CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 21, 2023
Expiration: March 20, 2024
In this module, Amod A. Sarnaik, MD, FACS, discusses current information on tumor-infiltrating lymphocyte (TIL) therapy for metastatic melanoma.
Please note that the key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be downloaded here or by clicking on any of the slide thumbnails in the module alongside the expert commentary.
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The first treatment to gain regulatory approval for metastatic melanoma was dacarbazine, a form of chemotherapy, in 1975. This drug was associated with a relatively low overall response rate of approximately 15% and rarely was durable beyond a few months because of development of tumor resistance, a common phenomenon associated with chemotherapy.1 However, a small number of patients did have durable responses lasting for years—sometimes even decades—providing the first clue that unresectable metastatic melanoma could be cured.
More than 2 decades elapsed before approval of another agent, interleukin-2 (IL-2), which is believed to act by inducing T-lymphocyte proliferation, a component of cellular immunity thought to be important for antitumor immunity.1 IL-2 treatment requires dosing up to tolerance as an inpatient, with a very narrow window separating achievement of therapeutic value from unacceptable toxicity.
The past 12 years have seen a rapid succession of new drug approvals, including targeted inhibitor therapies and immunotherapies. Despite this progress, approximately one half of patients with metastatic melanoma will die of their disease within 5 years.2 Adoptive cellular therapy with TILs represents an alternative emerging treatment strategy for metastatic melanoma and potentially other cancer histologies.3
One characteristic distinguishing melanoma from other cancers is its high mutational burden.4 Melanoma commonly arises in sun exposed skin that has sustained DNA mutational damage from UV radiation.5,6 These mutations result in changes to tumor protein sequences involved in immune self vs foreign recognition and create a target rich environment. T-cells that invade the tumor are referred to as TILs. Direct and indirect evidence suggests that TILs are beneficial. First, infiltration of primary melanoma tumors by TILs is associated with improved survival.7 Second, metastatic melanoma of unknown primary origin—where TILs have presumably destroyed the primary tumor—is associated with improved survival compared with known primary melanoma.8 Finally, response to immunotherapy is associated with the level of T cell infiltrate.9
Procedures involved in TIL therapy are seen in this figure, beginning with a patient who presents with metastatic melanoma unable to be completely cured with surgical resection.10 TILs are isolated from a fragment of the resected tumor and expanded in culture. Often, a tumor cell line separately derived from a small portion of the resected tumor can be used as a tumor target to validate the function of these TILs. Cultured TILs typically further undergo a rapid expansion protocol that results in proliferation of tens of billions of TILs. TILs are then assessed for properties associated with tumor response, and the most desirable are pooled into a product for infusion.
Before infusion, patients undergo preparative nonmyeloablative chemotherapy thought to be critical for TIL therapeutic function. After TIL infusion, patients receive an attenuated course of IL-2, resulting in fewer adverse events (AEs) compared with the historical use of IL-2 as stand-alone therapy. Of note, the total manufacturing time from tumor resection to TIL infusion can range from 3-8 weeks or longer.
It is helpful to compare TIL therapy with other forms of cellular therapy that you already may be aware of, such as chimeric antigen receptor (CAR) T-cell therapy. TIL therapy requires surgical resection of an autologous tumor sample, preparative lymphodepleting chemotherapy, and postinfusion IL-2 therapy. The TIL cellular product is polyclonal, and the targets of therapy are not defined.11,12
By contrast, transgenic T cell receptor (TCR) and CAR T-cell therapies require patient leukapheresis to recover peripheral blood mononuclear cells, followed by viral-mediated introduction of a transgene.11,13,14 The TCR transgene targets a specific cytoplasmic or extracellular tumor protein and must be matched to the human leukocyte antigen background of the patient. Lymphodepletion is required, and some protocols include IL-2 therapy. In CAR T-cell therapy, the CAR transgene targets cell-surface proteins, and CAR T-cells are not restricted by human leukocyte antigen matching. As with TIL and TCR therapy, lymphodepleting chemotherapy is required, but few protocols use IL-2.
All 3 cellular therapies described share the AEs associated with lymphodepleting chemotherapy, which commonly include fatigue, myelofibrosis, neuropathy, and cytopenias.11,12,15 In addition, TIL therapy involves potential AEs related to surgery, and postinfusion IL-2 is associated with risk of shaking rigors, cardiopulmonary insufficiency (eg, hypotension and hypoxemia), and the real possibility of multiorgan failure, especially renal failure.16 Fortunately, instances of multisystem organ failure tend to be transient and reversible with appropriate supportive measures.
On-target off-tumor toxicities—where infused cells react to normal cells of the body in addition to attacking tumor cells—are rare with TILs but possible with TCR and CAR T-cell therapies.11,13 Additional AEs observed with CAR T-cell therapy include cytokine-release syndrome, in which cytokines released by endogenous immune cells can cause life threatening low blood pressure and possibly multisystem organ dysfunction,11,14 and immune effector cell‒associated neurotoxicity syndrome, which occurs when CAR T-cells attack the nervous system cells, causing serious or even fatal neurotoxicity.15
The lymphodepletion regimen typically employed for cellular therapy comprises cyclophosphamide and fludarabine.11,17 The reasons lymphodepletion is required for effective cell transfer are not fully understood, but several mechanisms have been proposed. Depletion of immunoinhibitory cell populations such as regulatory T-cells and myeloid derived suppressor cells may play a role. Normal circulating immune cells act as a cytokine sink, and their depletion enhances bioavailability for the cellular product by removing endogenous competition for propagation and engraftment. Finally, chemotherapy depletes mucosal immune cells and disrupts the gastrointestinal blood barrier, activating toll like receptors and other factors that may improve function of the infused cells.
Escalating the intensity of the lymphodepletion, principally by adding total body irradiation, increases toxicity but not therapeutic efficacy.18
Researchers at the National Cancer Institute examined the effect of escalated-intensity lymphodepletion on TIL therapy outcomes by adding total body irradiation to the chemotherapy protocol in a randomized trial.18 Intensifying lymphodepletion did not improve either progression-free survival (PFS) or overall survival. However, increased AEs associated with total body irradiation were seen, including substantially higher incidences of thrombotic microangiopathy, ICU transfer, and cytokine related symptoms. Although some retrospective institutional data previously had suggested that total body irradiation was beneficial, this randomized, controlled trial refuted that premise and ended the use of total body irradiation with TIL cell therapy.19,20
This photograph from my own practice demonstrates rapid response of a SC metastasis from baseline to 8 days after infusion. Although response kinetics are variable between patients, this example shows that it is possible to see dramatic tumor response within days.
The pretreatment CT scan on the left shows a visceral tumor (circled in red) abutting the liver anteriorly, the pancreas posteriorly, and the stomach to the patient’s left.21 TILs were generated from a separate subcutaneous tumor site. Following TIL therapy, a complete radiographic response was observed that has lasted beyond 5 years, as seen in the posttreatment scan on the right. This example demonstrates that TILs harvested from 1 site can home to and mediate tumor response at other metastatic sites.
Even relatively large tumors may show excellent responses. In another case from my practice, this tumor on the bottom of a patient’s foot was significantly disabling, impairing the patient’s ability to walk, and was associated with such significant pain that the patient requested a palliative amputation. Instead, the patient received TILs harvested from a subcutaneous site and experienced a complete response lasting beyond 5 years. This patient also had lung metastases that responded to therapy, again demonstrating that TILs harvested from 1 site can home to various sites of disease. This case exemplifies the improved quality of life that TILs can offer to patients. Palliative amputation for metastatic melanoma is rarely performed, but in this case it was considered before the need was obviated by the use of TIL therapy.
These key clinical data show survival after TIL therapy at 2 different institutions: the National Cancer Institute and Moffitt Cancer Center.19 Of note, both curves exhibit the plateau commonly associated with immunotherapy, with survival at each institution now extending beyond 10 years. As mentioned earlier, TIL therapy was pioneered at the National Cancer Institute, but these data demonstrate that the treatment can be performed with similar outcomes at other institutions.
Data on TIL therapy has been reported recently from 2 larger studies. The randomized, controlled phase III M14TIL trial was conducted at 2 European centers.22 Patients enrolled on the trial had unresectable metastatic melanoma, were not heavily pretreated (≤1 line of previous therapy) and had good performance status. Patients were randomized 1:1 to receive either TIL therapy or ipilimumab immunotherapy and were stratified for known prognostic factors. The protocol involved metastasectomy for TIL production. Prior to infusion, patients were admitted to the hospital for lymphodepletion chemotherapy, a single infusion of TILs, and postinfusion IL-2 up to 15 doses. Patients in the ipilimumab arm received a maximum of 4 doses at 3 mg/kg IV every 3 weeks. The primary endpoint was PFS by RECIST v1.1 criteria.
Per the eligibility criteria, the enrolled patient population had a relatively low disease burden. The majority of patients had normal lactate dehydrogenase (LDH), and patients with LDH >2 times the upper limit of normal were excluded.22
Grade ≥3 AEs typically merit relatively intensive intervention, with hospitalization or prolongation of a hospitalization being common. Grade 3/4 AEs in the TIL arm are typical for the treatment and represent bone marrow toxicity resulting from lymphodepleting chemotherapy, including febrile neutropenia and transient major organ dysfunction, primarily cardiac, pulmonary, or liver.22 Major grade 3/4 AEs of the control arm were typical of ipilimumab and included immune related AEs such as colitis, hepatitis, and liver congestion.
PFS was statistically significantly improved in the TIL arm at 7.2 months vs 3.1 months in the ipilimumab arm (HR: 0.50; 95% CI: 0.35-0.72; P <.001), meeting the primary endpoint of the trial.22
The overall response rate in the TIL arm was 49% vs 21% in the ipilimumab arm.22 The waterfall plot shows that approximately two thirds of patients receiving TIL therapy had shrinkage of the target lesion vs fewer than one half of patients receiving ipilimumab.
A second randomized trial, C-144-01, was a multicenter, single arm phase II trial of the TIL therapy lifileucel in patients with treatment refractory metastatic melanoma.23,24 Unlike the previous trial, this trial enrolled patients with advanced, treatment-refractory disease. Eligibility criteria included 1 or more prior lines of systemic therapy, including an anti‒PD-1 antibody and a BRAF ± MEK inhibitor for those with BRAF V600 mutations.
The TIL product used at all treatment centers was manufactured at a centralized facility. Cohort 1 received a first-generation noncryopreserved TIL product with approximately 42 days of manufacturing time. Improved techniques for cryopreservation and shortened manufacturing time were used to manufacture TILs for cohorts 2 and 4, which have identical eligibility criteria. The second-generation cryopreserved TIL had a manufacturing time of 22 days. Patients receiving initial TIL treatment in any cohort could be retreated as part of cohort 3. The primary endpoint for this trial was objective response as measured by RECIST v1.1 criteria.
The baseline characteristics for this trial represent a much more heavily pretreated patient population with more advanced disease compared with M14TIL.24 These patients had received a median of 3 previous lines of systemic therapy. The majority had primary resistance to anti‒PD-1 therapy, defined as a best response of progressive disease to the line of therapy containing anti‒PD-1 . The median cumulative duration of anti‒PD-1 treatment was 7 months. This patient population also had a higher burden of disease compared with that of the M14TIL trial, as represented by elevated LDH in the majority of patients.
As in the previously discussed trial, common AEs resulting from TIL therapy are bone marrow toxicities associated with chemotherapy and hypotension associated with IL 2.24 The incidence of new AEs decreased rapidly over the first 2 weeks after TIL infusion and were minimal beyond 30 days. This short period of toxicity without the need for multiple cycles of treatment is a benefit of TIL therapy compared with traditional immunotherapy. Six deaths occurred within 30 days of infusion; 4 deaths were attributable to AEs, and 2 deaths were due to progressive disease. Of the 4 deaths related to AEs, 3 deaths were judged to be related to chemotherapy and/or IL-2, and 1 death was related to all 3 components of the regimen.
The objective response rate, which was the primary endpoint of the trial, was 31% for the combined cohorts 2 and 4, including 8 complete responses and 40 partial responses. The waterfall plot shows that 78.6% of patients evaluable for changes in target lesion had a reduction of disease.24
The median duration of response was not reached at a median follow up of 27.6 months,24 and 41.7% of responses were maintained for at least 18 months. The median PFS was 4.1 months, and the 12 month PFS rate was 28.3%, indicating durability of treatment effect in the absence of additional ongoing treatment.
Aside from the 2 trials with mature data discussed in this module, multiple TIL trials are in progress around the world in various cancer types, including lung, ovarian, colorectal, pancreatic, sarcoma, breast, cervical, renal cell, and head and neck, as well as uveal melanoma. Many of these trials are currently open for patient enrollment.
To conclude, TIL cellular therapy involves relatively complex procedures but is accessible through either on-site or centralized manufacturing strategies. TIL therapy has demonstrated superior PFS survival compared with ipilimumab as second-line or earlier treatment for patients with metastatic melanoma. It also can be efficacious in patients with metastatic melanoma refractory to multiple lines of prior immune checkpoint blockade.
Ongoing clinical trials are testing feasibility and efficacy in melanoma and other tumor histologies at sites around the world, so hopefully TIL therapy may be available to a large number of healthcare professionals and patients soon.
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