Feature: The Role of Tumor-infiltrating Lymphocytes (TILs) in the Treatment of Melanoma

Colleen McCabe, PharmD, BCOP
Clinical Pharmacy Specialist - Sarcoma/Melanoma
Vanderbilt University Medical Center
Nashville, TN

Jordyn Higgins, PharmD, BCOP
Clinical Assistant Professor of Pharmacy Practice in Oncology
Mercer University College of Pharmacy
Clinical Pharmacy Specialist- Medical Oncology
Emory Winship Cancer Institute
Atlanta, GA

The Immune System and Melanoma
In addition to protecting against external pathogens, the human immune system has evolved to produce defense mechanisms against a variety of diseases, including cancer.1 One such mechanism is the process called immunological surveillance, which monitors internal cell structure to recognize and destroy cancer cells. The human immune system plays a large role in the defense against melanoma in particular.2 Melanoma is widely recognized as one of the most immunogenic types of cancer and is the fifth most common cancer type in the United States.3

Although the human immune system employs many mechanisms to detect melanoma cells, melanoma cells employ numerous mechanisms to avoid detection. These mechanisms include downregulation of targetable molecules and elaboration of immunosuppressive cytokines. Therefore, the immune system alone is largely inadequate to fight off melanoma cells. However, understanding the immune mechanisms of melanoma cells offers an exciting opportunity for drug development and improved treatment modalities.2

Recent drug development has focused on exploiting the immunogenic nature of melanoma to develop effective therapies for treatment. This is particularly noticeable in the metastatic disease treatment setting, which heavily utilizes immune checkpoint inhibitors. This article explores the role of a specific immune-cell tumor-infiltrating lymphocytes (TILs)—and the role these cells play in disease prognosis and treatment.

Tumor-infiltrating Lymphocytes
TILs are a polymorphic group that is composed mainly by effector T lymphocytes, regulatory T lymphocytes, natural killer cells, dendritic cells, and macrophages.4 TILs can recognize cancer cells as abnormal, penetrate the tumor, and kill cancer cells.5 TILs are lymphocytes present within tumors, and in the case of primary melanoma, they are found alongside melanoma cells. TILs are classified as absent, nonbrisk, or brisk. Absent TIL indicates no lymphocytes directly opposed to tumor cells; nonbrisk TIL indicates the presence of isolated, multifocal, and segmental TIL infiltrate in the tumor, and brisk TIL is defined as the infiltration of the entire base of the tumor or diffusely meeting the tumor.6

The Relationship Between TILs and Regression in Melanoma
Lymphocyte infiltration of melanoma is a widespread response of the host immune system to the presence of tumor cells. Histologic regression is defined as the replacement of tumor cells with immune cells, melanin-laden macrophages, and fibrotic components.7 Immune cell infiltration of the cancer cells is a result of the host cells recognition of cancer cells and immunologic response as a defense mechanism.8 Studies have supported that histologic regression is associated with improved survival.7

Historically, the classification of melanoma stage is based on pathological features of the primary tumor and the spread of the disease at the time of diagnosis. Staging is a major contributor to treatment decision-making. As the level of understanding of the immunogenicity of the melanoma disease state grows, numerous studies have provided evidence to include immune system biomarkers in the staging of melanoma. A large meta-analysis of the data in 2020 supported the use of TIL level in prognostic criteria as they found the published literature to show brisk TIL grade had a better prognosis.8

In particular, TILs elicit immunity locally and may decrease the likelihood of sentinel lymph node (SLN) metastases. Interestingly, both TIL presence and differentiation and localization have been shown to determine clinical outcomes.9 TIL infiltration is manually quantified by pathological assessment; however, digital immune scores, which may provide the opportunity to translate the prognostic benefit of TILs into a clinically usable diagnostic tool, are still under development.9 Therefore, the presence of TILs is a marker of immune activity and a favorable biomarker.7 In fact, TILs have been associated with improved survival.10–13 In addition to its incorporation into staging guidelines, TIL presence can also be exploited for the treatment of melanoma. In fact, the National Comprehensive Cancer Network (NCCN) guidelines encourage utilization in prognosis determination in addition to Breslow thickness and other primary lesion characteristics.14

The Future Role of TILs in Treatment of Melanoma
TILs are an experimental cell therapy for the treatment of melanoma. Currently, this therapy is only available via a clinical trial for patients who have already received standard of care immunotherapy and BRAF/MEK inhibitors (if applicable). The process of extraction, engineering, and administration to the patient is similar to chimeric antigen receptor-T (CAR-T) therapy. TILs are harvested from the patient and taken to the lab for expansion and engineering. Patients receive a short-term chemotherapy regimen, then the patient receives the TILs through an infusion.

An advantage of TILs compared to CAR-T therapy is that these come directly from the tumor and do not need to be genetically engineered to recognize the tumor since they were innately designed to do so.5 Additionally, the use of CAR-T therapy in solid tumors is limited by organ toxicities. The risk of these toxicities occur due to activation of T cell effector function through the CAR as most tumor-associated antigens are also found in normal tissues.15 Another advantage of TILs is that they are highly polyclonal and do not have as high of a risk of organ toxicities. General side effects seem to be related to the chemotherapy or interleukin-2 (IL-2) if administered in combination with the TILS therapy.

Two TIL therapies show promise in the treatment of melanoma. The United States Food and Drug Administration (FDA) granted orphan drug designation to a novel TIL therapy (ITIL-168) for the treatment of stage IIB to IV melanoma based on the results of a retrospective study of 21 compassionate use patients assessing the feasibility of utilizing TILs for the treatment of advanced cutaneous melanoma. Patients were hospitalized for treatment administration and for side effect management. ITIL-1618 was administered at 600,000-720,000 IU/kg after cyclophosphamide 60 mg/kg/day for 2 days and fludarabine 25 mg/m2/day for 5 days.

In all evaluable patients (n=21), best overall responses were observed in 67% of patients (complete responses: 19%, partial responses: 48%). Median overall survival was 21.3 months (95% Confidence Interval [CI], 6.8-not evaluable). At median follow-up of 52.2 months 23% of the 14 responding patients experienced durable responses.16 The investigational new drug (IND) application was accepted by the FDA for DELTA-1, a global phase II clinical trial of ITIL-168 in patients with advanced melanoma whose disease has relapsed after a programmed death protein 1 (PD-1) inhibitor and if positive for a BRAF-activating mutation, a BRAF inhibitor.

Next, a phase II, open-label, single-arm, multicenter study in patients who had been previously treated with checkpoint inhibitor(s) and BRAF +/- MEK targeted agents was conducted in 66 patients. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel (LN-144), and up to six doses of high-dose interleukin-2. The overall response rate was 36% (95% CI, 25-49). Disease control rate was 80% (95% CI, 69-89) and median duration of response was not reached after the 18.7-month median study follow-up (range, 0.2-34.1 months).17

Conclusion
Melanoma has long been recognized as one of the most immunogenic of cancer diagnoses. Especially in comparison to other tumor types, melanoma has vast opportunities for the development of immunotherapeutic strategies. One marker of the immune system involvement in melanoma is the presence of tumor-infiltrating lymphocytes. Lymphocyte infiltration of melanoma is a widespread response of the host immune system to the presence of tumor cells. Histologic regression is defined as the replacement of tumor cells with immune cells, melanin-laden macrophages, and fibrotic components.7 TILs are still considered an experimental cell therapy for the treatment of melanoma, but clinical trial data has shown promising results for future incorporation into the treatment guidelines.

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