P1, N=95, Active, not recruiting, Immatics Biotechnologies GmbH | Recruiting --> Active, not recruiting | Trial primary completion date: Nov 2025 --> Mar 2026

P1, N=320, Recruiting, BioNTech SE | N=156 --> 320

P1, N=120, Active, not recruiting, USWM CT, LLC | Trial primary completion date: Apr 2026 --> Dec 2026

P1, N=120, Active, not recruiting, USWM CT, LLC | Trial primary completion date: Dec 2025 --> Apr 2026

This constituted only the second approval of a cell therapy in a solid tumor following lifileucel in melanoma and demonstrated the potential of cell therapies in sarcomas...However, the broader application of these therapies is hindered by the lack of targetable sarcoma-restricted immunogenic epitopes, spatiotemporal intratumoral heterogeneity, and a profoundly immunosuppressive tumor microenvironment that impedes effector-cell trafficking, expansion and persistence. While cell therapies hold promise for integration into precision medicine approaches for sarcomas, their successful implementation will require careful evaluation of clinical feasibility, logistical considerations and cost-effectiveness to optimize patient outcomes.

Lastly, TCR-NKs are not activated when co-cultured with normal cells, displaying a safe profile. Combining the innate cytotoxicity of NKs with MAGE-A4-specific targeting of an affinity-enhanced TCR, results in a potent and safe cellular product representing a promising and novel therapeutic off-the-shelf paradigm for the treatment of many solid cancers.

However, challenges remain regarding HLA restriction, tumor microenvironment resistance, manufacturing delays and cost. Future efforts should focus on broadening applicability, optimizing combinations, and ensuring equitable access.

P1/2, N=37, Completed, Baylor College of Medicine | Trial completion date: May 2027 --> Jul 2025 | Active, not recruiting --> Completed

P1, N=44, Active, not recruiting, Baylor College of Medicine | Recruiting --> Active, not recruiting

PDC∗lung01 was immunogenic and had a manageable safety profile in all cohorts and met the predefined clinical objectives when combined with anti-PD-1 in metastatic NSCLC. Median PFS was positively correlated with antigen-specific T-cell expansions.

Human leukocyte antigen (HLA)-based immunotherapeutics, such as tebentafusp-tebn and afamitresgene autoleucel, have expanded the treatment options for HLA-A*02-positive patients with rare solid tumors such as uveal melanoma, synovial sarcoma, and myxoid liposarcoma...Last, we emphasize the urgent need for further research to better understand HLA allotype heterogeneity and its influence on tumor immunopeptidome-driven immune responses. We anticipate that these strategies will accelerate the development and implementation of both personalized and broad-spectrum HLA-based immunotherapies, and will ultimately improve cancer treatment across genetically heterogeneous patient populations worldwide.

Sarcomas are promising targets for adoptive cell therapy (ACT), as shown by afami-cel's success in synovial sarcoma, but broader impact requires new target discovery, optimal cell selection, improved conditioning, combination treatments, deeper tumor microenvironment understanding, and predictive biomarkers to achieve more durable responses for more patients.