Tumor-Infiltrating Lymphocyte Therapy for Melanoma: Nursing Considerations

Abstract

Clinicians have used commercially available cellular therapy to treat hematologic malignancies since 2017. In February 2024, the U.S. Food and Drug Administration approved the first commercial cellular therapy—lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy—for the treatment of a solid tumor cancer, melanoma. This article reviews specific patient and caregiver teaching, as well as nursing considerations, in the coordination and administration of TIL therapy.

AT A GLANCE

• ■ Cellular therapy for melanoma includes specific nurse coordination among oncology, surgery, cellular therapy, and pharmaceutical teams.

• ■ There are special considerations for interleukin-2 administration and patient and caregiver education throughout TIL therapy.

• ■ The interprofessional team supports patients and caregivers through the often complicated TIL care journey.

On February 16, 2024, the U.S. Food and Drug Administration approved the first cellular therapy, lifileucel, for the “[t]reatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor” (U.S. Food and Drug Administration, 2024, para. 1). Lifileucil, a tumor-infiltrating lymphocyte (TIL) therapy, uses T cells from a patient’s surgically resected melanoma tumor, which is sent to a manufacturing facility. The T cells are separated from the tumor and multiplied into billions, creating an infusible, patient-specific product that is then shipped back to the treating hospital and infused into the patient after they receive lymphodepleting chemotherapy. Clinical trials have shown that as many as one-third of patients treated with lifileucel had at least some reduction in the size of their tumors (Phillips, 2024). Cancer centers considering offering this therapeutic option to patients must examine whether they have the resources to become authorized treatment centers (ATCs). An ATC often includes preexisting relationships with a cellular therapy laboratory and a surgical team, as well as physicians and nurses who care for patients receiving cellular therapies.

Patient Journey

Patient Identification

The patient journey begins with a referral to an ATC through an interprofessional approach typically involving a medical oncologist, surgeon, and cellular therapy nurse coordinator or cellular therapy physician to ensure proper patient identification and selection (Warner et al., 2024).

Patient referrals are screened to meet the following requirements prior to initial consultation with a medical oncologist. Patients referred to ATCs for TIL need to have advanced disease without brain metastasis that has progressed on prior lines of therapy including a programmed cell death-ligand 1 inhibitor, or if BRAF variant–positive, a BRAF inhibitor with or without a MEK inhibitor. Eligible patients have a 1.5–4 cm tumor, which is required for TIL production (Mullinax et al., 2022). Last, eligible patients must have an Eastern Cooperative Oncology Group Performance Status Scale score of less than or equal to 1 and can wait the time it takes to manufacture the TIL.

Patient Selection and Eligibility

Following patient identification, potential candidates see a medical oncologist or cellular therapy physician for an initial consultation. In tandem, patients visit a surgeon. Although TIL therapy is initiated with the tumor, to ensure a successful TIL yield, a surgeon evaluates the patient to ensure there is an optimal tumor resection site, preferably for a minimally invasive procedure (Mullinax et al., 2022).

Because of the toxicities associated with TIL therapy, following initial consultation, patients who can proceed obtain clearance, which may include an echocardiogram, a pulmonary function test, laboratory tests, and a cardiac stress test. The ideal candidate has (a) adequate renal function (glomerular filtration rate of greater than or equal to 40 ml/minute), (b) optimal cardiac reserve (left ventricular ejection fraction greater than 45%), and (c) pulmonary reserve (forced expiratory volume in 1 second/forced vital capacity greater than 70% or forced expiratory volume in 1 second greater than 50% of predicted normal) (Mullinax et al., 2022). In addition to medical clearance, a social worker evaluates patients to assess adequate caregiver support before, during, and following treatment, particularly if patients live more than a one-hour drive from the ATC. It may be helpful for the nurse coordinator to review the entire TIL therapy journey with patients at the initial consultation to help them plan ahead (see Figure 1).

FIGURE 1.

PATIENT JOURNEY THROUGH TUMOR-INFILTRATING LYMPHOCYTE THERAPY

MD—medical doctor

Precertification and Surgery

Following medical clearance and testing and prior to surgery, the hospital finance team authorizes treatment with TIL therapy. Some insurance plans require a single-case agreement in addition to an authorization, which can lengthen the waiting period. Because authorization times from each insurance may vary, it is imperative that the chosen candidate is able to wait for the surgery, manufacturing, and infusion of TIL.

As soon as the ATC secures authorization, the site selects a surgery date to match an available manufacturer date for tumor tissue procurement. On the day of surgery, the clinical team places the tumor tissue in a sterile medium, packages it, and ships it to the manufacturer via a courier. TIL manufacturing takes about five weeks from the time of surgery to the time of infusion.

Lymphodepletion

Prior to TIL product delivery, the medical oncologist evaluates the patient for final clearance, ensuring that they are still a suitable candidate for treatment. After the medical oncologist clears the patient, the manufacturer delivers the final TIL product to the ATC prior to the start of lymphodepleting chemotherapy.

The patient receives nonmyeloablative lymphodepletion with cyclophosphamide and fludarabine for seven days through a dual or triple lumen tunneled central venous catheter or a peripherally inserted central catheter inserted prior to or at the time of hospital admission for lymphodepletion (Warner et al., 2024). Lymphodepleting chemotherapy can occur in an inpatient or outpatient setting, depending on provider recommendation.

Infusion of TIL

Infusion of TIL therapy is often initiated 24 hours after the last dose of nonmyeloablative lymphodepleting chemotherapy. However, the infusion can be administered later per provider recommendation to allow time for recovery from toxicities related to lymphodepletion. About 3–24 hours after TIL infusion completion, the nurse administers the initial dose of interleukin-2 (IL-2) and a maximum of six IL-2 doses every 8–12 hours afterward.

Discharge

The day after TIL infusion, patients receive granulocyte–colony-stimulating factor to reduce the incidence of myelosuppression and infections and to help shorten hospitalization. Per Warner et al. (2024), patients may be discharged once laboratory parameters are met (including an absolute neutrophil count greater than 500 and a platelet count greater than 20,000 per microliter). In addition, patients should be able to safely perform activities of daily living, and the clinical team should be able to manage any ongoing patient symptoms in the outpatient environment. After TIL infusion, patients should stay within 30–50 miles of the ATC for 30 days for care management (Warner et al., 2024).

Nursing Considerations

Lymphodepleting Chemotherapy

The lymphodepletion schedule is as follows: cyclophosphamide 60 mg/kg IV daily for two days, followed by fludarabine 25 mg/m² IV daily for five days (Iovance Biotherapeutics, 2024a). To minimize known adverse events associated with lymphodepleting chemotherapy, nurses need to ensure timely administration of premedications. Premedications are ordered prophylactically to start day 1 of treatment (i.e., antiemetic medication, antibiotics, IV fluid hydration, mesna), and in the event of the onset of an adverse event, clinicians can administer these same medications as therapeutic treatment (Warner et al., 2024). Corticosteroids are known to interfere with the activity of lifileucel (Warner et al., 2024); as a result, most institutions avoid corticosteroid administration before and during the seven-day lymphodepleting chemotherapy regimen.

Cytopenias (e.g., thrombocytopenia, lymphocytopenia, neutropenia) are common adverse events associated with lymphodepleting chemotherapy regimens (Olsen et al., 2023). They are likely present during TIL therapy infusion and may remain problematic for weeks. If the patient requires blood product support, only irradiated blood products should be used (Warner et al., 2024). Granulocyte–colony-stimulating factor is a viable option to support neutrophil recovery starting the day TIL therapy infusion is completed (Warner et al., 2024). Infections, as well as renal, bladder, and gastrointestinal organ toxicities, also are common adverse events experienced by patients (Olsen et al., 2023). As a result, the nurse’s ability to recognize signs and symptoms of an infection; persistently monitor the patient’s vital signs, laboratory values, and urine output; and promptly report abnormalities and/or changes from baseline to the healthcare team is consequential for improved patient outcomes.

Administration of Lifileucel

Lifileucel TIL therapy is a one-time infusion requiring administration in the inpatient setting because life-supporting measures may be necessary, particularly considering the subsequent IL-2 administration (Iovance Biotherapeutics, 2024b). Hospital admission should be coordinated so that lifileucel is administered 24 hours after the patient’s final dose of fludarabine. If the healthcare team deems it necessary to allow time for the patient to recover from a concerning adverse event associated with lymphodepleting chemotherapy, TIL therapy can be delayed for as many as four days (Warner et al., 2024). As part of the healthcare team, nurses participate in the collection of baseline patient data prior to the start of therapy, which includes a physical examination with weight, pregnancy status (for those of childbearing potential), two x-ray views of the chest, vital signs, and laboratory tests (Warner et al., 2024).

Manufacturers may place a complete dose of lifileucel in as many as four infusion bags, each containing 100–125 ml of TIL, and deliver it to the ATC cryopreserved in metal cassettes requiring thawing prior to administration (U.S. Food and Drug Administration, 2024). The nurse tracks the timing of premedications and the thawing of the single or first infusion bag (when there is more than one) because they must administer acetaminophen and diphenhydramine 30–60 minutes prior to the start of the infusion. Lifileucel takes about 10 minutes to thaw to room temperature, and the nurse completes the infusion within three hours of thawing. If the nurse needs to administer more than one bag of lifileucel, they monitor the current infusion and plan the thawing of each subsequent infusion bag. Matching patient identifiers on patient armbands, metal cassettes, and infusion bag(s) prior to administration is vital for patient safety (Iovance Biotherapeutics, 2024b). Nurses administer IV lifileucel using tubing primed with normal saline, without a leukocyte-depleting filter, at an initial rate of 1 ml per minute for the first five minutes, then 5–10 ml per minute until all bags have been infused. After infusing the complete dose, the nurse flushes the tubing with normal saline at the same rate of the lifileucel infusion until the patient has received all of the therapy (Iovance Biotherapeutics, 2024b).

Administration of IL-2

The purpose of administering IL-2 is to further support the expansion and activity of the TIL cells post–TIL administration (Kwong & Yang, 2024). As a result, as soon as lifileucel infusion is complete, the patient receives the first dose of IL-2 within 3–24 hours, unless the patient experiences an untoward reaction from the lymphodepleting chemotherapy or lifileucel, such as a severe hypersensitivity reaction, sepsis of any etiology (including neutropenic sepsis), or unresolved fluid weight gain that warrants a delay or decision to withhold IL-2 (Warner et al., 2024). Although the standard IL-2 treatment plan includes one IL-2 dose every 8–12 hours up to six doses, this may not be attainable because of the severe, life-threatening adverse events associated with IL-2 (see Table 1). Nurses should take the initial IL-2 dose administration time into consideration. For instance, with the onset of chills, rigors, and/or fever occurring shortly after initiating the first IL-2 dose, careful nursing assessments, monitoring, and one-on-one patient care may be warranted. Warner et al. (2024) recommend that clinical teams administer IL-2 on a 0800, 1600, 2400 schedule, administering the initial dose at 1600.

TABLE 1.

ADVERSE EVENTS AND MANAGEMENT OF IL-2

ADVERSE EVENT	MANAGEMENT
Cardiac arrhythmias	Telemetry monitoring from the time of tumor-infiltrating lymphocyte infusion to at least 24 hours after the last IL-2 dose; maintain target blood pressure, and manage fever; medical conversion as needed; echocardiogram if tachycardic for more than 2 hours
Chills, rigors, and/or fevers	Monitor vital signs at baseline and every 4 hours; prophylactic treatment with acetaminophen and nonsteroidal anti-inflammatory drugs 30–60 minutes prior to infusion and then as needed for chills or fever; manage rigors with parenteral meperidine or morphine.
Confusion	Neurologic assessments every 8 hours; antipsychotic drugs as needed in cases of progressive neurologic symptoms
Diarrhea	Administration of antidiarrheal medications as needed
Dyspnea or hypoxia	Monitor oxygen saturation via pulse oximetry every 4 hours; maintain oxygen saturation greater than 92%–95%; oxygen therapy 2–4 L via nasal cannulae, increasing fraction of inspired oxygen up to 35% via a non-rebreather mask, if needed; administer sedative, diuretic, and bronchodialator as needed; monitor bicarbonate.
Edema or capillary leak	Monitor daily weight and rate of weight increase; diuretics may be required and administered more than 24 hours after IL-2 has been completed.
Hypotension	Maintain established target blood pressure; administer maintenance fluid infusions 5–125 ml per hour or 200–250 ml fluid boluses with caution, monitoring for pulmonary edema; may potentially administer a vasopressor instead of fluid infusion; monitor blood pressure every 2 hours if vasopressors are administered; antihypertensives should be discontinued prior to therapy.
Laboratory value abnormalities	Obtain complete blood count with differential, comprehensive metabolic panel, and blood chemistry before each dose.
Nausea or vomiting	Prophylactic and as-needed administration of antiemetic medications
Oliguria	Obtain baseline serum creatinine and monitor twice per day during treatment; monitor strict urine output before and after each dose; maintain urine output of at least 0.5 ml/kg per hour; administer fluid bolus with an output of less than 50–100 cc/8 hours; obtain daily weights; discontinue use of nonsteroidal anti-inflammatory drugs.
Rash	Apply emollient lotions and creams; oatmeal baths as needed; administer antihistamine as needed.

IL-2—interleukin-2

Note. Based on information from Dutcher et al., 2014; Warner et al., 2024.

Patients receiving cellular therapy products should have a designated home caregiver post–hospital discharge. If a patient is unable to identify a caregiver during the initial consultation, the hospital may not recommend TIL/lifileucel therapy or may work to identify a suitable alternative. The ATC team starts the patient and caregiver education during the initial consultation with the medical oncologist or cellular therapy physician evaluating the patient for therapy. The outpatient cellular therapy nurse coordinator usually provides this education, and the inpatient cellular therapy nurse reinforces it during the patient’s admission.

Many hospitals run a weekly class that patients and their identified caregivers are required to attend. The designated time required for caregiving support for cellular therapy products is hospital specific and typically ranges from one to two weeks postdischarge. The identified caregiver must live with the patient during this time and be available to assist with cooking, managing medication, cleaning, and transporting to appointments 24-7 for as many as two weeks. The patient may experience residual side effects from lifileucel or IL-2 and is discouraged from driving for a few weeks after discharge.

Caregiver education often includes what to expect after a patient who has received lifileucel returns home. Home chemotherapy precautions are discussed if the patient will be receiving any chemotherapy in the outpatient setting and returning home in the evenings. ATCs typically require patients to remain close to the hospital for the first two weeks after discharge in case they need to be readmitted for complications. Many hospitals educate caregivers on how to monitor temperature and blood pressure, prevent infections (e.g., hand hygiene, good food preparation practices), and encourage caregivers to be emotionally supportive to patients. The hospital provides a 24-7 telephone number to call if certain side effects like fever, nausea/vomiting, diarrhea, fainting, falling, burning while urinating, or neurologic changes develop at home.

Conclusion

Lifileucel is a first-of-its-kind cellular therapy for the treatment of melanoma, a solid tumor cancer. The unique coordination needs with this therapy, including surgical scheduling, working with the manufacturer, and monitoring the patient during administration and subsequent IL-2 doses, pose a challenge for nurses who are unfamiliar with previously approved cellular therapies (such as chimeric antigen receptor T-cell therapy for hematologic malignancies). Often, hospitals designate separate floors for treating solid tumor and hematologic malignancies; however, with treatments becoming more personalized and using patient-specific components, a shift in the treatment landscape is occurring, creating a need for specialized coordination.

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Consider how you can apply findings from this article to your own practice using the following questions:

• ■ What strategies can be implemented to support patients and caregivers through the complex tumor-infiltrating lymphocyte care journey, particularly in terms of education and coordination of care?

• ■ What resources and infrastructure are necessary for your institution to become an authorized treatment center for tumor-infiltrating lymphocyte therapy, and how can you address potential challenges in obtaining these resources?