How Do Tumor Infiltrating Lymphocytes Work?

Tumor infiltrating lymphocytes (TILs) are a biological product used in the treatment of solid tumors. Lymphocyte is a type of immune cell, and TILs are lymphocytes that penetrate the tumor microenvironment, identify the tumor cells by their unique proteins (antigens), mount an immune response and kill them. 

Lymphocytes are immune cells that are part of the body’s adaptive immune system which is responsible for regulation of immune response, antibody production and killing of tumor cells and virus-infected cells. Lymphocytes are of three main types, including T-cells, B-cells and natural killer cells.

Although tumor infiltrating lymphocytes can identify and kill tumor cells, active lymphocytes are not usually present in adequate quantity to effectively kill all of the tumor cells and overcome the tumor. Tumor infiltrating lymphocyte therapy is used to enhance the number and activity of natural TILs.

TIL therapy involves the removal of tumor tissue from the patient and extraction of lymphocytes that have infiltrated the tumor and have activity against tumor. The TILs are then grown in large numbers in the lab with the use of interleukin-2, a natural human protein that promotes rapid growth of TILs.

After multiplication of the lymphocytes in sufficient numbers, which may take 6 to 8 weeks, the TILs are washed, formulated as a suspension and frozen. The TILs are thawed before intravenous administration to the same patient from whose tumor the TILs were extracted. One patient’s TILs must not be used for other patients.

TILs are administered as an intravenous infusion along with interleukin-2. Interleukin-2 aids the rapid growth of TILs inside the body, which migrate to the tumor sites, penetrate the tumor microenvironment, specifically recognize the tumor-associated antigens and initiate death of the tumor cells.

TIL therapy may be more effective than other immunotherapies because TILs are better able to recognize tumor cells since they are from the tumor tissue. TILs also carry less risks for severe reactions and blood-borne diseases since they are from the patient’s own tissue (autologous product).

TIL therapy, however, has certain drawbacks. It requires surgery to remove the tumor, which may not be resectable or may be risky in some patients. In addition, TIL therapy involves a long waiting period of 6 to 8 weeks, and patients with rapidly progressing tumors may not be able to benefit from the treatment.

TIL therapy, at present, is only used as a second-line treatment. Unlike most other cancer treatments, TIL therapy is generally a one-time treatment with long-lasting effects. Occasionally, TIL therapy may be administered a second time in patients who have benefited from the treatment and require it again.

Currently, the first and only TIL product to be approved by the FDA is lifileucel for the treatment of unresectable or metastatic melanoma skin cancer. TILs are undergoing clinical trials for use in the treatment of other solid tumors including breast cancer, ovarian cancer, cervical cancer, head and neck cancers, lung cancer and genitourinary cancers.

Tumor infiltrating lymphocytes are approved by the FDA to treat unresectable or metastatic melanoma in adult patients who have been previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.

Tumor infiltrating lymphocytes are administered intravenously in combination with interleukin-2 (aldesleukin). TILs are administered as soon as possible after 24 hours after completion of pretreatment with lymphodepleting chemotherapy regimen of cyclophosphamide for 2 days followed by fludarabine for 7 days.

Common side effects of tumor infiltrating lymphocyte therapy include the following:

• Blood count abnormalities including:
• Low count of platelets (thrombocytopenia)
• Low neutrophil count (neutropenia)
• Low red blood cell count (anemia)
• Low white blood cell count (leukopenia)
• Low lymphocyte count (lymphopenia)
• Low phosphate level in blood (hypophosphatemia)
• Chills
• High body temperature (pyrexia)
• Neutropenia-associated fever (febrile neutropenia)
• Fatigue
• Swelling from fluid accumulation (edema)
• Nausea
• Vomiting
• Diarrhea
• Reduced appetite
• Rapid heart rate (tachycardia)
• Low blood pressure (hypotension)
• Capillary leak syndrome
• High blood pressure (hypertension)
• Rash
• Hair loss (alopecia)
• Itching (pruritus)
• Loss of skin pigment (vitiligo)
• Shortness of breath (dyspnea)
• Low tissue oxygen saturation (hypoxia)
• Head ache
• Brain damage (encephalopathy)
• Acute kidney injury
• Blood in urine (hematuria)
• Increase in weight
• Infections with specified pathogen
• Infections with unspecified pathogen
• Infusion-related reaction
• Hypersensitivity reactions
• Severe allergic reaction (anaphylaxis)
• Cytokine-release syndrome
• Eye disorders including:
• Inflammation of uvea (uveitis)
• Retinal detachment
• Retinal hemorrhage
• Vision impairment
• Blurred vision
• Reduced visual acuity
• Swelling around the eye (periorbital edema)

Serious side effects of tumor infiltrating lymphocyte therapy include:

• Acute respiratory failure
• Acute kidney failure
• Severe infections including:
• Sepsis
• Septic shock
• Pneumonia
• Brain inflammation (encephalitis)
• Irregular heart rhythm (cardiac arrhythmia)
• Internal organ hemorrhage
• Bone marrow failure
• Prolonged severe low blood cell count (cytopenia)
• Liver injury
• Fluid collection in the abdomen (ascites)
• Death

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of tumor infiltrating lymphocytes include:

• Amtagvi
• lifileucel