Checkpoint inhibitor/interleukin-based combination therapy of cancer

Abstract

Background: Immunotherapy using immune checkpoint inhibitors (ICIs) is the current focus in cancer immunotherapy. However, issues are raised in the area, as the recent studies showed that such therapeutic modality suffers from low durability and low or no efficacy for patients with some tumor types including cases with non-inflamed or cold cancers. Therefore, efforts have been made to solve the issue using immune combination therapy, such as the use of immunocytokines. The combination of ICI with interleukins (ILs) and IL-targeting agents is now under consideration in the area of therapy, and the primary results are promising.

Purpose: The focus of this review is to discuss the possibility of using ILs and IL-targeting drugs in combination with ICI in cancer immunotherapy and describing recent advances in the field using PEGylated ILs and fusion proteins. The key focus in this area is to reduce adverse events and to increase the efficacy and durability of such combination therapy.

Keywords: combination therapy; immune checkpoint inhibitor; interleukin; programmed death-1 receptor; programmed death-ligand 1.

FIGURE 1

The immunosuppressive activity of programmed death‐ligand 1 (PD‐L1) in tumor microenvironment (TME). Dendritic cells (DCs) express PD‐L1 to suppress responses from CD8⁺ T cells. PD‐L1⁺ tumor cells and PD‐L1⁺ myeloid‐derived suppressor cells (MDSCs) suppress CD8⁺ T cell effector function and promote their exhaustion. PD‐L1 expression is also related to the macrophage polarization toward the pro‐tumor macrophage type 2 (M2) phenotype. This preferential polarity is stimulated by PD‐L1⁺ regulatory T cells (Tregs). PD‐L1 acts via interaction with a programmed death‐1 receptor (PD‐1). High expression of this receptor in a PD‐L1^high TME stimulates Treg proliferation and promotes CD8⁺ T cell apoptosis

FIGURE 2

The impact of combinatory immune checkpoint inhibitor (ICI)/interleukin (IL) therapy on cellular immunity within tumor microenvironment (TME). Higher recruitment of CD8⁺ T cells into TME occurs upon a combination of programmed death‐1 receptor (PD‐1) inhibitors with IL‐2 agonist or IL‐6 inhibitors. Bispecific fusion proteins are promising agents in the current research in cancer immunotherapy. N‐809 is an example of such agents that encompasses a fusion complex for IL‐15 superagonist and anti‐programmed death‐ligand 1 (PD‐L1), and it can be used to promote the activity of both natural killer (NK) and CD8⁺ T cells. Fusion of IL‐21 to anti‐PD‐1 antibody promotes the formation of memory stem T cells (T_SCMs). Effector activity of NK cells is induced by PD‐1/T cell immunoglobulin mucin‐3 (TIM‐3) blockade along with intra‐tumoral rIL‐21. Recruitment and proliferation of CD8⁺ T cells is also induced by IL‐21 when used in combination with anti‐PD‐1 or anti‐cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4) antibodies

FIGURE 3

Promising objective response rate (ORR) for combinatory immune checkpoint inhibitor (ICI)/interleukin (IL) therapy in patients with cancer. The combination of programmed death‐1 receptor (PD‐1) inhibitors with IL12 plasmid and PEGylated recombinant IL‐10 (also called pegilodecakin) renders noticeable ORR in cancer patients. ORR is also significant for the IL‐15 superagonist ALT‐803. The most considerable objective response is for the IL‐2 agonist bempegaldesleukin (also called NKTR‐214), which is designed preferentially for CD122 (IL‐2β receptor)