Safety Considerations With TIL Therapy

TIL (tumor-infiltrating lymphocytes) therapy, while a promising treatment for advanced melanoma, is an intensive regimen with a significant side effect profile. Here, Anuradha Krishnamurthy, MBBS, medical oncologist at Roswell Park Comprehensive Cancer Center, discusses what physicians and patients must aware of regarding the safety of these agents.

The majority of side effects associated with TIL therapy stem not from the TIL cells themselves, but from the preparatory lymphodepleting chemotherapy and the subsequent administration of interleukin-2 (IL-2), which is given to stimulate the TILs.

Severe myelosuppression is very common due to the chemotherapy, leading to thrombocytopenia, neutropenia, and anemia. Prolonged severe cytopenia require close monitoring and supportive care (e.g., growth factors like filgrastim).

Organ-specific toxicities are primarily associated with IL-2 and include cardiopulmonary complications like tachycardia, arrhythmia, hypotension, capillary leak syndrome, and respiratory distress. Renal complications like acute kidney injury, hepatic complications, gastrointestinal effects like nausea and diarrhea, and neurological effects like headaches and dizziness are also known adverse events.

TIL therapy and IL-2 administration can lead to poor general constitutional symptoms like fever, chills, fatigue, edema, rash, and hair loss.

While the TIL infusion itself is usually not painful, some patients may experience acute reactions like fever, chills, rash, or shortness of breath shortly after the infusion. These are typically short-lived and manageable.

Due to the lymphodepleting chemotherapy, patients are highly immunocompromised for weeks after TIL infusion, significantly increasing the risk of severe bacterial, viral, and fungal infections. Prophylactic antimicrobials and strict infection control measures are essential.

While most acute side effects are temporary and resolve after the patient leaves the hospital, some may linger. Close follow-up is required to monitor blood counts, organ function, and for any new or persistent adverse events. The personalized nature of TIL therapy generally means a lower risk of certain immune-related adverse events seen with other immunotherapies, such as significant cytokine release syndrome or neurotoxicity seen with CAR T-cell therapy.

IL therapy requires an extended inpatient stay (typically 2-3 weeks) in a specialized center with intensive care capabilities due to the potential for severe and rapidly evolving toxicities. Patients must be relatively fit with good organ function (heart, lung, kidney) to tolerate the demanding treatment. Elderly patients or those with multiple significant comorbidities may not be suitable candidates.

Management of TIL therapy patients requires a highly experienced multidisciplinary team, including oncologists, critical care specialists, infectious disease specialists, and specialized nursing staff. Thorough pretreatment assessment of a patient's organ function, performance status, and comorbidity profile is crucial to identify and mitigate risks. Patients and their caregivers must be thoroughly educated about the potential adverse effects, the need for close monitoring, and the importance of reporting any symptoms promptly. Finally, a comprehensive discussion of the potential benefits (durable responses in advanced melanoma) vs the significant risks and intensive nature of the treatment is paramount for informed consent.

In summary, TIL therapy is a powerful but demanding treatment. While offering significant promise, its administration necessitates a robust supportive care infrastructure and careful patient selection to manage its well characterized, but often severe, adverse event profile.