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.

P2, N=12, Completed, Baylor College of Medicine | Active, not recruiting --> Completed

The FDA approval of afamitresgene autoleucel for advanced synovial sarcoma and the breakthrough designation of letetresgene autoleucel for myxoid/round cell liposarcoma signify a major turning point...Tumour infiltrating lymphocyte therapy, including lifileucel, is under investigation with checkpoint inhibitors or oncolytic agents to enhance efficacy and manage toxicity...Challenges include HLA restriction, tumour heterogeneity, and manufacturing complexity. Future strategies involving novel antigens, multi-targeting, and combinatorial regimens could broaden patient eligibility and improve therapeutic outcomes.

This represents the first FDA approval of a T-cell receptor gene therapy. It is also the first FDA approval specifically for SS, representing a new treatment modality for this rare population who lack effective therapies.

Clinically, these therapies highlight the need for improved patient selection criteria, and optimized antigen targeting. Toxicity management must also be taken into account, as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) can be severe. Further studies should focus on improving safety and T cell persistence, and refining manufacturing processes to increase accessibility and scalability.

Engineered TCRs, particularly those targeting MAGE-A4 and NY-ESO-1, have shown promising clinical results in synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS), leading to the recent FDA approval of afamitresgene autoleucel (afami-cel) and letetresgene autoleucel (lete-cel)...Future research will focus on optimizing lymphodepleting regimens, mitigating toxicity, enhancing in vivo persistence, and combining ACT with other therapeutic agents. As clinical trials expand, ACT holds the potential to revolutionize sarcoma treatment by offering durable, targeted therapies for previously refractory disease.

P1, N=120, Active, not recruiting, Adaptimmune | Recruiting --> Active, not recruiting

P1, N=95, Recruiting, Immatics Biotechnologies GmbH | N=50 --> 95 | Trial completion date: Nov 2027 --> Dec 2029