introduction to Combined Immune Checkpoint Therapy
In recent decades, chemotherapy is the only approach for patients with metastatic tumors, which always leads to severe adverse events as well as high rates of relapse. The immune cell activation has been served as the most effective approach for the activation of anti-tumor immune responses and cancer treatment. The studies have shown that combined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in numerous cancer indications. Compared with either monotherapy, the combined immune checkpoint therapy is sufficient to induce unique cellular responses for better efficacy.
Fig.1 Immune cell interactions via checkpoint molecules and their ligands. (Khair, 2019)
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are classical inhibitory checkpoints for cancer treatment. The combination of CTLA-4 and PD-1 blockers presents increased response rates and survival rates in multiple cancer types.
lymphocyte activation gene-3 (LAG-3) has been served as the foremost target next to PD-1 in the development of cancer therapy. As an inhibitory coreceptor, LAG-3 plays an important role in autoimmunity, tumor immunity, and anti-infection immunity. LAG-3 expression is correlated with CTLA-4 expression on tumor-infiltrating lymphocytes (TILs).
Indoleamine 2'3' dioxygenase (IDO, IDO1, and IDO2) is a catabolic enzyme that promotes immune tolerance. The combination treatment with anti-CTLA-4 and IDO inhibitors avoids the resistance and tumor growth derived from a single anti-CTLA-4 or anti-PD-1 treatment.
The combination immunotherapy targeting PD-1 and LAG-3 would encourage tumor-specific response and avoid the self-antigen-specific or non-specific immune response. The preclinical data showed that LAG-3 is synergistically efficacious in combination with anti-PD-1 therapies.
TIGHT is the novel checkpoint inhibitor in cancer immunity. Some studies have shown that the anti-PD-1 and anti-TIGIT combination therapy enhances antitumor immunity and survival in murine glioblastoma (GBM) models.
The combined therapy targeting both PD-1 and CD47 activates both innate and adaptive immune responses against multiple tumors. This approach can not only maximize the anti-tumor therapeutic effect but also elicit more durable responses.
Compared with the treatment with PD-L1 and 4-1BB mAb alone, the dual treatment induced further tumor regression and enhanced survival. The number of tumor-infiltrated CD103+ CD8+ T cells is significantly increased for improved antitumor efficacy.
V-domain Ig suppressor of T cell activation (VISTA) is the co-inhibitory receptor homolog with PD-L1. VISTA functions for T cell activation through nonredundant functions distinct from the PD-1/PD-L1 pathway.
In liver cancer, the combination treatment of GITR-ligation and CTLA-4 blockade enables the alleviation of immunosuppression mediated by Ti-Treg. Compared with either treatment alone, the combined treatment presents a stronger recovery of T cell function.
Studies have shown that combined anti-OX40/anti-CTLA-4 immunotherapy increased the effector CD4 and CD8 T cell expansion and differentiation, which results in enhanced survival of mice with prostate or sarcoma tumors.
Anti-CD73 mAb significantly enhanced the activity of anti-PD-1 mAb against colon and prostate subcutaneous tumors. The combined blockade of CD73 ad PD-1 can enhance the therapeutic activity for improved therapeutic strategies.
Services at Creative Biolabs
Creative Biolabs is a leading service provider that focuses on immune checkpoint therapy especially combined immune checkpoint therapy against multiple cancers. Based on our advanced drug discovery platform and extensive experience, now we can provide a series of services for our clients all over the world, which include but not limited to: