Emerging advances in CAR-T therapy for solid tumors: latest clinical trial updates from 2025 ASCO annual meeting

Each year, the American Society of Clinical Oncology (ASCO) Annual Meeting presents major breakthroughs in cancer research. In this article, we summarize the recent advances in chimeric antigen receptor T-cell (CAR-T) therapies for solid tumors presented at the 2025 ASCO Annual Meeting. Based on 12 phase I clinical studies, we highlight the emerging strategies that are beginning to unlock the full potential of CAR-T therapies for patients with solid tumors who have undergone multiple prior treatments.

Recurrent glioblastoma (rGBM) remains a disease with dismal outcomes, with the median overall survival (OS) historically ranging from 6 to 9 months. Therapeutic options for recurrent disease after initial chemoradiation and adjuvant temozolomide remain scarce, suggesting the need for novel treatments to improve outcomes. Compared with the earlier antigen-specific vaccine rindopepimut, which failed to improve overall survival in the phase III trial, Bagley et al. reported on the results of treating 18 patients with GBM with bivalent CAR-T cells. This construct simultaneously targeted epidermal growth factor receptor (EGFR) epitope 806 and interleukin 13 receptor subunit alpha 2 (IL13 Rα2) (CART-EGFR-IL13 Rα2) (NCT05168423) [1]. Participants received CART-EGFR-IL13Rα2 cells via intracerebroventricular administration without lymphodepleting chemotherapy. Tumor shrinkage was seen in 85% of evaluable patients, with reductions of 1%–62% (median 35%, interquartile range 12–39%) by modified response assessment in neuro-oncology (RANO) criteria. Durable stable disease (SD) beyond 17 months was noted in one patient. Another patient experienced grade 3 lethargy/fatigue at the highest dose, and acute neurotoxicity was observed in all patients, with 56% experiencing grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) but no grade 4–5 events. Gerstner et al. reported on the INCIPIENT trial (NCT05660369), which administered CARv3-TEAM-E T cells, engineered to target EGFRvIII and secrete a T-cell-engaging antibody molecule against wild-type EGFR, to 7 patients with rGBM [2]. CARv3-TEAM-E was administered via Ommaya catheter after lymphodepleting chemotherapy with fludarabine and cyclophosphamide. SD was achieved in 5 patients, including one who showed a 33% reduction in tumor diameter by immunotherapy RANO (iRANO) criteria, while all patients remained alive 3–8 months after the first infusion. No dose-limiting toxicities (DLTs) occurred, but all patients experienced grade 1 cytokine release syndrome (CRS), with one patient developing grade 2 CRS. Li et al. conducted a phase I dose-escalation study of B7H3-CAR-T cells (NCT05474378) in 11 rGBM [3]. B7H3-CART with the recommended phase II dose (RP2D) established at 25 × 10^6 cells was delivered to nine treated patients via intratumoral and intraventricular Ommaya reservoirs, without lymphodepleting chemotherapy. Inflammation-associated neurotoxicity (TIAN) was observed after 29 of 36 infusions (81%), and managed acutely with anakinra and dexamethasone. The median OS for patients receiving at least one dose of B7H3-CART reached 14.6 months (95% confidence interval: 2.3–26.8 months). iRANO response criteria were measured by complete, partial or minor response, stable disease, and progressive disease. The above studies indicate that localized CAR-T delivery might be tolerable, with early signals of efficacy for rGBM.

Four phase I studies presented at ASCO 2025 highlighted novel CAR-T strategies for thoracic and breast cancers. C406, a human epidermal growth factor receptor 2 (HER2)-targeted autologous CAR-T, showed a 75% disease control rate (DCR) in eight patients with HER2-positive breast cancer (ChiCTR2500096093) [4]. All patients experienced treatment-related adverse events (AEs) mainly including hematologic toxicities without leading to discontinuation and death. Sun et al. conducted a first-in-human phase I dose-escalation trial of non-viral anti-programmed cell death protein 1 (aPD1)-mesothelin (MSLN) JL-Lightning CAR-T cells (NCT06249256) in 7 patients with advanced malignant pleural mesothelioma [5]. At dose level (DL) 1, 1/4 patients achieved a partial response with a DCR of 75%. At DL2, the overall response rate (ORR) was 100% (3/3), including one complete response (CR) lasting >9 months. Manageable grade 3–4 CRS and immune-mediated pneumonia occurred in DL2, and all patients experienced reversible grade 3–4 hematologic toxicity. The logic-gated CAR-T A2B694, attacks tumor cells expressing MSLN but lacking HLA-A*02, and thus prevents on-target/off-tumor toxicity in normal cells expressing HLA-A*02. A2B694 showed expansion and tumor infiltration without dose-limiting CRS or neurotoxicity in ovarian, pancreatic, and non-small cell lung cancer (NCT06051695) [6]. DLL3-targeted LB2102, including a dominant-negative transforming growth factor beta receptor II (dnTGFβRII), demonstrated dose-dependent activity in small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma with no DLTs (NCT05680922) [7]. For DLL3, the bispecific T-cell engager tarlatamab has received FDA accelerated approval for extensive-stage SCLC and subsequently demonstrated overall-survival benefit versus chemotherapy, providing an approved DLL3-targeted benchmark against which investigational DLL3 CAR-T can be contextualized. Although the data are limited, these therapies showed the potential safety and anti-tumor activity of CAR-T therapies in thoracic and breast cancers, warranting further clinical studies.

Five studies highlight innovative CAR-T approaches for advanced colorectal, gastroesophageal, hepatocellular, and renal cancers. Anti-carcinoembryonic antigen (CEA) CAR-T (NCT05240950) prolonged relapse-free survival post-resection in patients with colorectal liver metastases, with 57% remaining recurrence-free at high dose, and no grade ≥ 3 AEs [8]. Within the broader therapeutic landscape, the CD3×CEA bispecific antibody cibisatamab has also entered phase I testing across multiple CEA-positive solid tumors. GCC19CART (NCT05319314) demonstrated dose-dependent responses (ORR 80% at DL2) in patients with refractory metastatic colorectal cancer, but treatment was complicated by severe diarrhea and one treatment-related death [9]. LB1908 (NCT05539430), targeting Claudin 18.2, achieved lesion shrinkage in 83% of patients (maximum ~ 41%) with no grade ≥ 3 CRS or ICANS, although upper gastrointestinal toxicity required management [10]. For the same target, zolbetuximab plus chemotherapy was approved by the FDA in 2024 for Claudin 18.2-positive, HER2-negative gastric/Gastroesophageal junction adenocarcinoma, providing a non-CAR benchmark. Ori-C101 (NCT05652920), a GPC3-directed armored CAR-T, yielded objective responses in any patients at DL3 but ongoing CR in any patient at 9 months [11]. In contrast, the monoclonal antibody codrituzumab failed to improve outcomes in randomized studies. ALLO-316 (NCT04696731), an allogeneic CD70 CAR-T, achieved a 20% ORR (33% in CD70-high tumors) with CRS (grade ≥ 3, 2%)/ICANS (grade ≥ 3, 0%). According to prior findings, three grade 5 adverse events were attributed to ALLO-316, comprising cardiogenic shock, failure to thrive, and sepsis [12]. Notably, in the CD70 target space, Antibody–Drug Conjugates and antibody-based therapies are also under active development, highlighting ALLO-316 as an exploratory early entrant among allogeneic CAR-T therapies. Collectively, these data support the expanding role of CAR-T therapies for gastrointestinal and genitourinary tumors, with encouraging efficacy and manageable safety. Nevertheless, further clinical trials are warranted to validate these findings and to better define their therapeutic potential.

Overall, recent phase I studies presented at ASCO 2025 demonstrate notable progress in the clinical development of CAR-T therapies for solid tumors. Nevertheless, given that these cohorts are small, single-arm studies without head-to-head or cross-trial comparisons, the findings should be interpreted strictly as preliminary efficacy and safety signals assessed at each study’s data cutoff. Despite these limitations, the early evaluations provide an important foundation for the design and conduct of subsequent phase II and III trials. The core trial characteristics and clinical outcomes are summarized in Tables 1 and 2.