Anti-TIGIT Overcomes Resistance to Immune Checkpoint Inhibitors in Lung Cancer

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Anti-TIGIT Overcomes Resistance to Immune Checkpoint Inhibitors in Lung Cancer

Annals of Oncology: Anti-TIGIT Overcomes Resistance to Immune Checkpoint Inhibitors in Lung Cancer.

In the era of precision therapy, the emergence of immune checkpoint inhibitors (ICIs) represented by anti-PD-1/PD-L1 antibodies has greatly changed the first-line treatment of many tumor types including non-small cell lung cancer (NSCLC). pattern, and brought significant survival benefits to patients.

Under this status quo, there are still many patients who do not benefit from ICIs therapy, and resistance to ICIs therapy is inevitable.

How to expand the population of patients benefiting from immunotherapy, overcome ICIs resistance, and further improve the efficacy of tumor immunotherapy has become the focus of current research .

The editor of Annals of Oncology combined with the latest published clinical research to discuss anti-TIGHT antibody combined with PD-1/PD-L1 therapy.

A detailed interpretation of the limitations and potential of , as follows.

Anti-TIGIT Overcomes Resistance to Immune Checkpoint Inhibitors in Lung Cancer

A new generation of immune checkpoint inhibitors is emerging

In the era of immune checkpoint therapy, the clinical outcomes of patients with advanced or metastatic non-small cell lung cancer (NSCLC) have improved significantly.

Immune checkpoint inhibitors (ICIs) represented by PD-1/PD-L1, monotherapy (PD-L1 ≥ 50% of tumors) or combined with platinum-based chemotherapy for EGFR and ALK wild-type squamous and non-squamous NSCLC patients with impressive long-term survival outcomes.

With the approval and successful clinical application of the first-generation ICIs targeting PD-1/PD-L1, CTLA-4 and other targets, immunotherapy has now become an indispensable part of tumor treatment, which has greatly changed the role of NSCLC in The treatment pattern of multiple tumor types.

At present, for driver gene-negative advanced NSCLC, the first-line treatment is mostly based on ICIs, and a small number of patients will receive ICIs as second-line or above treatment.

However, the applicable population of ICIs is limited, and there are still a large number of patients who fail to benefit from them.

Focusing on how to expand the group of patients benefiting from immunotherapy and further improve the efficacy of tumor immunotherapy, the new generation of ICIs targeting other tumor suppressor pathways, such as TIGIT, LAG-3, and TIM-3 inhibitors, have become the industry’s exploration The goal.

T cell immunoglobulin and ITIM domain (TIGIT) is an Ig superfamily receptor expressed on activated T cells, natural killer (NK) cells, and regulatory T cells (T-regs).

TIGIT can bind to two ligands, CD155 (PVR) and CD112 (PVRL2), but the affinity to CD155 is much higher than that of CD112. CD155 was also identified as the main functional ligand of TIGIT, mediating the negative regulatory function of TIGIT on T cells and NK cells (Fig. TIGHT regulatory network).

In the tumor microenvironment (TME), TIGIT is often co-expressed with PD-1, and TIGIT has also been evaluated as an immune co-suppressive target to increase antitumor activity and overcome resistance to ICIs.

Anti-TIGIT Overcomes Resistance to Immune Checkpoint Inhibitors in Lung Cancer

Fig. TIGHT regulatory network

TIGIT combined with PD-1/PD-L1 treatment is more effective

In the previous issue of Annals of Oncology , Niu et al. first published the results of a phase I clinical study of an anti-TIGIT humanized IgG1 monoclonal antibody (vibostolimab) alone or in combination with pembrolizumab. In the Part A study of 76 patients (15 with NSCLC), the objective response rate (ORR) was 0% in the vibostolimab monotherapy arm and 7% in the combination arm.

In Part B, 106 patients with NSCLC participated in the treatment.

Thirty-nine PD-1/PD-L1-naïve patients received the combination of vibostolimab 200 mg and pembrolizumab 200 mg (3-week course) with an ORR of 26%. Notably, the anti-PD-1/PD-L1-naïve population included 74% of previously treated patients, the ORR was 33% in the PD-L1 ≥1% population, and 27% in the PD-L1-negative population.

Moreover, 41% of the cases in the above study had a loss of PD-L1 expression status. In contrast, in the anti-PD-1/PD-L1 refractory cohort (n=67), the ORR was 3% for both vibostolimab monotherapy and combination therapy.

The above results indicate that single-agent anti-TIGIT therapy has relatively limited effect, while combined application with anti-PD-1 or anti-PD-L1 antibody can exert better immune anti-tumor activity.

ICIs resistance becomes a barrier to efficacy

Higher ORR can be obtained in the anti-PD-1/PD-L1 treatment-naïve setting, suggesting that the optimal timing of combination therapy with anti-TIGHT and anti-PD-1/PD-L1 antibodies would be earlier to prevent or Delayed ICIs resistance.

In contrast, the ORR was very low in anti-PD-1/PD-L1-refractory populations, highlighting the limitations of treatment-acquired resistance to ICIs.

In the study by Niu et al., anti-PD-1/PD-L1-refractory patients were defined as those who received ≥2 cycles of anti-PD-1/PD-L1 antibody therapy and were treated with ≥24 cycles of anti-PD-1/PD-L1 antibodies Disease progression was documented within weeks.

However, this definition includes those patients who did not benefit from treatment with ICIs (primary resistance), as well as those who initially experienced an objective response and later developed resistance to ICIs (acquired resistance).

The underlying mechanisms of primary and acquired resistance are quite different, and as recently discussed by Schoenfeld et al., the lack of a unified resistance population following immune checkpoint therapy is a major obstacle to overcoming resistance to ICIs.

CITYSCAPE is the first to evaluate the efficacy and safety of Tiragolumab (anti-TIGHT antibody) in combination with the PD-L1 inhibitor atezolizumab versus placebo plus atezolizumab as first-line treatment in patients with PD-L1-positive metastatic NSCLC A randomized controlled phase II clinical study.

The results showed that compared with placebo combined with atezolizumab, Tiragolumab combined with atezolizumab significantly improved ORR (37% vs 21%), and in the PD-L1 ≥50% subgroup, The ORR was 66% and 24% in patients treated with tiragolumab plus atezolizumab and placebo plus atezolizumab, respectively (PFS HR = 0.30, 95% CI 0.15-0.61), and is currently undergoing Phase 3 SKYSCRAPER -1 Validation test (NCT04294810). In addition, the clinical efficacy of tiragolumab in non-metastatic NSCLC is also under investigation.

At this stage, the reliable biomarker is none other than PD-L1

To date, PD-L1 remains the only proposed potential biomarker for anti-TIGIT antibody combined with anti-PD-1/PD-L1 antibody therapy.

The role of TIGIT expression levels was assessed in the CITYSCAPE trial, and 49 of 105 evaluable patients were defined as having high TIGIT expression (≥5%), with no significant difference in PFS between high and low expressing patients (PFS HR = 0.62, 95%CI 0.30-1.32).

The accuracy of 5% as a cutoff value and the role of TIGIT expression level as a predictive biomarker need to be confirmed by further studies.

In terms of the complex regulatory network involving TIGIT and its ligands (PVR and PVRL2), it is difficult to believe that a single biomarker can predict the effectiveness of ICIs resistance prevention and management in anti-TIGIT combination therapy.

In addition, non-biomarker-driven anti-TIGIT combined with anti-PD-1/PD-L1 therapy is likely to achieve moderate efficacy results.

Since TIGIT coexists with other immune signals with regulatory functions and competing functions, and binds on the same immune pathway, most of them play a synergistic effect, which has also been confirmed in the preclinical setting.

Furthermore, as TIGIT is expressed on distinct immune cells, better definition of the tumor microenvironment composition is critical. Anti-TIGIT antibodies (such as Tiragolumab and vibostolimab) can effectively activate APCs and enhance the activation function of T cells through inflammatory factors and chemokines.

In addition, it can also trigger antibody-dependent cell-mediated cytotoxicity (ADCC) and T-regs cell death.

Therefore, a better understanding of the balance between T cells, TILs, and T-regs in the TME may provide more clues for current biomarker exploration.

references
Attili I, Passaro A, de Marinis F, Anti-TIGIT to overcome resistance to immune checkpoint inhibitors in lung cancer: limits and potentials, Annals of Oncology (2021), doi: https:// doi.org/10.1016/j.annonc .2021.11.008.

Anti-TIGIT Overcomes Resistance to Immune Checkpoint Inhibitors in Lung Cancer

(source:internet, reference only)

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