Dual PD-1/PD-L2 Blockade: Expanding the Horizons of Cancer Immunotherapy

While PD-L1 is broadly expressed on various immune and tumor cells, PD-L2 expression is more restricted, typically found on dendritic cells and macrophages. However, certain tumors, including lung cancer, head and neck cancers, and lymphomas, express high levels of PD-L2, which contributes to immune evasion by engaging PD-1 on T cells.

The PD-L2/PD-1 interaction has unique implications in the TME:

• Localized immune suppression: PD-L2 expression in the TME can restrict T cell activation and infiltration at the tumor site.
• Enhancement of immune evasion: Tumors expressing both PD-L1 and PD-L2 have multiple
  avenues to inhibit T cells, making immune evasion more effective and potentially leading to resistance to PD-1 or PD-L1 monotherapy.

Given these distinct roles, dual blockade of PD-1 and PD-L2 may offer enhanced efficacy by addressing these additional immune-suppressive pathways.

TY25 is a monoclonal antibody designed to simultaneously block PD-1 and PD-L2 interactions, preventing the engagement of both ligands with the PD-1 receptor. By targeting both pathways, TY25 aims to:

1. Restore T cell function: Blocking PD-1/PD-L2 binding reactivates T cells, increasing their proliferation, cytokine production, and tumor-killing capacity.
2. Overcome T cell exhaustion: TY25 disrupts chronic PD-1 signaling, helping exhausted T cells regain function within the TME.
3. Enhance immune infiltration: Dual blockade can promote T cell infiltration into tumors, countering immune evasion mechanisms.
4. Reduce immunosuppression: By blocking both PD-L1 and PD-L2, TY25 minimizes the immunosuppressive signals within the TME, shifting the balance toward immune activation.

The dual blockade strategy offers several advantages, especially in tumors where PD-L2 expression is high. These benefits include:

• Improved response rates: By blocking both PD-1/PD-L1 and PD-1/PD-L2 pathways, dual blockade can provide a more comprehensive inhibition of immune checkpoints, potentially improving response rates in tumors resistant to PD-1 or PD-L1 monotherapy.
• Enhanced durability of responses: Dual inhibition may lead to more sustained T cell activation, improving the durability of anti-tumor responses.
• Broader applicability across cancer types: The dual PD-1/PD-L2 blockade could be particularly effective in cancers where both ligands are upregulated, such as non-small cell lung cancer (NSCLC), head and neck cancers, and Hodgkin lymphoma.

The tumor microenvironment is often characterized by high levels of immunosuppressive molecules, including PD-L1 and PD-L2, which engage PD-1 on T cells to inhibit their activity. By simultaneously blocking both PD-L1 and PD-L2, dual PD-1/PD-L2 blockade targets the redundant pathways tumors use to evade immune destruction.

Dual blockade also reduces myeloid-derived suppressor cell (MDSC) activity and regulatory T cell (Treg) function within the TME, both of which contribute to immune suppression and support tumor growth. This shift toward immune activation promotes T cell infiltration and cytokine production within the tumor, creating a more immunogenic environment that favors tumor clearance.

Dual PD-1/PD-L2 blockade with TY25 holds particular promise in cancers known for high PD-L2 expression, where immune suppression is pronounced. These include:

• Non-Small Cell Lung Cancer (NSCLC): Both PD-L1 and PD-L2 are expressed in NSCLC, and dual blockade may improve response rates and overcome resistance seen with PD-1 monotherapy.
• Head and Neck Squamous Cell Carcinoma (HNSCC): PD-L2 is frequently upregulated in HNSCC, making dual blockade a promising strategy to enhance T cell activity.
• Hodgkin Lymphoma: High expression of PD-L1 and PD-L2 on Reed-Sternberg cells makes Hodgkin lymphoma particularly responsive to checkpoint inhibition, and dual blockade may provide additional benefit by targeting both pathways.

Combining dual PD-1/PD-L2 blockade with other checkpoint inhibitors, such as anti-CTLA-4, may further enhance immune activation. Anti-CTLA-4 therapy can increase T cell priming and activation, complementing the effects of PD-1/PD-L2 inhibition, which focuses on T cell activity within the TME.

This combination approach can:

• Promote a stronger T cell response: Anti-CTLA-4 enhances T cell activation, while dual PD-1/PD-L2 blockade sustains T cell function in the TME. 
• Reduce immunotherapy resistance: Tumors resistant to PD-1 or PD-L1 monotherapy may respond to combined blockade strategies that target multiple immune checkpoints.

Chimeric Antigen Receptor (CAR) T cell therapy has shown promising results in hematologic cancers but faces challenges in solid tumors due to the immunosuppressive TME. Dual PD-1/PD-L2 blockade with TY25 could enhance CAR-T cell efficacy by reducing immune suppression, allowing CAR-T cells to function more effectively within the TME.

While dual PD-1/PD-L2 blockade holds promise for enhancing anti-tumor immunity, blocking multiple immune pathways can increase the risk of immune-related adverse events (irAEs), such as autoimmunity or inflammatory responses. Careful patient selection, dose optimization, and monitoring will be essential to maximize therapeutic benefits while minimizing risks.

Research into dual PD-1/PD-L2 blockade is still evolving, but future studies will likely explore its efficacy in other cancers where PD-L2 expression is a known resistance factor. Developing biomarkers that predict patient response to dual blockade will be critical in selecting patients who stand to benefit the most from this strategy.

Dual PD-1/PD-L2 blockade with agents like TY25 represents a promising advancement in cancer immunotherapy, offering a more comprehensive approach to overcoming tumor immune evasion. By simultaneously targeting PD-1 interactions with both PD-L1 and PD-L2, dual blockade enhances T cell activation, reduces immune suppression, and expands the efficacy of checkpoint inhibition. As research progresses, dual PD-1/PD-L2-targeted therapies have the potential to significantly improve treatment outcomes for patients with immune-resistant cancers and broaden the horizons of cancer immunotherapy.

1. Keir, M.E., et al., 2008. PD-1 and its ligands in tolerance and immunity. Annual Review of Immunology, 26, pp.677-704.
2. Callahan, M.K., et al., 2016. The role of PD-L2 in PD-1 checkpoint blockade and immune regulation. Current Opinion in Immunology, 39, pp.39-44.
3. Dong, H., et al., 2002. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nature Medicine, 8(8), pp.793-800.
4. Yearley, J.H., et al., 2017. Expression of PD-L2, PD-L1and PD-1 in neoplastic cells and the TME in different cancers. Cancer Immunology Research, 5(6), pp.480-488.
5. Yoshimura, K., et al., 2019. Dual blockade of PD-1 and PD-L2 in cancer immunotherapy. Cancer Immunology, Immunotherapy, 68(4), pp.601-613.
6. Freeman, G.J., et al., 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. The Journal of Experimental Medicine, 192(7), pp.1027-1034.
7. Wang, Y., et al., 2018. Blockade of PD-L2 enhances anti-tumor immunity by regulating the tumor microenvironment. Oncotarget, 9(9), pp.8121-8131.
8. Topalian, S.L., et al., 2015. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell, 27(4), pp.450-461.