MAGEA4 expression

P2, N=52, Active, not recruiting, Adaptimmune | Recruiting --> Active, not recruiting | N=120 --> 52

Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab in alveolar soft part tissue sarcoma, the γ-secretase inhibitor nirogacestat in desmoid tumours, the NTRK inhibitors larotrectinib and entrectinib in tumours with NTRK fusions, the mTOR inhibitor nab-sirolimus in PEComa, and the EZH-2 inhibitor tazemetostat in epithelioid sarcoma...The challenges in drug development in soft tissue sarcoma are due to the rarity and the molecular heterogeneity of the disease and the fact that many subtypes are associated with complex karyotypes or non-targetable molecular alterations. We believe that progress maybe possible with a better understanding of the complex biology, the development of novel compounds for difficult targets such as proteolysis targeting chimeras (Protacs), the utilisation of modern clinical trial designs, and enhanced collaboration of academia with industry to develop treatments with a strong biologic rationale.

In conclusion, the E701U Ab showed reliable specificity for MAGE-A4 expression among MAGE family genes. Patients with MAGE-A4(+) BC have an unfavorable prognosis and represent potential candidates for MAGE-A4-specific immunotherapy.

P2, N=66, Active, not recruiting, Adaptimmune | Recruiting --> Active, not recruiting

In conclusion, MAGEA4-AS1-p53 complexes bind to MK2 promoter, enhancing the transcription of MK2 and activating the downstream signaling pathways, consequently promoting the proliferation and metastasis of OSCC cells. MAGEA4-AS1 may serve as a diagnostic marker and therapeutic target for OSCC patients.

Among MAGE-As, MAGE-A4 had the highest prevalence (65%), followed by MAGE-A10 (15%) and MAGE-A9 (13%)...Complementary immunohistochemical analyses were used to establish the positive correlation between RNA and protein expression for MAGE-A4 and NY-ESO-1. These data inform the strategy for optimal coverage of the SyS patient population with T-cell therapies, offering patients with SyS new options for single or combined second lines of treatment.

P2, N=3, Terminated, Adaptimmune | N=45 --> 3 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2023 --> Apr 2023; Study was terminated due to difficulty recruiting subjects and lack of efficacy

Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies.

P1/2, N=20, Recruiting, Adaptimmune | Not yet recruiting --> Recruiting

P1, N=120, Recruiting, Adaptimmune | Trial primary completion date: Sep 2023 --> Dec 2025

P1, N=50, Recruiting, Immatics Biotechnologies GmbH | Phase classification: P1a/1b --> P1

Preliminary in vivo investigations revealed a significant deceleration in tumor growth, highlighting the therapeutic potential of these TCR-like CAR-T cells. Further investigations are warranted to validate these revelations fully and harness the complete potential of TCR-like CAR-T cells in overcoming cancer's resilient defenses.

Conclusions The high MAGE-A4 expression levels and the highly specific anti-cancer cell activity of CDR404 make it a highly attractive immunotherapy for development post-progression on ICI for patients with HLA-A*02:01+ SQ-NSCLC. A multi-tumor phase 1 trial of CDR404, including SQ-NSCLC, is expected to begin in 2024 with prospective patient selection for both HLA-A*02:01 and tumor MAGE-A4.

Conclusions The CLB MAGE-A4 immunostaining conditions were successfully adjusted and bridged to reach concordance with the clinical trial assay. This allowed the accurate assessment of the prognostic value of MAGE-A4 in SyS.

Lymphodepleting chemotherapy consisting of fludarabine (30 mg/m^2/day for 4 days) and cyclophosphamide (600 mg/m^2/day for 3 days) will be administered beginning one week prior to afami-cel infusion... N/A. Submitting under Trials in Progress.

P2, N=120, Recruiting, Adaptimmune | N=90 --> 120 | Trial completion date: Nov 2034 --> Apr 2038

P1, N=23, Terminated, Hoffmann-La Roche | N=260 --> 23 | Trial completion date: Feb 2024 --> Jul 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Feb 2024 --> Jul 2023; The study was terminated due to program discontinuation.

Nevertheless, inhibition of immunosuppressive pathways may improve anti-tumor responses; therefore, new SURPASS cohorts include ADP-A2M4CD8 combined with nivolumab or pembrolizumab. Data from additional pts treated by August 2023 will be presented. Conclusions ADP-A2M4CD8 continues to show an acceptable benefit-to-risk profile, including in pts receiving nivolumab combination therapy.

Lymphodepletion chemotherapy (fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 600 mg/m2/day for 3 days) will be followed by infusion of 1â10x10^9 ADP-A2M4CD8 T-cells. Adverse events will be monitored, with participants followed for 15 years from T-cell infusion. Conclusion SURPASS-3 is initiating in Q2 2023.

P2, N=66, Recruiting, Adaptimmune | Not yet recruiting --> Recruiting | Initiation date: Mar 2023 --> Jun 2023

P2, N=45, Active, not recruiting, Adaptimmune | Trial primary completion date: Apr 2023 --> Dec 2023

The current study provides a comprehensive evaluation of CTAs, and suggests that their association with immune cells may indicate in situ immunogenic effects. The findings support the rationale to harness CTAs as targets for immunotherapy.

Vaccine efficacy experiments on MAGED4B-expressing tumours are ongoing.ConclusionSignificant levels of myoCAF are present in around 50% of HNSCC, which have one of the lowest response rates to anti-PD1 immunotherapy (~15%). MAGED4B-directed vaccination has the potential to target both HNSCC cells and myoCAF simultaneously and has significant potential for combination immunotherapy in highly aggressive myoCAF-rich HNSCC.

Taken together, the combination of a highly active TCR with a strong specificity profile and a synthetic receptor that leverages an immunosuppressive cytokine to deliver a pro-inflammatory signal has the potential to safely enhance T cell potency in otherwise intractable solid tumors. Our data support an upcoming clinical trial to evaluate the safety and efficacy of autologous T cells co-expressing the pairing enhanced MAGE-A4 TCR with CTBR12 in solid tumors.

P2, N=45, Active, not recruiting, Adaptimmune | Recruiting --> Active, not recruiting | Trial completion date: Oct 2038 --> Dec 2023

P1/2, N=20, Not yet recruiting, Adaptimmune | Trial completion date: Apr 2038 --> Jun 2038

P1, N=120, Recruiting, Adaptimmune | N=90 --> 120

P1, N=260, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | Trial completion date: Oct 2026 --> Feb 2024 | Trial primary completion date: Oct 2026 --> Feb 2024

In addition, afami-cel has an acceptable benefit-risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.

P1/2, N=20, Not yet recruiting, Adaptimmune

P2, N=66, Not yet recruiting, Adaptimmune

Pre-selection for MAGE-A4 expression was not required as a majority of OC express MAGE-A4 (H score ≥ 1) and tebentafusp demonstrated OS benefit and ctDNA reductions regardless of H score, although RECIST responses were enriched at higher H scores (Leach 2021). IMC-C103C is clinically active but the low MAGE expression may have resulted in few RECIST responses. Dose optimization and signal detection continue in MAGE-A4 pos pts with additional tumor types.

P2, N=90, Recruiting, Adaptimmune | Trial completion date: Apr 2038 --> Nov 2034 | Trial primary completion date: Jan 2023 --> Oct 2021

HLA and MAGE-A4 biomarker data will inform the therapeutic opportunities for SPEAR T-cells targeting MAGE-A4 in metastatic solid cancers. 1. D’Angelo et al.

P2, N=90, Recruiting, Adaptimmune | Trial completion date: Nov 2034 --> Apr 2038

Histopathology of the excised specimen was positive for programmed cell death 1, programmed cell death ligand-1, New York esophageal squamous cell carcinoma-1, and melanoma-associated antigen 4; their expression may be a therapeutic target for cAS. Combining immunotherapy with surgical treatment may be effective for cAS.

P2, N=90, Recruiting, Adaptimmune | Trial primary completion date: May 2022 --> Jan 2023

There was no significant difference in the positive cell rates of NY-ESO-1 or MAGE-A4 between CDF cases and AWD or DOD cases. Overall, our results suggest that NY-ESO-1 and MAGE-A4 may be involved in the aggressiveness of OS.

P1a/1b, N=50, Recruiting, Immatics Biotechnologies GmbH | Not yet recruiting --> Recruiting

P1, N=90, Recruiting, Adaptimmune | N=60 --> 90

P1a/1b, N=50, Not yet recruiting, Immatics Biotechnologies GmbH

PD-1-, PD-L1-, NY-ESO-1-, and MAGE-A4-positive cell rates showed weak to moderate correlations with histological grade or tumor size, while the PD-1-, PD-L1-, and MAGE-A4-positive cell rates showed strong to very strong positive correlations with the SUVmax value. Thus, PD-1, PD-L1, NY-ESO, and MAGE-A4 expressions are correlated and may be involved in the aggressive elements of STSs.