Tecelra (afamitresgene autoleucel)

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.

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.

Pediatric STS are rare and biologically heterogeneous. Genomic advances have refined risk stratification and uncovered therapeutic targets; further progress relies on international collaboration and trials.

For solid cancers, these comprise the antibody-drug-conjugate Mirvetuximab Soravtansine for platinum-resistant ovarian cancer, the monoclonal antibody Zolbetuximab for Claudin-18.2 positive gastric adenocarcinoma and the checkpoint inhibitor Tislelizumab for esophageal squamous cell carcinoma. For the treatment of relapsed or refractory hematologic B cell malignancies, the use of bispecific T cell engaging antibodies like the BCMA-CD3 targeting Teclistamab and CD20-CD3 targeting Glofitamab were approved by the EMA recently.Combinatorial approaches of conventional chemotherapy and checkpoint inhibitors for the treatment of cholangiocarcinoma, urothelial carcinoma and endometrial carcinoma received recent approval.A CD38 antibody-based bridging therapy for the treatment of newly diagnosed multiple myeloma and the Glofitamab-based approach in combination with Gemcitabine and Oxaliplatin for relapsed DLBCL are the latest additions for hematologic malignancies after promising clinical trials.The first T cell products for the treatment of solid cancers using either tumor-infiltrating lymphocytes or TCR-engineered peripheral blood T cells were approved by the FDA in 2024, for the treatment of advanced melanoma (Lifileucel) and synovial sarcoma (Afamitresgene autoleucel). To further expand the success of T cell products to solid tumors, promising preclinical studies suggest solutions to main obstacles, such as modular CAR T cells, targeting of two antigens simultaneously or generation of cytokine-secreting 4th generation CAR T cells.

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.

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.

In this review, we discuss the landmark data that led to the commercialization of four novel FDA-approved T-cell-based therapeutics in solid malignancies, including tarlatamab for small cell lung cancer, afamitresgene autoleucel for synovial sarcoma, lifileucel for metastatic melanoma, and tebentafusp for metastatic uveal melanoma...Some solutions include addressing on-target, off-tumor toxicity; improving the manufacturing of CARs; optimizing the tissue-specific tumor microenvironment by combating immune desert tumors; and discovering natural tumor neoantigens and non-self-epitopes generated by tumor-specific mutations. These concepts can help provide transformative benefits for patients with solid malignancies in the coming years.

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