P1/2, N=0, Withdrawn, Immunocore Ltd | N=75 --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 Withdrawn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

P=N/A, N=0, Available, Adaptimmune

P1/2, N=73, Active, not recruiting, PDC*line Pharma SAS | Trial primary completion date: Dec 2025 --> Jul 2024

P1, N=0, Withdrawn, Genentech, Inc. | N=210 --> 0 | Recruiting --> Withdrawn

P1, N=30, Not yet recruiting, Marker Therapeutics, Inc.

"Thermo Fisher Scientific Inc...announced that its SeCore CDx HLA A Sequencing System has been granted 510(k) clearance by the United States Food and Drug Administration (FDA) for use as a companion diagnostic with TECELRA (afamitresgene autoleucel), Adaptimmune’s newly approved T-cell receptor (TCR) therapy 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 tumor expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. Synovial sarcoma is a rare, soft tissue cancer that most commonly impacts young adults."

"Agilent Technologies Inc...announced that it has received FDA approval for the use of MAGE-A4 IHC 1F9 pharmDx (SK032) as a diagnostic tool to aid in identifying patients with synovial sarcoma who may be eligible for treatment with TECELRA (afamitresgene autoleucel, also known as afami-cel or ADP-A2M4), a MAGE-A4-directed engineered TCR T-Cell therapy."

P1, N=44, Recruiting, Baylor College of Medicine | Trial completion date: Feb 2026 --> Feb 2027 | Trial primary completion date: Apr 2024 --> Apr 2025

P2, N=12, Active, not recruiting, Baylor College of Medicine | Trial completion date: May 2024 --> May 2025

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

P1, N=79, Recruiting, Marker Therapeutics, Inc. | N=37 --> 79

P1, N=42, Recruiting, CDR-Life AG | Not yet recruiting --> Recruiting

P1, N=42, Not yet recruiting, CDR-Life AG

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

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

P1/2, 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

P1, N=7, Completed, Immatics US, Inc. | Active, not recruiting --> Completed | N=22 --> 7 | Trial completion date: Dec 2024 --> Sep 2023

P1, N=20, Recruiting, Peking University

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

P1/2, N=73, Active, not recruiting, PDC*line Pharma SAS | Recruiting --> Active, not recruiting | Trial completion date: Sep 2025 --> Dec 2025 | Trial primary completion date: Sep 2025 --> Dec 2025

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.

P1/2, N=64, Recruiting, PDC*line Pharma SAS | Trial completion date: Aug 2024 --> Sep 2025 | Trial primary completion date: Aug 2024 --> Sep 2025

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.

Lack of response reported in another MAGE-A4 TCE trial (NCT03973333) where tumor screening in ovarian cancer was absent confirms that IHC selection will be essential for RNALOW tumors. In this regard, we have identified E7O1U as a highly specific MAGE-A4 antibody for precise IHC patient selection in the CDR404 trial.

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.

This report suggests that afami-cel in combination with LDRT safely enhanced clinical benefit. This provides evidence for further exploring the benefit of LDRT in TCR-T cell therapy.

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

P1, N=44, Recruiting, Baylor College of Medicine | Trial primary completion date: Apr 2023 --> Apr 2024

Van Tine, et al. Paper 61: CTOS 2022; Vancouver, Canada

Introduction: Affinity-enhanced T-cell receptor (TCR) T-cell therapies targeting the intracellular cancer testis antigen MAGE-A4 have shown encouraging results in adults with advanced solid cancers.1,2 Here we explore how TCR T-cell therapy manufacturing process evolution may modulate the function of ADP-A2M4CD8, the next generation counterpart of afamitresgene autoleucel (afami-cel; formerly ADP-A2M4), using single-cell RNA sequencing (scRNA-seq) and in vitro functional assessment. Whole-transcriptome, single-cell investigation of the cellular subsets produced during manufacturing of afami-cel and ADP-A2M4CD8 indicate that infusion of cells with a less cytotoxic GEP does not prevent broad anti-tumor efficacy and may correspond with beneficial characteristics. 1. Van Tine BA, et al.