Expanding Cellular Therapy for Solid Tumors

Cellular therapies are now a firmly established standard of care for the treatment of hematologic malignancies including B-cell lymphomas and multiple myeloma.Progress in developing cell therapy for solid tumors has been slower-limited by several factors including target antigen selection, tumor heterogeneity, and a complex tumor microenvironment.Despite these challenges, two solid tumor cellular therapies have recently demonstrated clinical benefit and achieved accelerated US Food and Drug Administration (FDA) approval-lifileucel for melanoma 1 and afamitresgene autoleucel (afami-cel) for synovial sarcoma. 2 In addition to these approvals, several novel cellular therapies show promise in early phase clinical trials.These advancements set the stage for expansion of cellular therapy options to multiple tumor types and a much larger patient population.Lessons from the chimeric antigen receptor (CAR)-T experience in malignant hematology will inform many practice-level aspects that affect the care delivery of solid tumor cellular therapies.In the article that accompanies this editorial, Maiocco et al 3 provide a comprehensive overview of solid tumor cell therapies currently in clinical practice or in development, with a particular focus on aspects of care delivery required to manage unique toxicity profiles. Types of Cell Therapy Tumor-Infiltrating LymphocytesTumor-infiltrating lymphocyte (TIL) therapy involves the resection or harvest of tumor tissue.Tumor fragments are then cultured with cytokines in a GMP facility to expand and generate a polyclonal T-cell product.In a successful product, a portion of T cells are tumor-reactive based on their proximity to tumor cells in the microenvironment although the exact antigen specificity of the T-cell product is unknown.The full TIL therapy regimen also includes lymphodepleting chemotherapy and intravenous IL2.In a single-arm phase II trial, the TIL product lifileucel demonstrated a 31.4% response rate in PD-1-refractory melanoma.In this population with limited therapy options, responses were durable, with 19.7% of patients remaining alive at 5 years. 1 A second TIL product developed by the Netherlands Cancer Institute was shown in a randomized phase III trial to have a progression-free survival (PFS) and quality-of-life benefit over ipilimumab monotherapy for anti-PD-1-refractory melanoma. 4Novel forms of TIL therapy are currently in early phase clinical trials, including OBX-115, a TIL product engineered with a membrane-bound IL15 (ClinicalTrials.govidentifier: NCT06060613) and IOV-4001, a PD-1 knockout TIL therapy (ClinicalTrials.govidentifier: NCT05361174).Lifileucel is also being studied for other tumor types including non-small cell lung cancer (ClinicalTrials.govidentifier: NCT04614103). T-Cell Receptor TherapyFor autologous T-cell receptor (TCR) therapies, a patient's peripheral blood T cells are collected through apheresis and then engineered to express a TCR that targets a tumor antigen.TCR therapies recognize specific peptides that are presented by tumors on major histocompatibility complex (MHC) molecules, leading to highly specific binding.In 2024, afami-cel was granted accelerated approval for treatment of MAGE-A4-positive synovial sarcoma in patients who have the human leukocyte antigen (HLA)-A*02:01P, A*02:02P, A*02:03P, or A*02:06P genotype.This was based on a phase I trial for treatment-refractory synovial sarcoma, where afami-cel demonstrated a 39% response rate with a median duration of response of 11.6 months. 2 A second TCR, IMA203, targets the cancer testis antigen PRAME and has shown promising results in early phase trials. 5It is now being evaluated in a registration-intent randomized phase III trial for anti-PD-1 refractory melanoma (ClinicalTrials.gov