1. Introduction to MAGE-A4

MAGE-A4 (Melanoma-Associated Antigen A4) is a cancer testis antigen that belongs to the MAGE-A protein family subtype. It is characterized by high expression in various tumor tissues but low expression in normal tissues, with the exception of testis and placenta. The MAGE-A family is primarily located in the q28 region of the X chromosome, spanning approximately 45 kb and consisting of 3 exons. MAGE-A4 is expressed in numerous cancer types, including esophageal, head and neck, lung, bladder, melanoma, breast, colorectal, and gastric cancers. This protein participates in the regulation of cell growth, cell cycle, and apoptosis through the expression of p53-related genes, and maintains DNA replication function via translesion synthesis (TLS).

Gabrielle Knafler,et al. Melanoma-associated antigen A4: A cancer/testis antigen as a target for adoptive T-cell receptor T-cell therapy, Cancer Treatment Reviews, 2025.

2. MAGE-A4 Expression in Solid Tumors

2.1. MAGE-A4 expression varies significantly across different tumor types. Studies have shown that the MAGE-A4 positive rate is highest in synovial sarcoma (70%, 140/201) and lowest in gastric cancer (9%, 6/70). Other tumors with notable MAGE-A4 expression include myxoid/round cell liposarcoma (MRCLS) (40%, 27/67), urothelial cancer (32%, 30/93), esophagogastric junction (EGJ) cancer (26%, 24/93), ovarian cancer (24%, 54/226), head and neck cancer (22%, 43/200), esophageal cancer (21%, 21/100), melanoma (16%, 39/243), and non-small cell lung cancer (NSCLC) (14%, 63/457). The expression level of MAGE-A4 is also highest in synovial sarcoma, with a median P score of 76, followed by MRCLS with a median P score of 15.

Tianjiao Wang,et al. Identifying MAGE-A4 positive tumors for TCR T cell therapies in HLA-A*02-eligible patients.

2.1.1. MAGE-A4 is expressed in a wide range of cancers, including esophageal, head and neck, gastric, ovarian, colorectal, lung, endometrial, cervical, bladder, breast, and prostate cancers, as well as soft tissue sarcomas, urothelial and hepatocellular carcinomas, osteosarcoma, and melanoma.

G.Knafler et al. Cancer Treatment Reviews 2025.

3. Clinical Benefits in Solid Tumors Beyond Synovial Sarcoma

3.1. Afamitresgene autoleucel (afami-cel, marketed as Tecelra), the first in class engineered autologous T cells with a high-affinity TCR specifically recognizing the MAGE-A4 230−239 peptide (GVYDGREHTV) presented by HLA-A*02 molecules on cancer cellsmade history as the first FDA-approved TCR T-cell therapy to treat solid tumor, receiving approval on August 2, 2024 for synovial sarcoma (SS) and mixed round cell liposarcoma (MRCL). The clinical efficacy of afami-cel has been well-documented, with an objective response rate (ORR) of 39% and median progression-free survival (mPFS) of 3.8 months in synovial sarcoma patients. Earlier Phase I data showed an ORR of 24% across multiple tumor types, with synovial sarcoma demonstrating the most promising response at 44%. The median duration of response was 25.6 weeks overall and 28.1 weeks specifically for synovial sarcoma patients. As of July 25, 2024, 13 of 52 (25%) Cohort 1 patients (12 with SyS, one with MRCLS) had OS>149 weeks (~34 months) after receiving afami-cel in Cohort 1 of SPEARHEAD-1.

Uzatresgene autoleucel (uza-cel, ADP-A2M4CD8) represents a significant advancement over afami-cel by incorporating CD8α co-receptor expression alongside the same MAGE-A4-targeted TCR. This engineering innovation fundamentally transforms the functionality of the therapy, particularly by enhancing CD4+ T cell capabilities. While afami-cel contains both CD4+ and CD8+ T cells, the CD4+ component has traditionally limited cytotoxic functionality against MHC class I-restricted targets like MAGE-A4.The added CD8α co-receptor addresses this limitation by enabling CD4+ T cells to better recognize and respond to MAGE-A4 peptides presented on MHC Class I molecules. Research demonstrates that CD4+ T cells expressing both the TCR and CD8α show significantly improved activation upon antigen recognition, with studies showing up to 80.2% CD40L+ cells within the TCR+ population compared to 40.1% in TCR-only cells when exposed to MAGE-A4+ tumor cells.

The CD8α co-receptor improves therapeutic efficacy through several interrelated mechanisms: Stabilized TCR-pMHC Interactions: CD8α physically stabilizes the connection between the T cell receptor and peptide-MHC class I complex, enhancing signal transduction and T cell activation. Enhanced Cytokine Production: CD4+ T cells with CD8α co-receptor demonstrate increased secretion of effector cytokines, including IFN-γ, IL-2, and IL-12, creating a more robust anti-tumor immune response. Improved Cytotoxic Capacity: The addition of CD8α transforms CD4+ T cells from primarily helper cells into more potent cytotoxic effectors capable of directly killing tumor cells, as demonstrated in studies with three-dimensional tumor spheroid models. Integrated Helper Functions: While gaining cytotoxic capabilities, these modified CD4+ T cells maintain their helper functions, leading to improved activation of dendritic cells via CD40L and creating a more comprehensive anti-tumor immune response.

3.2. Uza-cel is currently being evaluated in multiple clinical trials with promising preliminary results: SURPASS Trial: This Phase I trial has shown encouraging responses across multiple solid tumors, including ovarian, esophageal/EGJ/gastric, and urothelial cancers. As of August 2023, 56 patients had received uza-cel—46 as monotherapy and 10 in combination with nivolumab (aPD1 mAb).

SURPASS-3: A pivotal Phase II trial is ongoing in, head and neck cancers, and urothelial cancers, with data expected by 2025.

Efficacy Results (2023 ESMO) Overall response rate (ORR): 34.8% in monotherapy arm, 10% in nivolumab combination arm Median duration of response: 21 weeks (95% CI: 12-38) in monotherapy arm Higher ORR in ovarian (40%), head and neck (75%), and urothelial (57.1%) cancers Better responses observed in patients with fewer prior lines of therapy.

Translational Analyses Evidence of engineered T-cell tumor infiltration across tumor types Broad immune system engagement demonstrated by serum protein changes Reduction in MAGE-A4+ tumor cells, greatest in responding patients Lower M2/cytotoxic T-cell ratio and higher M1/M2 macrophage ratio associated with response.

4. Flip the script by MAGE-A4 TCR.CTBR12 strategy to create a more powerful NEXT Generation TCR-T JWTCR001

The development and application of MAGE-A4 TCR.CTBR12 therapy involve international collaborations. In 2022, 2seventy bio and JW Therapeutics announced a strategic alliance to establish a translational and clinical cell therapy development platform for the Chinese mainland, Hong Kong, and Macao. The initial focus of this collaboration is 2seventy bio's MAGE-A4 TCR .CTBR12 strategy in solid tumors, which is being developed as part of a collaboration with Regeneron. This partnership aims to leverage JW Therapeutics' understanding of the unmet medical needs and regulatory affairs in China to accelerate the development of MAGE-A4-targeted therapies.

The CTBR12 flip receptor retains the TGFβ-binding extracellular domain but replaces the native intracellular signaling domain of the TGFβ receptor with a pro-inflammatory signaling domain, such as IL-12 receptor associated domains (IL12R1 and R2). This re-engineering directs the signaling pathway to initiate immune-activating signals instead of the immunosuppressive Smad-dependent or Smad-independent pathways typically engaged by TGFβ.

4.1. By employing CTBR12 technology, the MAGE-A4 TCR.CTBR12 strategy actively converts TGFβ's inhibitory influences into activating signals for engineered T cells. Preclinical models have shown that the co-expression of CTBR12 significantly enhances antigen-dependent responses in T cells while maintaining a favorable safety profile. This adjustment allows the therapy to address a major barrier to effective immunotherapy, overcoming TGFβ-driven TME suppression that Tecelra cannot circumvent. JWTCR001’s unique CTBR12 flip receptor, capable of converting TGFβ signals into stimulatory ones, could be presented as a novel improvement addressing treatment challenges to heavily treated broad spectrum of solid tumors. Preclinical studies have demonstrated that this engineered TCR exhibits at least five times higher potency in vivo compared to Tecelra's TCR. Using melanoma and non-small cell lung cancer (NSCLC) tumor models, the MAGE-A4 TCR.CTBR12 strategy has shown enhanced tumor cell lysis, which is expected to translate into improved clinical outcomes.

5. The Next Generation MAGE-A4 TCR T cell (JWTCR001) is now recruiting in China

Broad Eligibility Reflects Real-World Patient Needs The inclusion criteria for the JWTCR001 IIT study reflect a thoughtful and inclusive approach: Patients with recurrent/metastatic solid tumors who have undergone extensive prior systemic treatment are eligible. MAGE-A4 expression testing ensures precision medicine recommendations. Adaptation to patients’ genetic backgrounds (e.g., consideration of HLA-A*02 alleles common in certain ethnic populations) maximizes widespread accessibility for trials, particularly for underrepresented Asian populations.

HLA-A*02:01, a common HLA allele in US and European caucasian populations, is observed to have a lower frequency in Asian populations. This reduced prevalence limits the eligibility of Asian patients for therapies exclusively targeting this allele.

The inclusion of alleles such as HLA-A*02:02, A*02:03, and A*02:06 greatly expands the proportion of eligible patients among Asian populations for immunotherapies targeting specific antigens, such as MAGE-A4.

By considering these additional alleles, approximately 28.5% of Asian patients can become eligible for TCR-T cell therapies. Notably, this subset does not overlap with patients expressing HLA-A*02:01.

Taken together, HLA-A genotype and MAGE-A4 tumor expression are key biomarkers to assess patient eligibility to enroll in various trials of TCR T cell therapy, including JWTCR001.

To participate in JWTCR001 trial, Fresh samples or FFPE (with 3 years prior to screening ), IHC-stained MAGE-A4 positive with intensity ++ or +++ and At least one reactive HLA-A*02 allele (HLA-A*02:01, HLA-A*02:02, HLA-A*02:04, HLA-A*02:05, HLA-A*02:06, HLA-A*02:08) matched with peripheral blood sample detected by central lab is required.

Tianjiao Wang,et al. Identifying MAGE-A4 positive tumors for TCR T cell therapies in HLA-A*02-eligible patients.

About JW Therapeutics

JW Therapeutics (HKEx:2126) is an independent and innovative biotechnology company focusing on developing, manufacturing and commercializing cell immunotherapy products. Since its founding in 2016, JW Therapeutics has built an integrated platform for product development in cell immunotherapy, as well as a product pipeline covering hematologic malignancies, solid tumors and autoimmune diseases. JW Therapeutics is committed to bringing breakthrough and quality cell immunotherapy products and the hope of a cure to patients in China and beyond, and to leading the healthy and standardized development of China’s cell immunotherapy industry. For more information, please visit www.jwtherapeutics.com.

About Relmacabtagene Autoleucel Injection

Relmacabtagene autoleucel injection (abbreviated as relma-cel, trade name for oncology indications: Carteyva®) is an autologous anti-CD19 CAR-T cell immunotherapy product independently developed by JW Therapeutics based on a CAR-T cell process platform of Juno Therapeutics (a Bristol Myers Squibb company). Being the first product of JW Therapeutics, Carteyva^® has been approved by NMPA for three indications, including the treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) after two or more lines of systemic therapy, the treatment of adult patients with follicular lymphoma that is refractory or that relapses within 24 months of second-line or above systemic treatment (r/r FL), and the treatment of adult patients with relapsed or refractory mantle cell lymphoma (r/r MCL) after two or more lines of systemic therapy including bruton tyrosine kinase inhibitors (BTKi), making it the first CAR-T product approved as a Category 1 biologics product in China. Currently, it is the only CAR-T product in China that has been simultaneously included in the National Significant New Drug Development Program, priority review and breakthrough therapy designations.

Forward-Looking Statements

The forward-looking statements are based on the management's expectations and beliefs and are subject to a number of risks and uncertainties that could cause actual results to differ materially from those described. Significant risks and uncertainties, include those discussed below and more fully described in Hong Kong Exchanges and Clearing Limited (HKEx) reports filed by the Company. Unless otherwise noted, the Company is providing this information as of the date it publicized, and expressly disclaims any duty to update information contained in the issues and relevant information, or provide any explanation. For detailed information, please visit the company website: www.jwtherapeutics.com/en/forward-looking-statements/.