Tumor-Infiltrating Lymphocyte Therapy Tackles Treatment Blind Spot in Advanced Melanoma

Anuradha Krishnamurthy, MBBS

Advanced melanoma is an aggressive disease that carried a very poor prognosis until the emergence of checkpoint inhibitors approximately 15 years ago, which gave us the ability to exploit the immunogenic nature of melanoma and improve survival significantly. However, there are still many patients who experience disease progression on checkpoint inhibitors.

Although therapeutic options after disease progression on anti–PD-1 and BRAF/MEK inhibitors have been limited both in terms of options and benefit, tumor-infiltrating lymphocyte (TIL) therapy has expanded the treatment landscape for patients with unresectable or metastatic melanoma.¹ The FDA granted accelerated approval in February 2024 to the TIL therapy lifileucel (Amtagvi) for the treatment of adult patients with unresectable or metastatic melanoma who received prior treatment with a PD-1–blocking antibody and a BRAF inhibitor, with or without a MEK inhibitor, if they have a BRAF V600 mutation.²

^{Harnessing the Immune System Combats Cancer}

TIL therapy is a type of adoptive cell therapy (ACT) that harnesses the body’s immune system to fight cancer. It involves isolating autologous T lymphocytes from a patient’s tumor, expanding them ex vivo, and then reinfusing them back into the patient. Solid tumors present a wide array of tumor-specific antigens (TSAs), but few TSAs are shared across patients with specific solid tumors. TILs are polyclonal and target a multitude of TSAs from a patient.³

The premise of TIL therapy is based on the observation that while lymphocytes within the tumor microenvironment are primed to recognize and attack tumor cells, their activity is often suppressed by the tumor’s immunosuppressive mechanisms.³ Tumor cell death mediated by TILs involves presentation of multiple TSAs by antigen- presenting cells (APCs) and APC priming of naive T cells by multiple TSAs that enter the tumor microenvironment, bind to different TSAs, and cause tumor cell death by releasing perforins and granzymes.⁴

ACT with TILs showed objective response rates (ORRs) between 31% and 35% in findings from an early clinical trial from 1994 in patients with metastatic melanoma (n = 86).⁵ The therapy has been optimized over the years, culminating in the FDA approval of lifileucel this year.

The approval was supported by safety and efficacy data from a global, multicenter, multicohort, open-label, single-arm study. Lifileucel was administered after lymphodepleting chemotherapy, and patients received IL-2 post TIL infusion. The median dose of lifileucel was 21.1 × 10⁹ viable cells. The FDA’s recommended dose of lifileucel is 7.5 × 10⁹ to 72 × 10⁹ viable cells. The main efficacy outcomes of the trial were ORR, which was 31.5% (95% CI, 21.1%-43.4%) in the lifileucel arm (n = 73), and median duration of response, which was not reached (NR; 95% CI, 4.1 months-NR). Additionally, the median time to response was 1.5 months. Response to lifileucel was observed across all subgroups analyzed regardless of age, PD-L1 status, prior anti-CTLA4 use, BRAF mutational status, and mucosal and nonmucosal disease.²

In multivariate analyses, ECOG performance status, elevated lactate dehydrogenase (LDH) levels, and target lesion sum of diameters greater than the median were independently correlated with lower ORR. Normal LDH levels and sum of diameters less than the median showed a greater likelihood of response. Grade 3 or 4 treatment-emergent adverse events included thrombocytopenia, anemia, febrile neutropenia, neutropenia, leukopenia, hypophosphatemia, lymphopenia, fever, hypotension, fatigue, chills, and diarrhea. FDA boxed warnings include treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment.^2,6,7

Given the complexity of TIL therapy, multidisciplinary care of patients who receive the treatment is recommended. Eligible patients will be referred for assessment at an authorized treatment center, such as Roswell Park Comprehensive Cancer Center in Buffalo, New York. The critical parameters for patient selection include performance status, presence of untreated brain metastases, presence of bowel metastases that can result in significant bleeding, adequate renal function, good cardiac function, and good pulmonary reserve. These parameters also dictate post-treatment complications and must be followed closely during treatment.⁸

^{Managing the TIL Therapy Manufacturing Process}

The TIL therapy process begins with the surgical resection of the patient’s tumor. The tumor is then fragmented, and the lymphocytes infiltrating these tumor pieces are cultured in the presence of IL-2 to promote T-cell growth. TIL manufacturing can take between 22 to 60 days. These lymphocytes undergo substantial expansion before being infused back into the patient. Prior to TIL infusion, the patient undergoes nonmyeloablative lymphodepletion with cyclophosphamide and fludarabine for 5 to 7 days. The lymphodepleting chemotherapy is currently administered in many centers in the inpatient setting, with outpatient administration under consideration at certain centers. The TIL infusion and IL-2 administration require hospital admission for supportive care and monitoring due to treatment-related toxicities. The purpose of lymphodepletion is to reduce endogenous lymphocytes and eliminate regulatory T cells, thereby removing “cytokine sinks” that compete with the TILs for cytokines and optimizing the tumor microenvironment for the incoming TILs. Cryopreserved TILs are administered approximately 24 hours after lymphodepletion. An abbreviated short course of IL-2 is commenced 3 to 24 hours after completion of TIL infusion at a dose of 600,000 IU/kg every 8 to 12 hours for a maximum of 6 doses. Patients are discharged from the hospital when they are deemed to have recovered appropriately by the inpatient team. Patients are required to stay within 60 minutes of the treating center for 30 days post–TIL infusion with a designated caregiver per institutional policy at most centers.⁸

TIL therapy is a treatment option for patients who experience disease progression on PD-1 and/or BRAF inhibitors with or without MEK inhibitors. Although this therapy has shown incredible promise, it is not without its challenges. Not all patients will be deemed eligible for this intensive treatment modality, given the toxicity profile of TIL therapy and the need to weigh factors including the pace of disease progression and the presence of comorbidities. The treatment is resource intensive, as the ex vivo expansion of TILs and TIL administration requires specialized facilities and expertise. There is also a time delay with treatment due to the time required to generate sufficient TILs. TILs cannot be isolated from all tumors, as some patients may not have enough viable lymphocytes within their tumor. Furthermore, responses to TIL therapy are variable and not all patients achieve deep or long duration of response. Further research is needed to address these issues.

Research is currently ongoing, where combination of TILs with other agents, TIL therapies in other cancer types such as lung cancer, and engineered TILs to express chimeric antigen receptors or T-cell receptors are all being explored.⁹ Roswell Park Comprehensive Cancer Center is involved in exciting TIL therapy research projects, including exploring TIL therapy in non–small cell lung cancer and combining the modality with a newer generation of interleukins.

References

1. Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 2022;10(12):e005755. doi:10.1136/jitc-2022-005755
2. FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. FDA. February 16, 2024. Accessed September 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma
3. Tran E, Robbins PF, Rosenberg SA. ‘Final common pathway’ of human cancer immunotherapy: targeting random somatic mutations. Nat Immunol. 2017;18(3):255-262. doi:10.1038/ni.3682
4. Raskov H, Orhan A, Christensen JP, Gögenur I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br J Cancer. 2021;124(2):359-367. doi:10.1038/s41416-020-01048-4
5. Rosenberg SA, Yannelli JR, Yang JC, et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst. 1994;86(15):1159-1166. doi:10.1093/jnci/86.15.1159
6. Medina T, Chesney JA, Whitman E, et al. Long-term efficacy and safety of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced melanoma: a 4-year analysis of the C-144–01 study. J Immunother Cancer. 2023;11(suppl 1):776. doi:10.1136/jitc-2023-SITC2023.0776
7. BLA Clinical Review and Evaluation BLA 125773: AMTAGVI, Lifileucel. FDA. February 6, 2024. Accessed September 4, 2024. https://www.fda.gov/media/176951/download?attachment
8. Betof Warner A, Hamid O, Komanduri K, et al. Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. J Immunother Cancer. 2024;12(2):e008735. doi:10.1136/jitc-2023-008735
9. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550-4557. doi:10.1158/1078-0432.CCR-11-0116