Overview of Immune Checkpoint Inhibitors in NSCLC

Overview of T-cell immune regulation

Pathways involved in T-cell regulation

Antigen-presenting cells (APCs) activate T-cell receptors via the major histocompatibility complex, but T-cell activation is ultimately controlled by costimulatory and coinhibitory molecules on T cells.¹ Molecules that costimulate T-cell activation include CD28, ICOS, and TNFRSF4.² Coinhibitory molecules that reduce T-cell activation include CTLA-4, PD-1, T-cell receptor with Ig and ITIM domains protein, LAG-3, TIM-3, BTLA.³ These coinhibitory receptors act as immune checkpoints, downregulating T-cell activation.¹

Role of CTLA-1 and PD-1 in T-cell regulation

CTLA-4 and PD-1 are key immune checkpoint molecules that attenuate T-cell activation.¹ CTLA-4, which is stored in effector T cells, is rapidly relocated to the cell surface through exocytosis of vesicles containing CTLA-4 when the costimulatory molecule CD28 interacts with CD80 and CD86 located on APCs.⁴ When released, CTLA-4 competitively inhibits CD28 and also may remove CD80 and CD86 from APCs, leading to reduced T-cell activation.⁵ After activation occurs, T cells express the coinhibitory molecule PD-1.¹ Once expressed, PD-1 interacts with its ligands, PD-L1 and PD-L2, and inhibits T-cell proliferation, cytokine production, and survival.^1,4

Immune regulation in cancer cells

Cancer evasion of immunity

T cells are central to anticancer immunity, yet tumors are able induce environments that lead to T-cell dysregulation.^6,7 The high antigen loads, particularly of PD-L1, produced by cancer cells result in chronic stimulation of tumor-infiltrating lymphocytes (TILs).^6-8 This persistent stimulation can result in T-cell exhaustion and dysregulation of immune function.^7,9 In non– small cell lung cancer (NSCLC) disease progression, CD8+ T cells shift from a pre-exhausted to exhausted state while regulatory T-cell (T_reg) activation increases.¹⁰ Tregs constitutively express CTLA-4 and suppress T-cell activation, possibly through downregulation of CD80 and CD86 on APCs.⁴

CTLA-4 and PD-1 in NSCLC

In cancer, dysregulation of immune function and disease progression are correlated with changes in the expression of coinhibitory molecules on TILs.^7,10,11 In a comparison of CD8+ T cells from patients with NSCLC and healthy donors, the coinhibitory molecules PD-1, CTLA-4, TIM-3, LAG-3, and BTLA were found at higher levels in TILs.⁷ PD-1 was expressed at the highest levels with disease progression, while the cumulative expression of the other coinhibitory molecules increased with disease stage.⁷ Guo et al also found an increase in PD-1 and CTLA-4 expression in exhausted CD8+ T cells.¹⁰ Exhausted CD4+ cells also expressed high levels of PD-1, whereas T_regs had increased levels of CTLA-4.¹⁰

Immune checkpoint inhibitors

Rationale for ICI in cancer

The increased expression of coinhibitory molecules in TILs makes them ideal targets for immune checkpoint inhibitors (ICIs).¹² ICIs interact with coinhibitory molecules or their ligands and reactivate T-cell immune function.^7,13 The first CTLA-4 inhibitor, ipilimumab, was approved by the FDA for use in melanoma in 2010, followed by the approval of nivolumab, a PD-1 inhibitor, for the treatment of lung adenocarcinoma.¹³

Overview of ICI monotherapies for NSCLC

Currently approved ICIs for NSCLC as of October 2022 are shown in Table 1.^13-20 The CTLA-4 inhibitor ipilimumab is approved as combination therapy with nivolumab, while nivolumab is indicated for use in combination with ipilimumab or as a single agent in patients with disease progression after chemotherapy.^14,15 All of the approved therapies, except durvalumab, are indicated as first-line treatment in specific patient populations.^14-20 Cemiplimab is a PD-1 inhibitor specifically indicated for patients with high PD-L1 levels (≥50%).¹⁷ The National Comprehensive Cancer Network recommends immunohistochemical testing for PD-L1 expression in all patients with metastatic NSCLC due to survival benefits seen with pembrolizumab as a first-line therapy.²¹

Table 1. FDA Immune Checkpoint Inhibitors Approved for NSCLC^13-20

^aSee full prescribing information for indication.

^bPD-L1 status determined by an FDA-approved test.

NSCLC, non–small cell lung cancer

Rationale for combining CTLA-4 and PDL-1 inhibitors

Synergistic effects of CTLA-4 and PD-1/PD-L1 inhibitor combination therapy

The combined use of ICIs is supported by studies that have shown increased levels of many coinhibitory molecules in TILs.^7,10 CTLA-4 and PD-1 are the most prominent coinhibitory molecules found in exhausted CD8+ and CD4+ T cells from advanced NSCLC tumors.10 In CheckMate 227 (NCT02477826), a phase 3 study in untreated adult patients with stage IV or recurrent NSCLC, patients treated with ipilimumab and nivolumab had longer progression-free survival and greater overall survival (OS) compared with patients treated with chemotherapy alone.²² These results led to FDA approval of the first combined CTLA-4/PD-1 immune checkpoint blockade therapy for NSCLC.^14,15

Ongoing clinical trials of combination therapies for NSCLC

Clinical trials of new combinations of CTLA-4 and PD-1/PD-L1 inhibitors are shown in Table 2.^23-31 Novel ICI combinations include ipilimumab and cemiplimab, botensilimab and balstilimab, and pembrolizumab with either ipilimumab or ONC-382.^23-27 An additional phase 1 trial will investigate a novel ICI formulation, a bispecific monoclonal antibody for both CTLA-4 and PD-1 inhibition.²⁸ A phase 3 trial of a CTLA-4/PD-L1 inhibitor combination, tremelimumab plus durvalumab, used as a first-line treatment did not meet its primary end points in patients with PD-L1 expression levels ≥25%.³² Tumor mutational burden (TMB) was found to be a better predictor of OS. Other clinical and mechanistic studies of NSCLC have found TMB to be more predictive than PD-L1 of immune dysfunction and treatment success.³³

Table 2. Clinical Trials Combining CTLA-4 and PD-1/PD-L1 Inhibitors in NSCLC^23-31

NSCLC, non–small cell lung cancer

Conclusions

Clinical trials of ICI monotherapy and combination therapy have demonstrated survival benefits in patients with advanced or metastatic NSCLC. As our understanding of the coinhibitory responses of T cells to the tumor microenvironment continues to grow, additional therapeutic combinations of ICIs will likely be identified.

References

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