Nivolumab

iStock/ Afry Harvy TIGIT-targeting therapies have largely disappointed in recent months, with failed studies, terminated partnerships and shuttered businesses. Here are five biopharma players staying alive with differentiated candidates against the once promising immuno-oncology target. When GSK turned its back on development partner iTeos Therapeutics in May, a terminal countdown began for the Massachusetts-based biotech. Weeks later, time ran out and iTeos was forced to shutter operations. The biotech is only the latest casualty in a therapeutic space that is turning into a drug development wasteland. The asset that led to iTeos’ ultimate demise was belrestotug, an anti-TIGIT therapy that was being assessed for multiple solid tumors, including non-small cell lung and head and neck cancer. Though the partners did not reveal specific data, iTeos noted in May that even when used with GSK’s PD-1 blocker Jemperli, belrestotug was unable to improve progression-free survival in patients with NSCLC versus Jemperli alone. Findings in patients with head and neck cancer were likewise disappointing. Belrestotug is just one therapy in the long line of TIGIT assets that have run into insurmountable clinical roadblocks. Found in certain cells of the immune system, TIGIT —which stands for T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domain—is a receptor with immunosuppressive effects. Under healthy circumstances, TIGIT helps regulate the release of cytokines, in turn suppressing the activity of T cells. TIGIT is overexpressed in many cancers , allowing tumor cells to inhibit the immune system’s anti-cancer response. Many biopharma players have seized on this mode of action, identifying molecules that can block TIGIT in cancers in hopes of boosting the body’s antitumor activity. But none have been successful so far, and the experience of GSK and iTeos has become the unfortunate standard. In July 2024, Roche’s tiragolumab failed to improve survival in patients with NSCLC in the closely watched SKYSCRAPER-06 trial . A few months later, another study of tiragolumab, SKYSCRAPER-01, flopped . Merck has also been stymied by TIGIT. In May 2024, the pharma scrapped a late-stage study for its anti-TIGIT antibody vibostolimab due to treatment toxicity that led to a high rate of study dropouts. Safety concerns also led to the demise of another Phase III study later that same year, this time in extensive-stage small-cell lung cancer. A key reason behind these failures, according to Padmanee Sharma, a professor in the department of Genitourinary Medical Oncology at MD Anderson Cancer Center, is that much remains unknown about how this pathway specifically works. Other proteins may also be involved in the overall TIGIT mechanism, she told BioSpace in an email, or TIGIT itself may have a role to play in other cellular functions. “TIGIT is a complex biologic target,” Sharma said. “The exact mechanism is not clear.” Still, many persist in developing a TIGIT therapy, largely because its signals of efficacy are encouraging. “Pre-clinical data indicate that TIGIT is a relevant pathway to pursue,” Sharma said, particularly for antibodies, which in lab studies have shown “anti-tumor responses.” But a more complete picture of the TIGIT pathway, including the biological pathways that regulate TIGIT, are required to set the field up for success. Here, BioSpace looks at four companies that claim differentiated approaches. Will they succeed where their peers have failed? AstraZeneca’s Sprawling Development Program for Rilvegostomig AstraZeneca’s TIGIT rilvegostomig is enrolled in an extensive late-stage development program, with 10 Phase III studies underway in NSCLC, gastric cancer, biliary tract cancer and other solid tumors, Shubh Goel, the company’s global franchise head of oncology, told BioSpace in an email. AstraZeneca is also leveraging its partnership with Daiichi Sankyo to test combinations of the TIGIT with the antibody-drug conjugate Datroway for specific subtypes of NSCLC. The goal of such a broad development push, Goel explained, is to establish rilvegostomig as a “best-in-class [immuno-oncology therapy] and the preferred IO backbone for combination therapies.” Aside from these late-stage programs, AstraZeneca is also running multiple early studies of rilvegostomig “across different tumor settings and in combination with a range of standard of care and novel agents,” Goel said. AstraZeneca’s steep investment into rilvegostomig is underpinned by what Goel called a “differentiated” mechanism of action. The molecule’s bispecific structure “optimizes dual PD1/TIGIT check point control.” Rilvegostomig first anchors itself to TIGIT before targeting PD-1, in turn “leading to enhanced immune activation and improving anti-tumor responses,” Goel explained, as compared with dosing patients with separate PD-1 and TIGIT agents. Simultaneously, rilvegostomig minimizes the unwanted depletion of effector immune cells that also express TIGIT, which results in a cleaner safety profile. Aside from a differentiated molecule, AstraZeneca is also being deliberate with its trials, focusing on patients most likely to respond to PD-1/TIGIT co-inhibition, Goel said. So far, AstraZeneca’s strategy seems to be working, at least in NSCLC. At the American Society of Clinical Oncology meeting in May, the pharma presented Phase Ib data showing that rilvegostomig plus Datroway could elicit a 57.5% confirmed overall response rate (ORR) and a 95% disease control rate as a first-line treatment for patients with advanced or metastatic NSCLC. Gilead, Arcus Forge New TIGIT Path With ‘Silent’ Killer Joining AstraZeneca in the late-stage TIGIT field are Gilead and Arcus Biosciences, which are co-developing the monoclonal antibody domvanalimab for solid tumors. Unlike rilvegostomig, domvanalimab only targets TIGIT. To address a second immune checkpoint, the partners are co-administering it with Arcus’ zimberelimab, an investigational PD-1 inhibitor, plus chemotherapy. The companies are proposing this regimen as a first-line therapy for NSCLC and upper gastrointestinal cancer—both programs are in late-stage development —and for head and neck carcinoma, currently in mid-stage studies. What sets domvanalimab apart from the rest of the TIGIT field, according to Ashish Jhingan, program strategy leader of oncology at Gilead, is its Fc-silent properties. That is, the antibody tail—the part that isn’t involved in binding to its targets—has been rendered inert. Such an approach, which goes against the current trend in the TIGIT space, minimizes the likelihood of inadvertently killing cells other than the malignant target, according to Arcus’ website . “By binding to TIGIT with Fc-silent properties, domvanalimab is believed to work by freeing up immune-activating pathways and activate immune cells to attack and kill cancer cells without depleting the peripheral regulatory T cells important in avoiding immune-related toxicity,” Jhingan told BioSpace in an email. This silent approach has so far worked well for the partners. In November 2023, they released data from the Phase II EDGE-Gastric trial, demonstrating a 59% ORR in patients after treatment with the domvanalimab-based regimen. This effect was stronger in those with high PD-L1 expression level, hitting 80% ORR. Six-month progression-free survival (PFS) at the time was 77%. Follow-up results in June 2024 showed that the domvanalimab combo could maintain its efficacy through a median of 49.4 weeks on treatment. ORR dipped only slightly to 58.5% while 12-month progression-free survival (PFS) reached 57.6% in the overall study population. Gilead and Arcus have moved domvanalimab into late-stage development. The partners are running the STAR-221 study, which will test the same regimen of domvanalimab plus zimberelimab and chemotherapy in locally advanced unresectable or metastatic HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Enrollment began in June 2024 , with initial findings expected in 2026, according to Jhingan. Agenus Pushes Ahead After Losing Powerhouse Partner In May 2021, when the TIGIT space was still young, Bristol Myers Squibb sought to get ahead of its cancer competitors with a $200 million spot payment to Agenus , licensing the biotech’s anti-TIGIT therapy AGEN1777. The deal included up to $1.36 billion in development, regulatory and commercial milestone payments. But ultimately, BMS found the partnership to be more burdensome than beneficial. In August 2024, the company walked away from the pact and returned AGEN1777 to Agenus, a move that was attributed to the “broader strategic realignment of [BMS’] development pipeline,” according to an Aug. 2, 2024 SEC document from Agenus. The contract termination formally took effect on Jan. 26. According to the regulatory filing, under the partnership, Agenus and BMS were able to generate “significant safety data” in early studies, with “indications of clinical activity.” With these in hand, Agenus in August said it intends “to explore further development and/or relicensing” of AGEN1777, but has yet to provide concrete plans for the molecule. Among these development prospects is the possibility of combining the asset with Agenus’ other immuno-oncology therapies. It might take some time, however, before Agenus provides next steps for its TIGIT program, since the biotech is currently in the midst of a strategic realignment initiative aimed at lowering its cash burn to $100 million during the 2025 fiscal year. Mereo Seeks Strategic Sponsors for Etigilimab Rounding out this list is Mereo BioPharma and its troubled program etigilimab , an IgG1 monoclonal antibody designed to target TIGIT, in turn, potentially “improving the activation and effectiveness of T-cell and NK [natural killer] cell anti-tumor activity,” as per its website. Unlike Gilead and Arcus, Mereo has decided against silencing the Fc domain of etigilimab, instead deliberately giving the TIGIT therapy the added functionality of reducing regulatory T cells while also maintaining the levels of CD8-positive cytotoxic T cells. In turn, etigilimab retains the immune system’s cancer-killing action while also delivering a clean safety profile, the biotech claims . Early testing of the mechanism suggests promise in the clinic so far. Phase Ib/II data published in October 2023 demonstrated an ORR of 25% in 40 treated patients, including three who achieved a complete response and seven who saw a partial response. Eleven patients had stable disease beyond 120 days, while seven maintained clinical benefit for more than a year. Despite a promising mechanism and clinical profile, however, Mereo has struggled to rally the support it needs to take etigilimab forward. In June 2019—just months before it would be swallowed by BMS in a $74 billion acquisition—Celgene decided not to exercise an option to license etigilimab. This was despite Mereo advancing the antibody as part of a two-therapy combo with BMS’ PD-1 blocker nivolumab. Since then, and even through a mid-stage readout in 2023, the industry has continued to overlook etigilimab. In a 2024 year-end report, Mereo revealed that it has put TIGIT on the backburner . “We intend to out-license or sell etigilimab . . . to third parties for the further development, recognizing the need for greater resources to take [this asset] to market,” the company wrote.

撰文丨王聪编辑丨王多鱼排版丨水成文基于免疫检查点抑制剂（ICI）的免疫检查点阻断疗法，已彻底改变了多种实体瘤的治疗方式，但其仍面临着耐药性的问题。此外，在晚期和复发性卵巢癌中，免疫检查点阻断疗法效果不佳，患者对单药 PD-1/PD-L1 抑制剂的应答率仅在 5%-15% 之间，因此，仍需探索新的策略的来改善患者的临床解决。2025 年 7 月 2 日，德克萨斯大学MD安德森癌症中心 Amir Jazaeri 教授、王凌华教授、张如刚教授团队合作（王凌华团队的戴一博、党明浩等作为共同第一作者），在 Nature 期刊发表了题为：PPP2R1A mutations portend improved survival after cancer immunotherapy 的研究论文。研究团队在临床试验中观察到，携带 PPP2R1A 基因突变的卵巢透明细胞癌患者在接受抗 PD-1/PD-L1 单抗与抗 CTLA4 单抗联合免疫治疗后，生存期显著优于 PPP2R1A 野生型的患者。研究团队进一步发现，PPP2R1A 基因突变可提高肿瘤对于免疫疗法的响应，并在多种不同癌症类型的接受免疫治疗的临床队列中证实了这一发现。因此，靶向抑制 PPP2R1A 有望增强多种癌症类型的免疫治疗效果，提高生存率，改善预后。一些数据表明，在复发性卵巢癌中，同时靶向 PD-1/PD-L1 和 CTLA-4 的免疫检查点抑制剂联合疗法，可能更有效。一项随机临床试验表明，在复发性上皮性卵巢癌患者中，接受纳武利尤单抗（抗PD-1单抗）联合伊匹木单抗（抗CTLA4单抗）治疗的患者缓解率为 31.4%，而仅接受纳武利尤单抗治疗的患者缓解率为 12.2%。此外，在这项试验中，卵巢透明细胞癌（OCCC；一种罕见的卵巢癌亚型，预后更差）与更常见的高级别浆液性卵巢癌（HGSOC）相比，其治疗响应概率是 HGSOC 患者的 5 倍。因此，复发性 OCCC 患者可能尤其能从免疫检查点阻断疗法中获益；然而，该组患者的应答率也仅约为 15%，这表明只有一部分 OCCC 患者能从中获益。基于这些观察结果，研究团队前瞻性地将卵巢透明细胞癌（OCCC）患者纳入一项在铂类耐药情况下探索双重免疫检查点阻断（ICB）疗法治疗效果的试验。在试验过程中，研究团队观察到，肿瘤中存在 PPP2R1A 基因失活体细胞突变的患者，其总生存期（OS）和无进展生存期（PFS）显著延长，PPP2R1A 基因编码蛋白磷酸酶 2A 复合物中最常见支架成分。更关键的是，研究团队在多种癌症类型的接受免疫检查点阻断疗法的外部患者队列中证实了这一发现。对肿瘤活检样本进行的转录组分析表明，在 PPP2R1A 突变型肿瘤中，基线时存在增强的 IFNγ 信号转导和三级淋巴结构，免疫细胞浸润增强以及肿瘤邻近区域 CD45RO+ CD8+ T 细胞扩增，且在免疫检查点阻断治疗后亦是如此。研究团队还在几种不同的临床前模型中开展了研究，结果显示，在体外和体内模型中靶向抑制 PPP2R1A（通过药物抑制或基因编辑），与多种免疫疗法（包括 CAR-T 细胞疗、免疫检查点阻断疗法）治疗时生存率提高相关。总的来说，这些研究结果表明，靶向抑制 PPP2R1A 可能代表了一种有效策略，能够改善免疫检查点阻断（ICB）或其他形式免疫治疗后的癌症患者的预后。论文链接：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41586-025-09203-8设置星标，不错过精彩推文开放转载欢迎转发到朋友圈和微信群 微信加群 为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。点在看，传递你的品味