MAGEA4 (Melanoma antigen family A, 4)

Novel approaches to treating synovial sarcoma include immune-based therapies (such as TCR-T cell therapy to NY-ESO-1, MAGE4, PRAME or using immune checkpoint inhibitors), epigenetic modifiers (HDAC inhibitors, EZH2 inhibitors, BRD disruptors), as well as novel or repurposed receptor tyrosine kinase inhibitors. In the presented review, we aimed to summarize the genetic and epigenetic landscape of SS as well as to find out the potential niches for the development of novel diagnostics and therapies.

P1/2, N=0, Withdrawn, Immunocore Ltd | N=75 --> 0 | Terminated --> Withdrawn

In August 2024, afamitresgene autoleucel was approved in the USA under accelerated approval for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P or -A*02:06P positive and whose tumour expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. This article summarizes the milestones in the development of afamitresgene autoleucel leading to this first approval for the treatment of advanced synovial sarcoma.

He was started on a course of levofloxacin with no improvement...He was prescribed amoxicillin-clavulanic acid...Once diagnosed, treatment of Mycoplasma pneumoniae includes azithromycin, macrolides, doxycycline, or fluoroquinolones. We are reporting a novel case of Mycoplasma pneumoniae mimicking as a bronchogenic carcinoma exhibiting discordant radiographic images and the rare symptom of pleurisy. The new Nodify® proteomic biomarker blood test contributed to the workup and averted the need for unnecessary invasive procedures.

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.

We identified the following 9 HLA Class I alleles with very high immunogenicity and binding affinity against all 11 melanoma antigens: A*02:14, B*07:10, B*35:10, B*40:10, B*40:12, B*44:10, C*07:11, and C*07:13, and C*07:14. These 9 HLA alleles possess the potential to aid in the elimination of melanoma both by themselves and by enhancing the beneficial effect of immune checkpoint inhibitors.

Taken together, the present study successfully demonstrated that tumor antigen-specific IL-10-producing T cells exist in the peripheral blood of patients with HNSCC and that Lag-3+ T cells may serve an important role in modulating IL-10-producing T cells. These findings provide novel insights into the roles of IL-10 and Lag-3 in mediating antitumor immune responses.

The abrogation of MAGE-A4-responsive plasma cells (MARPs) decreased tumor burden, increased T cell infiltration and activation, and reduced CD163 + CD206 + macrophages in mouse lungs. These findings suggest MAGE-A4 promotes NSCLC tumorigenesis, in part, through the recruitment and retention of IgA + MARPs in the lungs.

This study is a comprehensive study providing real-world data on the expression of several actionable proteins in a large proportion of SynSa samples. All evaluated markers were expressed in a clinically meaningful proportion of cases represented in our TMA, supporting the relevance of ongoing preclinical and clinical research with novel agents directed against these targets.

This study was the first to screen three multi-epitope long peptides targeting MAGE-A4 and assess their immunogenicity, immune function, and potential as adjuvant peptides. The results showed that the MAGE-A4 long peptide vaccine can be used as a novel immunoprophylaxis method to prevent TNBC. Moreover, the proposed development model is capable of screening multiple target antigens, which lead to its clinical application.

The covariates were generally not associated with MAGE-A4 expression, except for patient age in ovarian cancer and histology in non-small cell lung cancer. This report shows the eligibility rate from biomarker screening for TCR T cell therapies and provides epidemiological data for future clinical development of MAGE-A4-targeted therapies.

P2, N=66, Recruiting, Adaptimmune | Trial completion date: Oct 2025 --> Aug 2026 | Trial primary completion date: Oct 2025 --> Aug 2026

Those who remained high in SED with <3 comorbidities (p's =.005) had significantly better social well-being than those who increased SED. As we transition to a post-pandemic era, behavioral strategies for cancer survivors should focus on reducing screen time to improve QoL and fatigue.

LUSC MAGE-A4HIGH tumors had a differentiated TiME profile. Our findings are consistent with an INFLAMLOWVASCLOW phenotype possibly indicative of an "immune desert" [Desbois et al 2020]. In contrast, LUAD MAGE-A4HIGH tumors had an INFLAMHIGHVASCLOW phenotype indicating that MAGE-A4 associations with TiME may be histology dependent in NSCLC.

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

Off-target sequences feature an amino acid motif that allows a structural groove-coordination mimicking that of the target peptide, therefore allowing the interaction with the engager molecule. We conclude that our strategy offers an accurate, scalable route for evaluating the non-clinical safety profile of TCR-like antibody therapeutics prior to first-in-human clinical application.

Further analysis signified that the expression of MAGEA3 mRNA was positive correlation with neutrophil, macrophages M2, dendritic cells resting, and eosinophilic, but negatively correlated with B cells, plasma cells, CD8 + T cells, CD4 + T cells, Th17 cells, macrophages and dendritic cells. Collectively, our results suggested that the MAGEA3 expression in mRNA and protein were upregulated in LUAD, and MAGEA3 could be used as a diagnostic biomarker and immunotherapy target for LUAD patients.

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.

Using interaction proteomics, we found that another Type-I MAGE, MAGE-C2, interacts with the RING ubiquitin ligase TRIM28 in a manner similar to the MAGEA4/RAD18 complex, suggesting that the MAGEA4 peptide-binding groove also serves as a ligase-binding cleft in other type-I MAGEs. Our data provide new insights into the mechanism and regulation of RAD18-mediated PCNA mono-ubiquitination.

BNT116 + DTX shows encouraging antitumor activity, consistent induction of immune responses, a manageable safety profile, and no signs of additive toxicity. Updated safety and clinical activity data will be presented along with additional biomarker data.

By applying a single-sample gene-set enrichment analysis (ssGSEA), we identified four distinct immune subtypes. Immune cell distribution suggests that the memory T cells (central and effector) and follicular helper T cells could serve as important stratification parameters.

The novel insight that cryptozoospermic patients can be divided into two subgroups will facilitate the strategic search for underlying genetic etiologies. Moreover, the shared alterations of the spermatogonial stem cell compartment between the two cryptozoospermic subgroups could represent a general response mechanism to the reduced output of sperm, which may be associated with a progressive phenotype. This study therefore offers novel approaches towards the understanding of the etiology underlying the reduced sperm formation in cryptozoospermic patients.

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

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

P1/2, N=75, Terminated, Immunocore Ltd | N=144 --> 75 | Trial completion date: Feb 2024 --> Sep 2023 | Active, not recruiting --> Terminated; The Sponsor terminated the study and there is no further enrollment. Endpoints will not be assessed for this trial.

P1, N=71, Active, not recruiting, Adaptimmune | N=52 --> 71 | Trial completion date: Sep 2035 --> Sep 2032

Of note, a comprehensive analysis revealed that a broad range of amino acid sequences of the MAGE-A4p peptide were critical for the recognition of MAGE-A4 pMHC by these CAR-T cells, and no cross-reactivity to analogous peptides was observed. Thus, MAGE-A4-targeted CAR-T therapy using this scFv antibody may be a promising and safe treatment for solid tumors.

Of 214 screened patients, 14 were treated (6, IMA101; 8, IMA101 and atezolizumab). Target-specific T cells expanded to constitute up to 78.7% of CD8+ cells. In conclusion, IMA101 was feasible and well tolerated, leveraging the potential of multi-targeted ACT that warrants further investigation.

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

Both were improved compared with either the standalone Mayo or Brock model. This multi-center prospective study indicates a panel of nine autoantibody markers that can help in the detection of lung cancer and the classification of pulmonary nodules in the Chinese population.

The positive rate of the model combined with cytokeratin 19 fragment to diagnose ESCC reached 78.0%. The study identified anti-MAGEA autoantibodies with potential diagnostic value for ESCC, which may provide new promising for the detection of the disease.

Nevertheless, adjustments to the timing, content, and format of this intervention are warranted, prior to a future feasibility/acceptability trial. This study not only provides the foundational data required to proceed with future CALM trials, but it also provides valuable considerations for those developing interventions for caregivers of PwMG largely.

AI identified CRG subgroups in pan-cancer based on CRGs-related TDGs, and 44-gene-based AI modeling is a novel tool to identify chemotherapy sensitivity in breast cancer, in which CDKN2A/MAGEA4 pathway played the most important role.

Children's Oncology Group clinical trial AHOD1331 was a randomized phase III trial for newly diagnosed high risk cHL ages ≥2 to 22 years which compared standard chemotherapy with doxorubicin, bleomycin, etoposide, prednisone and cyclophosphamide (ABVE-PC) to Bv + AVE-PC with response adapted radiation. Our results have implications for identifying immune markers of response to guide future immunotherapies and cytotoxic T cell therapy in cHL. (NCT02166463)

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.

MAGE-A4, NY-ESO-1, PRAME and KK-LC-1 are overexpressed in breast cancer, especially in TNBC. Positive expression of MAGE-A4 or PARME may be associated with prolonged DFS. A panel of CTAs is attractive universal targets for immunotherapy.

The CCT4 up-regulation and PRAME mutations were correlated with a good prognosis for ovarian cancer, while higher levels of GAGE2A and CT45A1 mRNAs were correlated with a poor prognosis for ovarian cancer patients. Thus, GAGE2, CT45, CCT4, and PRAME cancer/testis antigens can be considered as potential prognostic markers for ovarian tumors, and GAGE2, CCT4, and PRAME were revealed to be correlated with the prognosis for ovarian cancer patients for the first time.

P1/2, N=144, Active, not recruiting, Immunocore Ltd | Recruiting --> Active, not recruiting | Trial completion date: Jul 2025 --> Feb 2024 | Trial primary completion date: Jul 2025 --> Sep 2023

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 Taken together, these data demonstrate the feasibility and potential of generating optimised TCR-NK cells from PB-NK resulting in a highly potent cell product combining TCR-mediated and innate NK killing functions. Based on the potency and safety profile, ZI-MA4–1 has advanced into manufacturing with a preclinical package underway to enable a clinical trial for treatment of patients with advanced solid tumours.

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.