Aug 2026· Cancers· Vol 18, pp. 2725· 0 citations· 68 references
TL;DR
Rational TCE design, incorporating costimulatory signaling, antigen selection informed by parallel ADC validation data, and evidence-based combination strategies, offers the most credible path toward expanding this platform’s impact in metastatic lung cancer.
Abstract
Background: Lung cancer remains the leading cause of cancer-related mortality worldwide, with five-year survival below 5% for metastatic small cell lung cancer (SCLC) and below 10% for metastatic non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors have improved outcomes, but primary and acquired resistance, driven by tumor microenvironment immunosuppression, antigen heterogeneity, and T-cell exhaustion, leaves a substantial unmet need. T-cell engagers (TCEs), bispecific antibodies that redirect cytotoxic T-cells to tumor cells independent of MHC-I-restricted antigen presentation, offer a mechanistically distinct approach. Methods: We conducted a structured narrative review, without formal PRISMA methodology or meta-analytic pooling, of PubMed, Embase, and ClinicalTrials.gov through June 2026, supplemented by conference abstracts from ASCO, ESMO, AACR, and ATS, covering clinical, translational, and preclinical evidence for TCEs across established and emerging targets in thoracic malignancy. Results: Tarlatamab, a DLL3/CD3 bispecific TCE, received full FDA approval in November 2025 based on DeLLphi-304 data showing a median overall survival benefit of 13.6 versus 8.3 months over chemotherapy (HR 0.60; p < 0.001), establishing proof-of-concept for the TCE platform in lung cancer and NCCN Category 1 status in ES-SCLC. Beyond DLL3, an expanding pipeline of targets, including Claudin-18.2, TROP-2, FOLR1, CD70, and HER2, is under active TCE development; several of these antigens have independently validated tumor-selective expression through approved or late-stage antibody-drug conjugates (ADCs), providing target-level clinical de-risking for TCE development, though the two modalities have distinct requirements for antigen density and internalization that must be independently validated. Novel tri-specific constructs incorporating costimulatory domains and combination strategies with checkpoint inhibitors are in early clinical development. Conclusions: Tarlatamab approval validates the TCE platform in lung cancer, but overcoming TME-mediated resistance, antigen heterogeneity, and class-specific toxicities including cytokine release syndrome remains the central challenge. Rational TCE design, incorporating costimulatory signaling, antigen selection informed by parallel ADC validation data, and evidence-based combination strategies, offers the most credible path toward expanding this platform’s impact in metastatic lung cancer.
It is found that ICI monotherapy significantly improves overall survival in NSCLC with PD-L1 expression ≥50% compared with platinum-based chemotherapy, and first-line atezolizumab plus chemotherapy extended median overall survival to 12.3 months, compared with 10.3 months in extensive-stage SCLC.
Mojeeb Abdo Abdullah Qasem, T. Budhy, D. Suprabawati et al.· Health Dynamics· 0 citations
Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of solid tumors, response rates in patients with small cell lung cancer (SCLC) remain limited, and acquired resistance is highly prevalent. The underlying mechanisms of this immunotherapy resistance remain to be fully elucidated. Clinically, SCLC typically manifests as an "immune-cold" tumor, characterized by a paucity of CD8+ T cell infiltration and the rare formation of tertiary lymphoid structures (TLS). While DNA damage repair (DDR) is closely linked to innate immune responses, how DDR networks orchestrate the SCLC immune microenvironment remains obscure. In this study, we integrated single-cell transcriptomic data (comprising 344,447 high-quality cells) from six cancer types (BCC, CRC, HCC, HNSCC, iCCA, and SCLC). Our comparative analysis revealed a fundamental depletion of TLS-associated cellular subpopulations (e.g., CXCL13+ CD8+ T cells, HLA-DRB5+ B cells, and CXCL9+ dendritic cells) in SCLC, which was significantly correlated with aberrant DDR activity. Through high-dimensional weighted gene co-expression network analysis (hdWGCNA), we identified ZNF385A as the core hub gene within the DDR-associated module. ZNF385A is highly expressed in SCLC and is associated with poorer prognosis. In vitro, ZNF385A depletion suppressed SCLC cell proliferation and induced apoptosis, accompanied by R-loop accumulation and activation of cGAS-STING signaling, indicating a potential link between ZNF385A, genomic stability and tumor-intrinsic innate immune signaling. Collectively, these findings identify ZNF385A as a potential regulator associated with TLS deficiency and immune evasion in SCLC.
Jia-Bao Hou, Xiaoyue Zhu, Jingwei Guo et al.· Biochimica et Biophysica Act...· 0 citations
Lung cancer is the leading cause of cancer-related death worldwide, with ∼230,000 new U.S. cases projected in 2026. Non-small cell lung cancer (NSCLC), the most common subtype, is treated with surgery, chemotherapy, radiation, targeted therapy, and immunotherapy. While checkpoint blockade therapies have improved outcomes, only ∼15% of advanced NSCLC patients achieve long-term survival, leaving most patients with limited options after relapse. This underscores the need for more effective treatments. Natural Killer (NK) cells play a key role in tumor surveillance, and higher NK cell levels correlate with better patient outcomes. To harness them, we developed Tri-specific Killer Engager (TriKE) molecules to enhance NK cell function through CD16 engagement, IL-15 signaling, and tumor antigen targeting. However, current TriKEs face limitations including rapid clearance (through the glomerulus) and restriction to single-antigen targeting. To overcome these challenges, we engineered TriKE-PACCs (Poly-Antigen Cytokine Complexes), a next-generation platform designed to extend NK cell persistence and enable dual-antigen targeting. TriKE-PACCs combine an anti-CD16 single domain antibody (sdAb), an IL-15 moiety, and an anti-mesothelin single chain variable fragment (scFv), along with a PACC module consisting of IL-15 receptor alpha linked to an anti-B7H3 sdAb. This bifunctional design enables dual targeting of mesothelin and B7H3, addressing both tumor heterogeneity and antigen escape, as seen in NSCLC. Using H322 NSCLC cells with B7-H3 and/or mesothelin CRISPR knockouts to model tumor heterogeneity and antigen loss, we evaluated NK cell degranulation (CD107a), cytokine production (IFNγ, TNFα), and cytotoxicity (Xcelligence and Incucyte live imaging assays). Treatment with TriKE-PACCs significantly enhanced NK cell degranulation, cytokine production, and tumor killing compared to single-antigen TriKEs and IL-15 alone, particularly in heterogeneous antigen settings. Next steps include validating our findings in NSCLC 3D organoid and spheroid models, as well as confirming the efficacy of TriKE-PACCs in vivo. To summarize, our findings show that TriKE-PACCs are a promising immunotherapy approach for NSCLC, with potential to overcome antigen escape, improve NK cell persistence, and enhance clinical outcomes for lung cancer patients.
Rachel N. Steinmetz, Shee Kwan Phung, Joshua T. Walker, Tumpa Dasgupta, Yvette Soignier, Philippa R. Kennedy, Martin Felices. Enhancing NK cell immunotherapy in non-small cell lung cancer using dual-antigen targeting Tri-Specific Killer Engagers (TriKEs/TriKE PACCs) [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A021.
R. N. Steinmetz, S. Phung, Joshua T Walker et al.· Clinical Cancer Research· 0 citations
Breast cancer (BC) remains the leading cause of cancer-related mortality and a major contributor to disease burden among women worldwide. Although PD‑1/PD‑L1‑targeting immune checkpoint inhibitors have become a standard treatment for certain triple‑negative breast cancer subgroups, their use across the broader BC population is limited by intrinsic resistance, an immunosuppressive tumor microenvironment (TME), and treatment‑related adverse effects. The present review offers a comprehensive synthesis of the immunotherapeutic paradigm in BC, spanning ICIs, adoptive cellular therapies (CAR-T, CAR-NK, CAR-M, TIL, TCR-T, and CIK cells), and emerging immune modulators. We critically evaluate pivotal clinical trials, discuss cross-cutting challenges—including biomarker development, therapy resistance, and the practical limitations of cellular products—and highlight rational combinatorial strategies. By contrasting the translational readiness of diverse modalities and outlining a framework for personalized therapy, this review aims to inform future research and clinical practice in harnessing immunity against BC.
Ali Mussa, Mahasin Hamid, M. Talib et al.· Journal of Translational Med...· 0 citations
Adoptive cellular therapies may expand treatment options for pediatric brain tumors by focusing activity on tumor antigens and limiting off-tumor effects. We systematically reviewed preclinical and clinical evidence for CAR T cells, TCR-engineered T cells, and NK or γδ T-cell platforms directed against HER2, B7-H3 (CD276), EGFR806-reactive EGFR, GD2, IL13Rα2, and EphA2 or EphA3, with attention to delivery route, safety, persistence, and combination strategies. Following PRISMA, we searched PubMed, Embase, and Scopus from inception through September 17, 2025, restricted to English. The search yielded 324 records; 103 duplicates were removed; 221 titles and abstracts were screened; 180 full texts were reviewed; and 34 studies were extracted by two independent reviewers. We captured design, tumor and molecular features, product engineering, route and schedule, lymphodepletion, toxicities including cytokine release syndrome, immune effector cell associated neurotoxicity, and tumor inflammation associated neurotoxicity, radiographic or clinical response, survival, and correlatives such as persistence or trafficking in blood, cerebrospinal fluid, or tumor tissue, cytokines, and antigen dynamics. In vivo studies showed reproducible antitumor activity for HER2 in medulloblastoma, GD2 in diffuse midline glioma, and multi-antigen constructs incorporating IL13Rα2 and EphA2 in medulloblastoma and ependymoma, with significant survival advantages compared with controls. γδ T cells targeting the EphA axis selectively killed medulloblastoma with neural sparing; GD2 CAR NK-92 inhibited diffuse intrinsic pontine glioma growth. In early clinical programs, route shaped safety and pharmacodynamics. For GD2, low-dose intravenous induction followed by repeated intraventricular dosing produced objective radiographic regressions and manageable tumor inflammation associated neurotoxicity, while dose-limiting cytokine release syndrome was confined to higher intravenous doses. Intraventricular B7-H3 CAR T cells, given without lymphodepletion, enabled multi-cycle dosing with mainly grade 1 to 2 events and cerebrospinal fluid localized persistence. Weekly intracranial EGFR806 CAR T cells were feasible and well tolerated, with stable disease as the best response in a small cohort. Across trials, persistence and immune activation were most evident in cerebrospinal fluid, supporting cerebrospinal fluid centered pharmacodynamic monitoring. Mechanism-based combinations, including IGF-axis inhibition in diffuse midline glioma and epigenetic priming of GD2 with an integrated safety switch in medulloblastoma, enhanced activity. The evidence supports pediatric-centric antigen selection and a CNS-first, locoregional dosing approach to increase on-tumor exposure and reduce systemic toxicity. Priorities include multi-antigen strategies to prevent escape, incorporation of safety switches, earlier deployment when tumor burden is low, and prospective cerebrospinal fluid pharmacodynamics in multisite phase II studies.
Yaxel Levin Carrion, Jayant Bhasin, Sraavya Anne et al.· Neurosurgical review· 0 citations
T-cell engager (TCE)-based therapies represent an emerging and rapidly expanding class of immunotherapies in oncology. Initially developed for hematologic malignancies, TCEs are now entering the field of solid tumors. To date, two agents have received regulatory approval in this setting: Tebentafusp for metastatic uveal melanoma and Tarlatamab for small-cell lung cancer (SCLC). By physically linking a tumor-associated antigen (TAA) to a T-cell activating domain, most commonly cluster of differentiation (CD) 3, TCEs induce an immunological synapse that promotes targeted T-cell mediated cytotoxicity. This narrative review summarizes the most clinically relevant toxicities associated with TCEs in solid tumors, drawing on data from clinical trials and real-world experience. Tebentafusp exemplifies the safety profile of this therapeutic class, which is dominated by cytokine release syndrome (CRS) and cutaneous adverse events (AEs). These toxicities are typically early in onset, predictable, and reversible, occurring predominantly during the initial step-up dosing phase and decreasing substantially with subsequent administrations, consistent with immune adaptation. Tarlatamab, a Delta-like ligand 3 (DLL3) × CD3 bispecific TCE recently approved for SCLC, displays a toxicity profile similarly driven by immune activation, with CRS as the most frequent AE, generally of low grade and confined to early treatment cycles. In contrast, neurotoxicity including immune effector cell-associated neurotoxicity syndrome (ICANS) occurs more frequently, though events are usually low grade, delayed relative to CRS. Other TCEs currently in clinical development target a wide range of TAAs and display a broadly similar toxicity profile, with CRS emerging as a class effect related to CD3-mediated T-cell activation. The incidence and severity of CRS are influenced by dosing strategies, with step-up dosing mitigating early toxicity. Cutaneous, immune-related, and hematologic AEs are generally infrequent and rarely severe. Continued optimization of antigen selection, molecular engineering, and pharmacokinetic parameters will be critical to improving the safety profile of TCEs gathering data from clinical trials and real-world experience.
E. Bastien, C. Vacheret, R. Sanchez et al.· Therapeutic Advances in Medi...· 0 citations
