CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Nurses: 1.00 Nursing contact hour
Released: April 27, 2022
Expiration: April 26, 2023
In this module, Diwakar Davar, MD, and Jyoti D. Patel, MD, discuss TIGIT, an emerging immune checkpoint target, as well as available data on investigational therapies targeting this pathway.
The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be found here or downloaded by clicking on any of the slide thumbnails in the module.
Clinical Care Options plans to measure the educational impact of this activity. Some questions will be asked twice: once at the beginning of the activity and then again after the discussion that informs the best choice. Your responses will be aggregated for analysis, and your specific responses will not be shared.
Jyoti D. Patel, MD:
We have made significant discoveries over the past several years in harnessing immunotherapies and immune checkpoint inhibitors (ICIs) across a broad range of cancers. Most impressively, we have learned that the immune checkpoints PD‑1 and PD‑L1 mediate immune evasion and that monoclonal antibodies (mAbs) developed to target these proteins can harness the immune system to facilitate tumor killing.
Many tumors show overexpression of PD-L1, which binds to PD-1 and inhibits T‑cell killing of tumor cells. A broad range of antibodies are able to block this interaction, thus allowing T‑cell activation and killing of tumor cells. Commercially available anti–PD‑1 inhibitors include cemiplimab, nivolumab, and pembrolizumab, and anti–PD‑L1 inhibitors include atezolizumab, avelumab, and durvalumab. These drugs are approved for a range of cancers, as well as different indications ranging from the neoadjuvant/adjuvant to metastatic settings.
Jyoti D. Patel, MD:
NSCLC provides an example of the remarkable improvements that ICIs have brought to the clinic in the past half-decade. In the 1990s and early 2000s, our approach to lung cancer was monolithic chemotherapy as primary treatment. Then, we saw the development of targeted therapies, primarily EGFR inhibitors. We’ve seen approval of a number of additional targeted therapies in more recent years, but those largely benefit small groups of patients with specific molecular alterations. Immunotherapy, however, has really changed our clinical approach with durvalumab for stage III disease, atezolizumab for adjuvant therapy, nivolumab in the neoadjuvant setting, and atezolizumab, cemiplimab, nivolumab, and pembrolizumab with various approvals either as monotherapy or in combination with chemotherapy for advanced or metastatic NSCLC. We also have the anti–CTLA-4 antibody ipilimumab in combination with nivolumab with or without chemotherapy.
Jyoti D. Patel, MD:
PD‑1 inhibition alone or in combination with chemotherapy or CTLA-4 inhibition are primary therapies in the first-line setting for patients with advanced NSCLC without driver mutations. PD‑1–targeted monotherapy produces response rates of approximately 50% in patients with PD‑L1–high expression (TPS ≥50%). As demonstrated by KEYNOTE-407 in squamous histology and KEYNOTE-189 in nonsquamous histology, the combination of chemotherapy and immunotherapy shows response rates and disease control rates that translate to significant improvements in OS compared with chemotherapy alone.1,2
The approval of the CTLA-4 inhibitor ipilimumab in combination with nivolumab has led to response rates in more than one third of individuals. Addition of chemotherapy to ipilimumab plus nivolumab further increases response rates, but the chemotherapy‑free regimen is also an option in patients with PD‑L1 expression ≥1%.3,4
Unfortunately, despite the multitude of available treatment options, a sizeable number of patients have no response or eventually develop resistance to either PD‑1/PD-L1 inhibition or the combination of PD‑1 and CTLA-4 inhibition.
Diwakar Davar, MD:
It is now clear that the responses to ICIs are dependent on multiple factors that sculpt tumor growth, as well as antitumor immune responses from several different components. The first is the tumor genome and epigenome, which control various factors that affect tumor antigen–specific CD8 T‑cell infiltration. Second, factors within the tumor microenvironment—particularly those associated with vasculature, neovascularization, and lymphatic drainage—that promote tumor infiltration or exfiltration will affect the ability of CD8 T‑cells to respond to immunotherapy. Third is the host immune response, including factors such as HLA haplotypes. And finally, more recent data support a role of the host’s intestinal microbiome in mediating response to checkpoint inhibitor immunotherapy. It is clear that there is a vast array of factors, controlled both within the tumor and outside the tumor, that affect the likelihood of an individual responding to anticancer immune therapy.
Diwakar Davar, MD:
Of these factors, one that has emerged most consistently in determining the response to checkpoint inhibitor immunotherapy is the presence of alternative immune inhibitory checkpoints such as TIM3, LAG3, and T-cell immunoreceptor with Ig and ITIM domains, or TIGIT. The TIGIT axis is very complex. It comprises the inhibitory receptors TIGIT and CD112R, as well as the excitatory receptors CD226 and CD96, which mediate a series of engagements with ligands of varying specificity, including PVR (CD155) and PVRIG (CD112). The resulting complex cascade of excitatory and inhibitory signals through this axis collectively determines the activation state of T-cells.
More recently, the role of TIGIT signaling upon the activity of NK cells was elucidated in a pivotal paper that illustrated that the balance of NK cell function was dependent on the CD226:TIGIT ratio and could be rescued by IL‑15 stimulation in human melanoma cells ex vivo.5
Finally, it is worth noting that a very provocative paper showed that the CD155 ligand of TIGIT bears sequence homology with the Fap2 protein of the bacterium Fusobacterium nucleatum.6 It is theorized that this bacterium, which has been found in patients with colorectal cancer, actually may be associated with colorectal carcinogenesis and tumor progression.7 It is important to note, however, that the effect of TIGIT blockade in colorectal cancer has not been effectively demonstrated.
Diwakar Davar, MD:
Thus, it is clear that the TIGIT axis inhibits innate and adaptive immune responses through multiple nonoverlapping mechanisms. For example, it is involved in both T-cell and NK cell intrinsic inhibition through engagement of TIGIT ligands on TIGIT‑bearing T‑cells or NK cells. Through the action of IL‑10, TIGIT may mediate the activity of immunosuppressive dendritic cells. Engagement with TIGIT ligands may inhibit the excitatory activity of CD226 upon antigen‑specific CD8 T‑cells. TIGIT expression on tumor‑associated dendritic cells may inhibit CD8 T‑cell function indirectly by stabilizing extremely suppressive regulatory T-cells (Tregs). Finally, Fap2-induced TIGIT engagement, possibly related to certain bacteria, as discussed earlier, may inhibit T-cell or NK cell function.5
Diwakar Davar, MD:
TIGIT has shown the ability to mediate antitumor immune responses through its effects on CD8 T‑cells and Tregs. Of most importance, TIGIT‑positive Tregs are highly immune suppressive, a phenomenon illustrated by Kurtulus and colleagues in 2015.8 TIGIT signaling marked the most dysfunctional subset of Tregs, and TIGIT upregulation on T‑cells in the tumor microenvironment was associated with co‑expression of other inhibitory receptors, including TIM3.
However, it is the ratio of TIGIT to CD226 in Tregs, not the absolute level of TIGIT alone, that correlates with high Treg frequencies in the tumor microenvironment of metastatic melanoma patients.9 This suggests that TIGIT potentially could act as a decoy receptor for its ligands.
Diwakar Davar, MD:
In the context of tumor‑associated CD8-positive T‑cells, TIGIT expression marks a particularly dysfunctional subset of T‑cells, based on the presence of extremely low amounts of the immune‑competent cytokines TNF‑alpha and IL‑2 and the expression of extremely high levels of the immunosuppressive cytokine IL‑10, which is produced by TIGIT‑positive Tregs. This profile shows that TIGIT‑positive CD8 T‑cells were extremely dysfunctional compared with TIGIT‑negative cells.8
In addition, in an ex vivo experiment, TIGIT blockade, alone or in combination with anti–PD‑1 inhibition, increased both the frequency and the function of antigen‑specific CD8-positive T‑cells from melanoma patients.10
Diwakar Davar, MD:
In the context of Treg and NK cell function, effective TIGIT blockade is dependent on different factors. High expression of CD155 is associated with poor outcome with checkpoint inhibitor therapy, with a significantly shorter PFS seen in melanoma patients with high expression after treatment with anti–PD-1 or combination of anti-PD-1 and anti–CTLA-4.11 In an NK cell model, TIGIT blockade alone was insufficient and required IL‑15 augmentation to suppress the development of experimental lung metastases in melanoma models.5
Diwakar Davar, MD:
Those preclinical experiments did not clarify the role of co-engagement of the Fcγ backbone of the inhibitory receptor mAb. Data from Waight and colleagues12 in 2018 suggested that Fc engagement is critical to the effectiveness of TIGIT blockade in mediating its function upon T‑cells. In ex vivo models, effective TIGIT blockade upon IL‑2 production by peptide‑stimulated T‑cells required an Fc‑active TIGIT mAb. This effect was abrogated by Fc‑inactive TIGIT mAb.
The interaction between the Fc region of the antibody and the Fcγ receptor on antigen‑presenting cells enhanced antigen‑presenting T‑cell responses and antitumor activity of tumor antigen‑specific T‑cells.
As shown in the right half of the slide, that Fc–Fcγ receptor interaction is dependent on the co-engagement of Fc‑active TIGITs and is abrogated by any kind of alteration of the Fc backbone of the mAb, such as glycosylation or deglycosylation. The Fc receptor activity of Fc‑active TIGITs was completely independent of regulatory T‑cell function in this model, but similar results were recapitulated in another model system by Han and colleagues.13 However, it is also important to keep in mind that the clinical efficacy of Fc‑active and Fc‑inactive TIGIT backbones is still being evaluated. Ultimately, this will require clinical trials in patients with advanced cancer treated with each of these agents alone or in combination.
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