Advancements in immune checkpoint inhibitors (ICIs) have revolutionized oncology therapy.1 Several ICIs targeting PD-1 or PD-L1 are available for the treatment of advanced non–small cell lung cancer (NSCLC).1,2 However, there remains a need for alternative treatments due to ICI resistance, failure to respond to therapy, or disease relapse.2-5 Even when ICIs are used in combination with chemotherapy, patients may experience cancer progression within 12 months.6 Oncology providers should identify opportunities for clinical trials and investigational strategies that provide options for patients with advanced NSCLC beyond ICIs and biomarker-directed therapies.
Adoptive cell therapy (ACT) is a type of immunotherapy where an individual’s immune cells are harvested and expanded to help elicit a tumor-specific, cell-mediated response against cancer cells; it includes chimeric antigen receptor (CAR) T-cell therapy (CAR-T), engineered T cell receptor (TCR)-based T cell (TCR-T) immunotherapy and tumor-infiltrating lymphocytes (TILs).7 The first promising results evaluating the use of autologous (self) TILs in patients with metastatic melanoma were published in 1988, and they sparked further research.7,8
Endogenous TILs are composed of T cells isolated from tumor tissue that can recognize tumor-specific antigens to target and attack cancer cells.9,10 In most cancers, immune infiltrate includes various macrophage subtypes and several different types of T lymphocytes.11 Helper T lymphocytes and cytotoxic T lymphocytes (CTLs) play an important role in identifying cancer cells and arresting their growth.
During tumorigenesis, genetic instability can lead to somatic mutations producing new proteins, or neoantigens, in cancer cells. Neoantigens expressed only in tumor cells are referred to as tumor-specific antigens (TSAs). All T cells, including CTLs, express a unique T-cell receptor (TCR) specific to a single TSA. Major histocompatibility complex molecules present TSAs on the tumor cell surface, which are recognized upon TCR binding. Once tumor cells are recognized as non-self, T-cell activation occurs.12,13 CTLs release cytotoxic granules, which fuse with the target cell membrane. Granulysin and perforin create pores in the cell membrane, allowing granzymes to be released into the cytoplasm. Granzymes then initiate a caspase cascade leading to apoptosis.1,14,15 However, tumor cells can initiate adaptive mechanisms to evade CTL activity, including the production of immunosuppressive cytokines that can impede the antitumor immune response.9,16 Therefore, methods to overcome immune evasion and improve upon TIL-mediated tumor cell destruction have been explored.
Development and Potential Utility of TILs for Treatment of Solid Tumors
As noted above, endogenous TILs possess TCRs with the ability to recognize and destroy tumor cells. Removing TILs from the immunosuppressive tumor environment through tumor excision allows for ex vivo assessment of antitumor activity. Once highly active TILs are identified, they are rapidly expanded to produce billions of activated, tumor-specific T cells, which are then infused back to the host to target and destroy tumor cells.13 This approach has potential utility for treating a variety of solid tumors, including NSCLC.7,17-19
Addressing Limitations of Current Treatment Strategies
TIL Therapy in Immunologically Cold Tumors
NSCLC tumors are often categorized as “immunologically cold,” meaning that they have features thought to impede a strong immune response, including the lack of TILs within the tumor microenvironment. This may be due to a lack of tumor antigens, defective recruitment of antigen-presenting cells, lack of T-cell costimulation and activation, and modified production of chemokines and cytokines involved in cell trafficking and activation.6,20 TIL therapy may improve immunological response within the tumor by providing more T cells to mount an attack. Moreover, TIL therapy given in combination with an ICI may help to prevent T-cell inactivation via tumor-mediated mechanisms once they have infiltrated the tumor.4,21
Limitations With Other Adoptive Cell Therapies
ACT methodologies are centered around the manipulation of an individual’s own immune cells to generate a tumor-specific, cell-mediated response against cancer.7 However, CAR-T and TCR-T therapies have faced challenges in the treatment of solid tumors, including the lack of stable tumor antigen expression and the need for human leukocyte antigen restriction. Severe and unpredictable toxicities can also occur with CAR-T and TCR-T due to cross-reactivity or trace expression of tumor-associated antigens in healthy cells.22-24 Further, acquired resistance can occur following a clinical response, which may be attributed to deletion or mutation of the target antigen, antigenic heterogeneity, or impaired trafficking.6,24,25
Unlike other ACTs, TILs are composed of polyclonal cells capable of simultaneously recognizing multiple tumor antigens.19 TILs are derived from genetically unmodified host cells, which may reduce the risk for complications from immune-mediated responses. TILs are also capable of targeting truncal neoantigens clonally expressed by a cancer cell, which may reduce the risk of resistance due to deficient target antigen expression.7
Durable Remissions With TIL Therapy
TIL therapy has the potential for durable, complete remissions.26 This partially is due to the transdifferentiation potential and lifespan of memory T cells.6 Such responses have been observed in heavily pretreated patients with metastatic melanoma after disease progression following treatment with chemotherapy, IL-2, anti–CTLA-4 monoclonal antibodies, or a combination of these.26 Additionally, durable remissions following TIL therapy have been reported in a variety of other solid tumor types, including cholangiocarcinoma and cervical, colorectal, and breast cancers.27-30
Clinical trials in metastatic melanoma have demonstrated complete and durable responses from TIL therapy, even in patients who progressed on multiple prior therapies, including anti–PD-1 agents.31,32 These findings suggest that TIL therapy may be a viable option for patients with PD-1 resistance or in cancers with lower immunogenicity. Observed similarities between NSCLC and melanoma suggest a role for TIL therapy in the treatment of NSCLC and warrant further investigation.
For information regarding advancements in TIL therapy, resources and further information are available from TILs Working Group at https://www.tilsinbreastcancer.org/.
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