anti-PD-1 resistance is responsive to SEA-TGT, an effector-function enhanced anti-TIGIT monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6361.

148P AdvanTIG-105: Phase Ib dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC)

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor with an anti-programmed cell death protein 1 (PD-1) antibody is a promising combination showing antitumor activity in solid tumors. Phase 1/1b open-label study AdvanTIG-105 assessed safety and preliminary antitumor activity of anti-TIGIT monoclonal antibody (mAb) OCI + anti-PD-1 mAb TIS in pts with advanced unresectable solid tumors (NCT04047862). In dose-escalation, OCI + TIS was well tolerated showing preliminary antitumor activity, establishing the recommended phase 2 dose (RP2D) of OCI 900mg IV every 3 weeks (Q3W) plus TIS 200mg IV Q3W.

126P AdvanTIG-105: Phase Ib dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) in patients (pts) with checkpoint inhibitor (CPI)-experienced advanced non-small cell lung cancer (NSCLC)

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor with an anti-programmed cell death protein 1 (PD-1) antibody is a promising combination showing antitumor activity in solid tumors. Phase 1/1b open-label study AdvanTIG-105 assessed safety and preliminary antitumor activity of anti-TIGIT monoclonal antibody (mAb) OCI + anti-PD-1 mAb TIS in pts with advanced solid tumors (NCT04047862). During dose-escalation, OCI + TIS was well tolerated showing antitumor activity, establishing the recommended phase 2 dose (RP2D) of OCI 900mg IV Q3W plus TIS 200mg IV Q3W.

1017P AdvanTIG-105: Phase Ib dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy (chemo) in patients (pts) with metastatic squamous (sq) and non-squamous (non-sq) non-small cell lung cancer (NSCLC)

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor + an anti-programmed cell death protein 1 (PD-1) antibody is a promising combination which shows potent efficacy in solid tumors. AdvanTIG-105 is a Phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with metastatic unresectable solid tumors (NCT04047862). In the dose-escalation part, OCI + TIS was well tolerated, preliminary efficacy was observed, and the recommended Phase 2 dose (RP2D) of OCI 900 mg intravenous (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion (Cohorts 1 [C1] & 2 [C2]) of the AdvanTIG-105 study. Treatment-naïve adult pts with histologically/cytologically confirmed metastatic sq (C1) or non-sq with EGFR/ALK/ROS-1 wild-type tumors (C2) NSCLC were enrolled. Pts in C1 received the RP2D of OCI + TIS with paclitaxel/nab-paclitaxel + carboplatin and pts in C2 received the RP2D of OCI + TIS with pemetrexed + cisplatin/carboplatin, both until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included safety. As of March 18, 2022, 84 pts were enrolled (C1: n=41; C2: n=43). The median study follow-up was 17.7 weeks (range 1.1–42.6) in C1 and 15.0 weeks (3.0–51.1) in C2. Of the 76 efficacy-evaluable pts, the confirmed ORR in C1 was 45.9% (95% confidence interval [CI]: 0.3, 0.6) and 25.6% (95% CI: 0.1, 0.4) in C2. In total, 81 pts (96.4%) experienced ≥ 1 treatment-emergent adverse event (TEAE), and 48 pts (57.1%) had ≥ Grade 3 TEAEs. Serious TEAEs occurred in 26 pts (31.0%). The most common TEAEs were anemia (41.7%), neutrophil count decreased (33.3%), and white blood cell count decreased (33.3%). The RP2D of OCI 900 mg IV Q3W and TIS 200 mg IV Q3W + chemo was generally well tolerated and showed antitumor activity in pts with treatment-naïve metastatic sq/non-sq NSCLC. Prof. Y. Yu and Prof. D. Huang have contributed equally to the study.

AdvanTIG-206: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (BGB-A1217; OCI) plus anti-programmed cell death protein-1 (PD-1) mAb tislelizumab (TIS) plus BAT1706 versus TIS plus BAT1706 as first-line (1L) treatment for advanced hepatocellular carcinoma (HCC).

TPS4172 Background: Treatment with PD-1/programmed death ligand 1 (PD-L1) inhibitors and anti-angiogenic agents has demonstrated significant survival improvements in patients with untreated HCC. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory immune checkpoint receptor upregulated on T cells and natural killer cells in multiple solid tumors. OCI is a novel, humanized mAb that binds TIGIT with high specificity and affinity, blocking interaction with its ligands on tumor cells. TIS is an anti-PD-1 mAb that has demonstrated clinical activity in patients with previously treated, unresectable HCC (NCT03419897). BAT1706 is a similar biological product to the anti-angiogenic agent bevacizumab. OCI combined with TIS and BAT1706 could further enhance both anti-angiogenic and anti-PD-1 therapies for patients with HCC. Methods: AdvanTIG-206 is a Phase 2, randomized, open-label clinical study (NCT04948697). Patients aged ≥ 18 years with histologically confirmed advanced HCC that is not amenable to a curative treatment approach are eligible. Patients must have a Child-Pugh A score, ECOG PS ≤ 1, and have received no prior systemic therapy for HCC. Approximately 90 patients will be randomized 2:1 to OCI 900 mg combined with TIS 200 mg plus BAT1706 15 mg/kg (Arm A) or TIS 200 mg plus BAT1706 15 mg/kg (Arm B), all administered intravenously (once every 3 weeks [Q3W]). The primary endpoint is objective response rate as assessed by the investigator (RECIST v1.1). Radiological assessment of tumor response status will be performed Q6W for the first 48 weeks and Q12W thereafter. Secondary endpoints include duration of response, time to response, disease control rate, clinical benefit rate, and progression-free survival (all by investigator’s assessment), overall survival, safety, pharmacokinetics, and immunogenicity. Study enrollment is ongoing. Clinical trial information: NCT04948697.

AdvanTIG-206: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (BGB-A1217; OCI) plus anti-programmed cell death protein 1 (PD-1) mAb tislelizumab (TIS) plus BAT1706 versus (vs) TIS plus BAT1706 as first-line treatment for advanced hepatocellular carcinoma (HCC).

TPS488 Background: Treatment with PD-1/programmed death-ligand 1 (PD-L1) inhibitors and anti-angiogenic agents has demonstrated significant survival improvements in patients with untreated HCC. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory immune checkpoint receptor upregulated on T cells and natural killer cells in multiple solid tumors. OCI is a novel, humanized mAb that binds TIGIT with high specificity and affinity, blocking interaction with its ligands on tumor cells. TIS is an anti-PD-1 mAb that has demonstrated clinical activity in patients with previously treated, unresectable HCC (NCT03419897). BAT1706 is a similar biological product to the anti-angiogenic agent bevacizumab. OCI combined with TIS and BAT1706 could further enhance both anti-angiogenic and anti-PD-1 therapies for patients with HCC. Methods: AdvanTIG-206 is a phase 2, randomized, open-label clinical study (NCT04948697). Patients aged ≥ 18 years with histologically confirmed advanced HCC that is not amenable to a curative treatment approach are eligible. Patients must have a Child-Pugh A score, ECOG PS ≤ 1, and have received no prior systemic therapy for HCC. Approximately 90 patients will be randomized 2:1 to OCI 900 mg combined with TIS 200 mg plus BAT1706 15 mg/kg (Arm A) or TIS 200 mg plus BAT1706 15 mg/kg (Arm B), all administered intravenously (once every 3 weeks [Q3W]). The primary endpoint is investigator-assessed objective response rate per RECIST v1.1. Radiological assessment of tumor response status will be performed Q6W for the first 48 weeks and Q12W thereafter. Secondary endpoints include duration of response, time to response, disease control rate, clinical benefit rate, and progression-free survival (all investigator-assessed overall survival), safety, pharmacokinetics, and immunogenicity. Study enrollment is ongoing. Clinical trial information: NCT04948697.

167TiP AdvanTIG-301: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (OCI) + tislelizumab (TIS) + concurrent chemoradiotherapy (cCRT) followed by OCI + TIS or TIS + cCRT followed by TIS vs cCRT followed by durvalumab (DUR) in previously untreated, locally advanced, unresectable NSCLC

Around one third of patients (pts) with NSCLC present with Stage III, locally advanced disease at initial diagnosis. Programmed death-ligand 1 (PD-L1) inhibitor, DUR, is the current standard of care for pts whose disease had not progressed following cCRT. Anti-T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory immune checkpoint receptor upregulated on T cells and natural killer cells in multiple solid tumors. OCI is a humanized mAb that binds TIGIT with high specificity and affinity, blocking interaction with its ligands on tumor cells.

Activation of Cascade-Like Antitumor Immune Responses through In Situ Doxorubicin Stimulation and Blockade of Checkpoint Coinhibitory Receptor TIGIT.

Although T cell centered immune checkpoint blockade (ICB) therapies have shown unprecedented success in various cancer types, only a minority of patients benefit from these treatments due to the lack of neoantigen burden and exhaustion of tumor-infiltrating immune stimulating cells. Inspired by the crucial role of NK cell based immunity and potential immunostimulating effect of chemotherapeutic drugs, the therapeutic efficiency on tumor inhibition through combination of doxorubicin (DOX) and blockade of TIGIT (T-cell Ig and ITIM domain), a coinhibitory receptor expressed by both NK and T cells, in a matrix metalloproteinase 2 (MMP-2)-degradable hydrogel is thoroughly evaluated in this study. Due to the distinct release kinetics from destructed framework of hydrogels, the differentially released DOX and anti-TIGIT monoclonal antibody (aTIGIT) molecules can elicit immunogenic tumor microenvironment and reverse the exhaustion of NK and effector T cells to realize not only durable localized tumor inhibition but also systemic and long-lasting immune memory responses. Thus, this work pioneers the union of chemotherapeutic drugs and NK cell centered ICB therapies for activating cascade-like antitumor immune responses through eliciting immunogenic tumor microenvironment and boosting both innate and adaptive immunity.

Involvement of TIGIT in Natural Killer Cell Exhaustion and Immune Escape in Patients and Mouse Model With Liver Echinococcus multilocularis Infection.

Alveolar echinococcosis (AE) is a lethal helminthic liver disease caused by persistent infection with Echinococcus multilocularis. Although more attention has been paid to the immunotolerance of T cells caused by E. multilocularis infection, the role of natural killer (NK) cell, a critical player in liver immunity, is seldom studied. Here, we observed that NK cells from the blood and closed liver tissue (CLT) of AE patients expressed a higher level of inhibitory receptor TIGIT and were functionally exhausted with a lower expression of granzyme B, perforin, interferon-gamma (IFN-γ), and TNF-α. Addition of anti-TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) monoclonal antibody into AE patients' peripheral blood mononuclear cell culture significantly enhanced the synthesis of IFN-γ and TNF-α by NK cells, indicating the reversion of exhausted NK cells by TIGIT blockade. In the mouse model of E. multilocularis infection, liver and splenic TIGIT+ NK cells progressively increased dependent of infection dosage and timing and were less activated and less degranulated with lower cytokine secretion. Furthermore, TIGIT deficiency or blockade in vivo inhibited liver metacestode growth, reduced liver injury, and increased the level of IFN-γ produced by liver NK cells. Interestingly, NK cells from mice with persistent chronic infection expressed a higher level of TIGIT compared to self-healing mice. To look further into the mechanisms, more regulatory CD56bright and murine CD49a+ NK cells with higher TIGIT expression existed in livers of AE patients and mice infected with E. multilocularis, respectively. They coexpressed higher surface programmed death ligand 1 and secreted more IL-10, two strong inducers to mediate the functional exhaustion of NK cells. Our results indicate that inhibitory receptor TIGIT is involved in NK cell exhaustion and immune escape from E. multilocularis infection.

Abstract 1583: SEA-TGT is an empowered anti-TIGIT antibody that displays superior combinatorial activity with several therapeutic agents

Abstract TIGIT is an immunoregulatory receptor expressed on activated and memory T cells, Tregs, and NK cells. TIGIT binding to CD155 and CD112 on tumor cells drives an inhibitory signal resulting in decreased T cell functionality. TIGIT targeting has been reported to release these inhibitory signals, drive Treg depletion, augment CD8+ T cell generation, and promote anti-tumor responses. Anti-TIGIT therapies have come to prominence recently as new strategies for anti-cancer therapy particularly in combination with other immune checkpoint inhibitors because of their complementary mechanisms of action. We have recently developed an investigational anti-TIGIT monoclonal antibody that employs our proprietary sugar engineered antibody (SEA) technology to create a nonfucosylated antibody, termed SEA-TGT. In the present studies, we have expanded our investigation of SEA-TGT and compared it to other antibody formats to understand how differences in complementarity-determining regions (CDR) and backbone effect both in vitro activity and in vivo anti-tumor response. We also investigated how these differences affect the ability of anti-TIGIT mAbs to combine with other anti-tumor therapies. The nonfucosylated SEA-TGT demonstrates a unique activating to inhibitory FcγR binding profile. SEA-TGT demonstrates enhanced FcγRIIIA binding with concomitant reduction in inhibitory FcγRIIb receptor binding. This binding with SEA-TGT was distinct from standard IgG1 backbones and gains effector function modifications compared to other anti-TIGIT mAbs. The differential ability to engage activating vs. inhibitory Fcγ receptors translated into distinct differences in preclinical activity. The differences seen in vitro were recapitulated in vivo as SEA-TGT led to enhanced tumor activity in syngeneic tumor models. Anti-TIGIT treatments are being pursued clinically in combination with other therapeutic modalities, as such we evaluated treatment with the TIGIT mAbs with different effector function backbones with various other anti-tumor therapies. When used at sub-therapeutic doses, SEA-TGT exhibited greatly enhanced anti-tumor activity in combination with both checkpoint therapy as well as with an ICD inducing vc-MMAE antibody-drug conjugate. Collectively, these data continue to strengthen our findings that the nonfucosylated effector function enhanced backbone of SEA-TGT confers superior preclinical anti-tumor activity as a monotherapy agent and in combination with PD(L)1 agents and vc-MMAE ADCs. We have initiated a phase 1 trial testing the safety and activity of SEA-TGT alone and in combination with anti-PD-1 therapy in patients with advanced solid tumors and select lymphomas. Citation Format: Alyson Smith, Weiping Zeng, Sasha Lucas, Bryan Grogan, Amber Blackmarr, Serena Wo, Scott Peterson, Shyra Gardai. SEA-TGT is an empowered anti-TIGIT antibody that displays superior combinatorial activity with several therapeutic agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1583.

AdvanTIG-302: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (OCI) plus tislelizumab (TIS) versus pembrolizumab (PEM) in programmed death ligand-1 (PD-L1) selected, previously untreated, locally advanced, unresectable or metastatic non-small cell lung cancer (NSCLC).

TPS9128 Background: Monotherapy with programmed death 1 (PD-1)/PD-L1 antibodies has improved clinical outcomes for patients (pts) with non-oncogenic driven NSCLC but clinical responses are limited by primary and secondary resistance, and improvements in durability of response are required. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) is a co-inhibitory, immune checkpoint receptor upregulated on T-cells and natural killer cells in multiple solid tumors, which can inhibit anticancer immune responses. OCI (BGB-A1217) is a novel, humanized mAb that binds to TIGIT with high affinity and specificity, which has demonstrated competent binding with C1q and all Fcγ receptors while inducing antibody-dependent cellular cytotoxicity. Preclinical and clinical studies suggest that dual targeting with anti-TIGIT and anti-PD-1 antibodies produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-302 is a Phase 3, multicenter, international, randomized, double-blind study (NCT04746924) investigating OCI in combination with TIS compared with PEM in adult pts (≥ 18 years of age) with PD-L1 selected, previously untreated, locally advanced, unresectable or metastatic NSCLC without oncogenic EGFR or ALK mutation. Approximately 605 pts will be randomized 5:5:1 to receive: OCI 900 mg intravenously (IV) plus TIS 200 mg IV every three weeks (Q3W; Arm A), PEM 200 mg IV plus placebo IV Q3W (Arm B) or TIS 200 mg IV plus placebo IV Q3W (Arm C). Pts will be treated until disease progression, loss of clinical benefit, intolerable toxicity or withdrawal of consent. Stratification factors include histology (squamous vs non-squamous) and region (Asian vs non-Asian). Cross-over is not permitted. Key eligibility criteria include histologically confirmed disease, PD-L1 expression ≥ 50%, no known EGFR or ALK mutations and no prior checkpoint inhibitor therapy. Dual primary endpoints are investigator-assessed progression-free survival (PFS; RECIST v1.1) and overall survival (Arms A and B) in the Intention-to-Treat population. Secondary endpoints include PFS (assessed by Blinded Independent Review Committee), investigator-assessed overall response rate and duration of response, safety and tolerability, and patient-reported health-related quality of life (EORTC-QLQ-C30, QLQ-LC13 and EQ-5D-5L; Arms A and B). Exploratory endpoints include disease control rate, clinical benefit rate and time to response. This study will also evaluate the association between biomarkers and response or resistance. Study enrollment has begun and recruitment is ongoing. Clinical trial information: NCT04746924.