TNFR2 Advances as a Novel Target for Restoring Antitumor Immunity Across Lymphoma and Solid Tumors

Tumor necrosis factor receptor 2 (TNFR2) has been identified as a major driver of tumor cell proliferation and has emerged as a promising therapeutic target across hematologic malignancies and solid tumors, with the first-in-class monoclonal antibody BI-1808 leading the charge as a TNFR2-targeted agent with potential as monotherapy and in combination regimens.

TNFR2, a main TNFR expressed in tumor cells, is a key regulator in the tumor microenvironment (TME) that promotes tumor cell proliferation.¹ TNFR2 is also present on T regulatory cells (Tregs), and activating the TNFR2 signaling pathway on Tregs impedes their proliferation, survival, and immunosuppressive nature. Preclinical research has also shown that TNFR2-directed agents may have a synergistic effect when combined with PD-1 or CTLA-4–directed antibodies.

Anti-TNFR2 therapy has been most recently studied in the phase 1/2 19-BI-1808-01/KEYNOTE-D20 trial (NCT04752826), where the first-in-class monoclonal antibody BI-1808 was investigated as monotherapy and in combination with the PD-1 inhibitor pembrolizumab (Keytruda) in patients with T-cell lymphomas, including cutaneous T-cell lymphoma (CTCL), a disease that is characterized by the enrichment of TNFR2-expressing Tregs.² BI-1808 binds to TNFR2 and inhibits it with a ligand, which has multiple potential influences on the immune system, including reprogramming myeloid cells and promoting CD8+ T-cell infiltration and cytotoxic activity.

“TNFR2 is a new target in CTCL and has emerged as a pathogenic driver through various mutations or other alterations that lead to upregulation of TNFR2 on CD4+ [and] CD26+ cells,” Stefan K. Barta, MD, MS, MRCPCUK, said in an interview with OncLive^®. “[BI-1808] leads to the depletion of Tregs and, through the antibody interaction, also leads to reprogramming of the myeloid cells to a more dendritic cell phenotype. That’s also advantageous.”

Barta is director of the T-Cell Lymphoma Program and executive officer of the AIDS Malignancy Consortium at Penn Medicine Abramson Cancer Center, as well as an associate professor of medicine (hematology-oncology) at the Hospital of the University of Pennsylvania in Philadelphia.

What data have been seen so far with BI-1808 in T-cell lymphoma?

“T-cell lymphomas are rare, and unfortunately, we have a lot of therapies available that are effective for B-cell lymphomas or other B-cell malignancies, [but] this is not entirely true for T-cell malignancies,” Barta said of the rationale for developing TNFR2-directed therapies for T-cell lymphomas. “Particularly, immunotherapies can be difficult to [use] in T-cell malignancies. T cells are a big part of the immune system [and]…antitumor immunity. How do you balance the effect of enhancing the immune response without, at the same time, leading to, for example, disease progression or heating up the T-cell lymphoma as well? Also, finding a target on T cells can be difficult. It’s more difficult than in B cells because T cells are heterogeneous. There’s a lot of plasticity, so these targets can shift over time.”

In part A of the phase 1 dose-escalation portion of the 19-BI-1808-01/KEYNOTE-D20 trial, patients received BI-1808 monotherapy at ascending dose levels.³ Treatment with the agent led to Treg depletion and CD8+ T-cell activation compared with baseline levels.

The trial investigators also hypothesized that TNFR2-mediated Treg depletion and myeloid reprogramming via BI-1808 could enhance tumor responsiveness to checkpoint inhibitors, supported by data from preclinical models and early clinical studies.² Therefore, in the phase 2a signal-seeking T-cell lymphoma cohort, patients with CTCL or peripheral T-cell lymphoma (PTCL) received BI-1808 at 1000 mg every 3 weeks with or without pembrolizumab.

Preliminary efficacy data from the trial supported the 2025 granting of FDA breakthrough therapy designation to the agent for the treatment of adult patients with relapsed/refractory CTCL across 2 subtypes: mycosis fungoides and Sézary syndrome.⁴

Updated data presented at the 6th World Congress on Cutaneous Lymphomas showed that of the patients treated with BI-1808 monotherapy (n = 15), the overall response rate (ORR) was 40%, including 1 complete response (CR) and 5 partial responses (PRs).² Notably, 1 patient with stage IV PTCL who had been treated with 6 prior lines of therapy responded by week 9, and 1 patient with CTCL, characterized as mycosis fungoides, who had been treated with 5 prior lines of therapy responded by week 21. In the full population, the disease control rate (DCR) was 93%.

Eight total patients received BI-1808 in combination with pembrolizumab. In this cohort, the ORR was 50%, including 4 PRs, and the DCR was 75%.

“We have decreased suppression and increased activation at the same time, and that leads to an influx of CD8+ cytotoxic T cells that then restore antitumor immunity,” Barta said. “We see that on our trial in the paired biopsy samples, where we see a pre- and posttreatment infiltration of these cytotoxic CD8+ T cells. [BI-1808] can also work through antibody-dependent cytotoxicity and increased phagocytosis by binding to CTCL cells that express TNFR2. There was a high rate of stable disease [SD], and although that might not be as important in other diseases, for a disease such as CTCL, where it is hard to meet classical criteria for PR or CR, even stabilizing the disease for a long time with an agent that has limited toxicity can be meaningful.”

In the monotherapy arm, 9% of safety-evaluable patients (n = 23) experienced grade 3 or higher treatment-related adverse effects (TRAEs), and 4% of patients discontinued treatment due to TRAEs. Among safety-evaluable patients in the combination arm (n = 10), these respective rates were 40% and 10%.

Due to the increased toxicity seen with the addition of pembrolizumab but the relatively safe profile of BI-1808 alone, Barta reported that future studies of BI-1808 may focus on the agent as monotherapy or in combination with other immunotherapies that are effective at least to the point of prolonged disease stabilization and do not contribute many added toxicities. He emphasized that BI-1808 on its own was safe and mostly associated with low-grade, manageable fatigue.

What data have been seen with BI-1808 in solid tumors?

Beyond T-cell lymphoma, TNFR2 has also been identified as a potential therapeutic target in solid tumors. Additional cohorts of the 19-BI-1808-01/KEYNOTE-D20 trial are studying BI-1808 in patients with non–small cell lung cancer, melanoma, and ovarian cancer.

Data from the phase 2a ovarian cancer cohort presented at the 2026 American Society of Clinical Oncology Annual Meeting showed that among 17 patients treated in the monotherapy arm (including those with high-grade serous, clear cell, serous papillary, endometrioid, and carcinosarcoma), 1 patient experienced a CR, and 6 patients had a best response of SD, translating to a 41% DCR across disease subtypes.⁵ Among the 26 patients with varying disease subtypes who received BI-1808 plus pembrolizumab, the ORR was 24%, including 1 CR and 5 PRs. Additionally, 8 patients had SD, and the DCR was 56%. Furthermore, a preliminary analysis showed a median progression-free survival of 10.2 months.

Translational data continued to show BI-1808–mediated Treg depletion and myeloid reprogramming. Additionally, the combination resulted in the activation of CD8+ cells and cytokines that indicate the formation of tertiary lymphoid structures within the TME, which support and maintain antitumor T-cell responses.

Based on these data, in August 2026, the FDA granted fast track designation to BI-1808 plus pembrolizumab for the treatment of patients with ovarian cancer.⁶

What are the next steps for evaluating TNFR2 targeting in cancer?

Preclinical data from the ovarian cancer analysis of 19-BI-1808-01/KEYNOTE-D20 showed a longer time to response than historically seen with immune checkpoint inhibition, although the investigators noted that this may be indicative of additional delayed responses that were missed at the initial scan. Therefore, circulating tumor DNA will be monitored closely in future patients.

Additional cancer subtypes have been identified as having the potential to benefit from TNFR2 inhibition, including colorectal cancer, where TNFR2 is heavily involved in disease pathogenesis and progression; acute myeloid leukemia, which is associated with elevated TNFR2 levels; and breast cancer, where TNFR2 expression level is associated with disease stage.¹

Several preclinical and early clinical studies continue to investigate TNFR2-directed antibodies in combination with immunotherapy, as well as with chemotherapy, radiotherapy, and other targeted agents.

“I’m most excited about using [BI-1808] in conjunction with other drugs,” Barta said. “Having the effective T cells go where they need to be and helping direct them for other therapies that also enhance the immune system is going to be exciting. There’s going to be a lot of possibilities and a lot of combination regimens that might help us treat [T-cell lymphoma] more effectively.”

References

1. Li L, Ye R, Li Y, Pan H, Han S, Lu Y. Targeting TNFR2 for cancer immunotherapy: recent advances and future directions. J Transl Med. 2024;22(1):812. doi:10.1186/s12967-024-05620-x
2. Querfeld C, Barta S, Morris S, et al. Targeting TNFR2 with BI-1808: immune activation and promising responses in advanced T-cell lymphomas. Presented at: 6th World Congress on Cutaneous Lymphomas; June 25-27, 2026; Montreal, Canada. Abstract 6.02.
3. Rohrberg KS, Papai Z, Eefsen RL, et al. 19-BI-1808-01, a phase 1/2a clinical trial of BI-1808, a tumor necrosis factor receptor 2 (TNFR2) blocker/depleter with or without pembrolizumab. J Clin Oncol. 2024;42(suppl 16):2641. doi:10.1200/JCO.2024.42.16_suppl.2641
4. BioInvent receives FDA fast track designation for BI-1808 for the treatment of cutaneous T-cell lymphoma. News release. BioInvent. April 29, 2025. Accessed August 10, 2026. https://www.bioinvent.com/en/press/bioinvent-receives-fda-fast-track-designation-bi-1808-treatment-cutaneous-t-cell-lymphoma
5. Williams A, Kristelleit R, Lopez JS, et al. BI-1808 + pembrolizumab: responses to a chemotherapy-free regimen in advanced ovarian cancer. J Clin Oncol. 2026;44(suppl 16):2605. doi:10.1200/JCO.2026.44.16_suppl.2605
6. BioInvent receives FDA fast track designation for BI-1808 for the treatment of ovarian cancer. News release. BioInvent. August 7, 2026. Accessed August 10, 2026. https://www.bioinvent.com/en/press/bioinvent-receives-fda-fast-track-designation-bi-1808-treatment-ovarian-cancer-2472829