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

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated a transformative impact in hematologic malignancies and offers a promising strategy to offer new hope for patients with solid tumors who have failed multiple lines of treatment. The clinical application of CAR-T therapy in solid tumors, however, still has challenges, including tumor heterogeneity, an immunosuppressive tumor microenvironment, and safety concerns. These hurdles have mean that CAR-T therapy has become both a focal point and a pivotal trend in contemporary clinical research. The American Society of Clinical Oncology (ASCO) Annual Meeting serves as a premier venue for unveiling groundbreaking clinical data. In this review, we highlight the main phase I clinical trial advances in CAR-T therapy for solid tumors presented at the 2025 ASCO Meeting.

To the editor

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.

Updates for glioblastoma

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.

Updates for thoracic and breast cancers

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.

Updates for Gastrointestinal and genitourinary tumors

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.

Table 1.

Characteristics of chimeric antigen receptor (CAR) T-cell therapy

Target antigen	Agent	CAR-T construct	Allogeneic/autologous	Lymphodepletion chemotherapy	Administration	Dosing	Disease indications
EGFR	CART-EGFR-IL13Rα2 [1] (targeting EGFR epitope 806 & IL13Rα2)	Autologous T cells transduced with a bicistronic lentiviral vector containing a murine scFv targeting EGFR and a humanized scFv targeting IL13Rα2	Autologous	Without lymphodepleting chemotherapy	Intracerebroventricular	3 + 3 design (DL: 5.0 × 106, 1.0 × 107, and 2.5 × 107 cells)	Patients with EGFR-amplified GBM that was recurrent/progressive following front-line radiotherapy (with prescreening for EGFR-amplified)
	CARv3-TEAM-E T Cells[2] (targeting EGFRvIII & wild-type EGFR (via TEAM))	Second generation Autologous T lymphocyte population that contains cells transduced ex-vivo with a CARv3-TEAM-E lentiviral vector encoding a chimeric antigen receptor (CAR)	Autologous	Fludarabine and cyclophosphamide	Intraventricular	Up to 6 doses of 1 × 107 cells	Patients with recurrent GBM with EGFRvIII mutation and/or EGFR amplification (with prescreening for EGFRvIII mutation and/or EGFR amplification)
B7H3	B7H3-CART[3]	-	Autologous	Without lymphodepleting chemotherapy	Intratumoral and/or intraventricular	3 + 3 design (DL1: 1 × 107 - DL4 :1 × 108cells)	Patients with recurrent GBM undergoing repeat resection (without prescreening for target expression)
HER2	C406[4]	CAR modified autologous T cell, which is a CART targeting HER2	Autologous	Without lymphodepleting chemotherapy	Intravenous	Fixed dose	HER2-positive recurrent or refractory breast cancer (with prescreening for HER2)
Mesothelin	aPD1-MSLN JL-Lightning-CAR-T[5]	Fast autologous mesothelin (MSLN)-targeted chimeric antigen receptor (MSLN-CAR) T cells secreting PD-1 nanobodies	Autologous	Fludarabine 30 mg/m²/day, Cyclophosphamide 300 mg/m²/day for 2–3 days	Intravenous	DL1 : 0.5–0.63 × 10⁶/kg DL2: 0.8–1.03 × 10⁶/kg	MPM patients who had failed standard therapies and had confirmed MSLN and PD-L1 expression on tumors by IHC (with prescreening for MSLN and PD-L1)
	A2B694[6] (targeting Mesothelin + HLA-A*02 blocker)	Combine a CAR-activating receptor targeting MSLN with a blocker CAR that recognizes HLA-A*02, to distinguish between normal and tumor cells	Autologous	Undergo lymphodepletion before A2B694 infusion	Intravenous	DL1: 1 × 108 Tmod positive cells increase up to DL 5: 14 × 108 in combination with low-dose IL-2	Adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression who have progressed after standard-of-care therapy (with prescreening for MSLN)
DLL3 (armored with dnTGFβRII)	LB2102[7]	CAR-T cell therapy engineered to target DLL3 and armored with a TGF-β receptor blockade to overcome the immunosuppressive tumor microenvironment	Autologous	3-day lymphodepletion (LD) with fludarabine (30 mg/m²), and cyclophosphamide (300 mg/m²).	Intravenous	3 + 3 design (DL: 0.3, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 × 106 cells/kg)	Patients with SCLC/LCNEC who are relapsed/refractory to at least 1 prior line of therapy (without prescreening for target expression)
CEA	Anti-CEA CAR-T[8]	-	-	Without lymphodepleting chemotherapy	Intravenous	3 + 3 design (DL: 1, 3, and 6 × 106 cells/kg)	Patients diagnosed with liver metastasis of colorectal cancer underwent radical surgery for the primary lesion of colorectal cancer, and R0 resection was performed for the liver metastasis (with prescreening for CEA)
GCC + CD19 (CoupledCAR)	GCC19CART[9]	Single infusion of Chimeric Antigen Receptor (CAR) transduced autologous T cells	Autologous	Fludarabine 30 mg/m² and cyclophosphamide 300 mg/m² on day-3	Intravenous	Leukapheresis, lymphodepleting chemotherapy (fludarabine 30 mg/m² and cyclophosphamide 300 mg/m2 on day-3), and a single dose of GCC19CART	Metastatic colorectal cancer (without prescreening for target expression)
Claudin 18.2	LB1908[10]	Claudin 18.2-Targeted autologous Chimeric Antigen Receptor T-cells	Autologous	Without lymphodepleting chemotherapy	Intravenous	3 + 3 design (DL: 0.5, 1.5, and 3 × 106 cells/kg)	Patients with advanced GC/GEJC/EC relapsed/refractory to at least prior line of therapy, and with at least 1 + CLDN18.2 expression in 50%+ of tumor cells by central testing (with prescreening for CLDN18.2)
GPC3	Ori-C101[11]	GPC3-directed chimeric antigen receptor modified T cells	Autologous	Without lymphodepleting chemotherapy	Single hepatic arterial infusion	Single hepatic arterial infusion with a total dose of 0.9 to 6 × 108 CAR-T cells.	Advanced hepatocellular carcinoma (with prescreening for GPC3)
CD70	ALLO-316[12]	-	Allogeneic	Fludarabine and Cyclophosphamide ± ALLO-647 (anti-CD52)	Intravenous	3 + 3 design (40–240 × 108 allogeneic CAR + T cells)	Advanced clear cell renal cell carcinoma (with prescreening for CD70)

ALLO-647, Anti-CD52 monoclonal antibody; AEs, Adverse events; CAR-T, Chimeric antigen receptor T cell; CEA, Carcinoembryonic antigen; CD70, Cluster of Differentiation 70; CLDN18.2, Claudin 18.2; CR, Complete response; CRS, Cytokine release syndrome; DCR, Disease control rate; DL, Dose level; DLT, Dose-limiting toxicity; DLL3, Delta-like ligand 3; dnTGFβRII, Dominant-negative transforming growth factor beta receptor II; EC, Esophageal cancer; EGFR, Epidermal growth factor receptor; EGFRvIII, Epidermal growth factor receptor variant III; GCC, Guanylate cyclase-C; GBM, Glioblastoma multiforme; GEJC, Gastroesophageal junction cancer; GPC3, Glypican-3; HCC, Hepatocellular carcinoma; HER2, Human epidermal growth factor receptor 2; HLA-A*02, Human leukocyte antigen A*02; IHC, Immunohistochemistry; IL-2, Interleukin-2; IL13Rα2, Interleukin 13 receptor subunit alpha 2; LCNEC, Large cell neuroendocrine carcinoma; LDC, Lymphodepleting chemotherapy; MPM, Malignant pleural mesothelioma; MSLN, Mesothelin; ORR, Overall response rate; OS, Overall survival; PD-1, Programmed cell death protein 1; PD-L1, Programmed death-ligand 1; R0 resection, Complete resection with negative margins; RCC, Renal cell carcinoma; RP2D, Recommended phase II dose; SCLC, Small cell lung cancer; scFv, Single-chain variable fragment; SD, Stable disease; TEAM, T-cell engaging antibody molecule; TIAN, Tumor inflammation–associated neurotoxicity; Tmod, Tmod™ platform (logic-gated CAR design)

Table 2.

Overview of clinical trials using CAR-T in patients with solid tumors

Agent	NCT	Pts	Response criteria	Efficacy highlights	TRAEs	Cutoff date	Phase	Status	Sponsor	Reference
CART-EGFR- IL13Rα2	NCT05168423	18	iRANO criteria	Tumor shrinkage :85% Reductions range: 1–62% (median 35%) confirmed PR: 5.6%	DLT: 1 at the MTD ICANS : Grade 3 56%; Grade 4–5 0% Fever: Grade 1–2 100%	-	Phase I	Active, not recruiting	University of Pennsylvania	[1]
CARv3-TEAM-E T Cells	NCT05660369	7	iRANO criteria	SD: 71.4% with 1 patient achieving SD for 6 months All patients are alive 3–8 months after first infusion	DLTs: 0 CRS: Grade 1 100% with only 1 patient experiencing CRS Grade 2 for 1 day ICANS: Grade 1 14.3% Hematologic toxicity: 14.3%	-	Phase I	Recruiting	Marcela V. Maus, M.D.,Ph.D	[2]
B7H3-CART	NCT05474378	11	iRANO criteria	mOS:14.6 months (95% CI: 2.3–26.8 months)	DLT: 1 in DL 2 TIAN: 81%, and can be managed acutely with anakinra and dexamethasone	-	Phase I	Recruiting	Stanford University	[3]
C406	ChiCTR2500096093	8	RECIST v1.1	DCR: 75% (0 PR, 6 SD, 2 PD); PFS up to 8 months	Hematologic toxicity: 100% (white blood cell count decrease 8, neutrophil count decrease 8, lymphocyte count decrease 8) CRS: 25%, all manageable No TRAEs leading to discontinuation and death	January 18, 2025	Phase I	Completed	Jinan Central Hospital	[4]
aPD1-MSLN JL-Lightning-CAR-T	NCT06249256	7	mRECIST 1.1 or RECIST 1.1	DL1: PR 1, DCR: 75% DL2: ORR 100%, CR 33.3%	DL1: CRS 25% (Grade 1), no ICANS or DLT DL2: CRS 67.7% (Grade 3–4), with no ICANS. Grade 3 immune-mediated pneumonia 67.7% Hematologic toxicity: 100% (Grade 3–4), all reversible with supportive care	-	Phase I	Recruiting	Shanghai Cell Therapy Group Co.,Ltd	[5]
A2B694	NCT06051695	5	RECIST v1.1	-	No CRS, no neurotoxicity, mild lymphopenia	January 15, 2025	Phase I/II	Recruiting	A2 Biotherapeutics Inc.	[6]
LB2102	NCT05680922	9	RECIST v1.1	Dose-dependent efficacy at DL3: 1 PR, 2 SD	No DLT; Grade 1 CRS :1 in DL3 Grade 3 TEAEs: anemia (n = 2), leukopenia (n = 2) and neutropenia (n = 2) None were classified as serious, and all were deemed related to lymphodepletion.	December 13, 2024	Phase I	Recruiting	Legend Biotech USA Inc	[7]
Anti-CEA CAR-T	NCT05240950	12	-	Median follow-up 23 months In the 6 × 10⁶/kg dose group, 4/7 remained relapse-free survival	Mild AEs (lymphopenia, arthralgia, rash) No severe AEs	December, 2024	Phase I	Recruiting	Changhai Hospital	[8]
GCC19CART	NCT05319314	9	RECIST v1.1	ORR: DL1 25%, DL2 80% (3 PR, 1 pCR) PFS: DL1 5 months, DL2 7.8 months DFS: DL1 2.2 months, DL2 6.9 months	CRS: 100% Diarrhea/colitis: 88.8% ICANS: 22.2% 1 (DL2) died 48 days post-infusion	January 23, 2025	Phase I	Unknown status	Innovative Cellular Therapeutics Inc.	[9]
LB1908	NCT05539430	6	RECIST v1.1	83% lesion shrinkage 1 PR at 7 months	DLT: 1 (upper GI toxicity) CRS: 100% (all Grade 1–2) no ICANS	January 4, 2025	Phase I	Recruiting	Legend Biotech USA Inc	[10]
Ori-C101	NCT05652920	10	RECIST v1.1	66% disease control at DL2 or higher 100% ORR at DL3 1 ongoing CR at 9 months	DLT: 1 (CRS-related DIC) CRS: 100%, 30% (Grade 3) no ICANS	December 17, 2024	Phase Ib/II	Recruiting	OriCell Therapeutics Co., Ltd.	[11]
ALLO-316	NCT04696731	39	RECIST v1.1	ORR: 20% overall CD70-high (≥ 50%) tumors:33% ongoing responses	CRS:57%, 2% (Grade 3) ICANS: 9%, 0% (Grade 3) no GvHD	January 2, 2025	Phase IA/IB	Active, not recruiting	Allogene Therapeutics	[12]

AE, Adverse event; CAR-T, Chimeric antigen receptor T cell; CR, Complete response; CRS, Cytokine release syndrome; CSF, Cerebrospinal fluid; DCR, Disease control rate; DL, Dose level; DLT, Dose-limiting toxicity; DIC, Disseminated intravascular coagulation; GBM, Glioblastoma; GI, Gastrointestinal; GvHD, Graft-versus-host disease; ICANS, Immune effector cell-associated neurotoxicity syndrome; IHC, Immunohistochemistry; MTD, Maximum tolerated dose; NCT, National Clinical Trial identifier; ORR, Overall response rate; OS, Overall survival; PD, Progressive disease; PD-1, Programmed cell death protein 1; PD-L1, Programmed death-ligand 1; PFS, Progression-free survival; PR, Partial response; RP2D, Recommended phase II dose; rGBM, Recurrent glioblastoma; SD, Stable disease; TEAE, Treatment-emergent adverse event; TIAN, Tumor inflammation–associated neurotoxicity; TRAEs, Treatment-related adverse events; WBC, White blood cell; Inc, Incorporated; Co., Ltd, Company Limited

Abbreviations

ADC

Antibody–Drug Conjugate

AE

Adverse event

ASCO

American Society of Clinical Oncology

CAR-T

Chimeric antigen receptor T cell

CEA

Carcinoembryonic antigen

CR

Complete response

CRS

Cytokine release syndrome

DCR

Disease control rate

DL

Dose level

DLT

Dose-limiting toxicity

dnTGFβRII

Dominant-negative transforming growth factor beta receptor II

EGFR

Epidermal growth factor receptor

GEJ

Gastroesophageal junction

GPC3

Glypican-3

HER2

Human epidermal growth factor receptor 2

HLA-A02

Human leukocyte antigen A02

ICANS

Immune effector cell-associated neurotoxicity syndrome

iRANO

Immunotherapy Response Assessment in Neuro-Oncology

LCNEC

Large cell neuroendocrine carcinoma

MSLN

Mesothelin

ORR

Overall response rate

OS

Overall survival

RANO

Response Assessment in Neuro-Oncology

rGBM

Recurrent glioblastoma

RP2D

Recommended phase II dose

SCLC

Small cell lung cancer

SD

Stable disease

TIAN

Tumor Inflammation–Associated Neurotoxicity

Author contributions

WZL and DFZ wrote the draft papers and prepared tables. MC and XJY reviewed, revised, and edited the draft paper, and contributed to the publication and submission of the manuscript. All authors have read and approved the final manuscript.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All the authors consent for publication.

Competing interests

The authors declare no competing interests.