Combined Therapy of CTLA-4 and IDO

Introduction to CTLA-4 and IDO

Indoleamine 2’3’ dioxygenase (IDO, IDO1, and IDO2) is a catabolic enzyme produced by macrophages and T-regs to convert tryptophan needed for T cell effector function to kynurines. IDO has been demonstrated to inhibit immune responses through several mechanisms, including depleting the essential amino acids and promoting differentiation of FoxP3⁺ Tregs. Expressed by numerous cancers, high IDO expressivivion levels have repressed anti-tumor responses and been correlated with a worse prognosis.

Especially, upregulation of the IDO in the tumor microenvironment is a possible mechanism of resistance to CTLA-4 blockade immunotherapy. A preclinical study in a melanoma model in mice demonstrated that IDO is overexpressed and decreases response in both anti-CTLA-4 and anti-PD1/PD-L1. Thus, due to its upstream effects on the antigen-presenting milieu, IDO may be non-redundant with the more distal T cell checkpoints. Blocking IDO concurrently with CTLA-4 or PD-1 might confer additive benefits. In line with this notion, combination approaches of anti-CTLA-4 with IDO inhibition have recently been shown to mediate superior therapeutic effects against tumors.

Double Immune Checkpoint Blockade of CTLA-4 and IDO

Pharmacological inhibition of IDO combined with CTLA-4 blockade gave superior responses. Several preclinical studies demonstrated a therapeutic benefit of combinations of anti-CTLA-4 with IDO inhibition. Studies using the melanoma mouse model have shown that combinations of CTLA-4 or PD-1/PD-L1 with IDO blockade restored IL-2 production and CD8⁺ T cell proliferation and resulted in significant enhancement of response rates and therapeutic efficacy, pointing to the potential merits of a combinational targeting approach.

Evaluation of combinations of IDO inhibitors is currently being tested in melanoma patients in a phase I/II study, with preliminary data indicating promising activity. Therefore, IDO inhibition strategies might lead to re(activation) of tumor-targeting immune responses, and combination approaches with IDO inhibition may be efficacious, especially in patients with a high IDO expression.

Fig.1 Mechanisms of IDO pathway activity in immune tolerance. (Brochez, 2017)

Services at Creative Biolabs

Creative Biolabs is a leading service provider that focuses on immune checkpoint drug development. Combining state-of-the-art technology with personal service and attention, Creative Biolabs offers a series of custom services for immune checkpoint CTLA-4 and IDO, including but not limited to:

• Immune Checkpoint Antibody Development
• Immune Checkpoint Targeted Small Molecule Drug Development
• Immune Checkpoint Assays
• Custom Immune Checkpoint Protein Development
• Immune Checkpoint Targeted Peptide Development
• Preclinical Research for Immune Checkpoint Drugs

Please do not hesitate to contact us for more detailed information.

Reference

1. Brochez, L.; et al. The rationale of indoleamine 2, 3-dioxygenase inhibition for cancer therapy. European Journal of Cancer. 2017, 76, pp.167-182.

All listed customized services & products are for research use only, not intended for pharmaceutical, diagnostic, therapeutic, or any in vivo human use.