HosTIL territory: mapping the landscape of toxicity in TIL therapy

Autologous tumor-infiltrating lymphocyte (TIL) therapy has recently been approved by the US Food and Drug Administration and Health Canada for the management of patients with advanced melanoma refractory to first-line immune checkpoint inhibitors, with regulatory assessments underway in other jurisdictions. TIL therapy typically involves a multistep process including surgical tumor resection, non-myeloablative lymphodepletion, infusion of autologous polyclonal T cells, and administration of high-dose interleukin-2 (HD-IL-2). Toxicities are predominantly associated with the induction chemotherapy regimen and post-TIL infusion HD-IL-2, rather than the TIL product itself. Over half of treated patients experience cytopenias, pyrexia, rigors, and gastrointestinal symptoms, with additional toxicities including acute kidney injury, rash, peripheral neuropathy, diarrhea, alopecia, and hypotension. Severe but less frequent adverse events include neutropenic sepsis, cytokine release syndrome, capillary leak syndrome, neurotoxicity, autoimmune sequelae, and cardiac dysfunction. These toxicities typically occur in a predictable temporal window and resolve within 10-12 days post-TIL infusion. Despite this, management often requires rigorous supportive care, and thus, toxicity remains a barrier to broader patient eligibility and wider implementation. Currently, no validated biomarkers exist to predict toxicity risk, underscoring the need for further research. This is particularly critical in the context of emerging combinatorial approaches integrating TIL therapy with other immunomodulatory agents, which may compound toxicity and complicate clinical management.