Innate Immune Checkpoint Inhibitors: The Next Breakthrough in Medical Oncology?

Abstract

While immunotherapy has revolutionized the treatment of many types of advanced cancer, most patients still do not derive benefit. The currently available immune checkpoint inhibitors target the adaptive immune system, generating a T-cell antitumor response. However, an antitumor immune response depends on a complex interplay of both innate and adaptive immune cells. The innate immune system is a promising new target, and innate immune checkpoint inhibitors can disrupt inhibitory interactions ("don't eat me" signals) between tumor and both phagocytes and natural killer cells. The checkpoint inhibitor may also provide a stimulatory interaction ("eat me" signal), or this can be achieved through use of combination therapy. This generates antitumor effector functions including phagocytosis, natural cytotoxicity, antibody-dependent effects, and synergistic activation of the adaptive immune system via antigen presentation. This is a rapidly expanding area of drug development, either alone or in combination (with anticancer antibodies or adaptive immune checkpoint inhibitors). Here, we comprehensively review the mechanism of action and up-to-date solid tumor clinical trial data of the drugs targeting phagocytosis checkpoints (SIRPα/CD47, LILRB1/MHC-I, and LILRB2/MHC-I) and natural killer-cell checkpoints (TIGIT/CD112 + CD155, PVRIG/CD112, KIRs/MHC-I, and NKG2A-CD94/HLA-E). Innate immune checkpoint inhibitors could once again revolutionize immune-based cancer therapies.

Figure 1.. Innate immune cell-surface regulatory interactions & therapeutic targets

Innate immune cell anti-tumor function is regulated in part by stimulatory (“eat me”) and inhibitory (“don’t eat me”) cell-surface interactions with the cancer cell, generally involving a receptor on the immune cell and antigen on the cancer cell. Inhibitory interactions (“checkpoints”) exist to maintain physiologic immune responses, i.e. to induce tolerance. Normal human cells generally avoid immune destruction by expressing more inhibitory than stimulatory antigens. Cancer cells, likewise, can evade the innate immune system by expressing inhibitory antigens and lacking stimulatory antigens (figure left). Cancer cells may also express stimulatory antigens, activating innate immune cells and resulting in phagocytosis (phagocytes) or natural cytotoxicity (natural killer cells). Conceptually, there are four scenarios under which the balance of stimulatory and inhibitory signaling favors innate immune cell anti-tumor effects. Firstly, the cancer cell lacks inhibitory antigens and stimulatory signals are present; radiation/chemotherapy may increase cancer cell expression of stimulatory antigens (figure right, #1). Secondly, an innate immune checkpoint inhibitor can block the inhibitory checkpoint while a stimulatory signal is present (figure right, #2). Thirdly, a combination therapy approach can block the inhibitory checkpoint (with an innate immune checkpoint inhibitor lacking an active Fc region) while a second drug (anti-cancer antibody) can provide the stimulatory signal upon interacting with innate immune cell Fc receptors (figure right, #3). Finally, an innate immune checkpoint inhibitor containing an active Fc region can both block the inhibitory checkpoint and provide the stimulatory signal upon interacting with an innate immune cell Fc receptor (figure right, #4). This final strategy is often limited by hematologic toxicity. Created with BioRender.com.

Figure 2.. Innate immune checkpoints and inhibitors

Tumor cells express ligands (“don’t eat me” signals) which interact with phagocyte (Panel A) and natural killer (Panel B, NK) cell-surface receptors, stimulating signaling pathways which inhibit phagocytosis and natural cytotoxicity, respectively. The phagocytosis checkpoints (Panel A) include (a) SIRPα/CD47, (b) LILRB1/MHC-I, and (c) LILRB2/MHC-I. Drugs are being developed to interrupt these signaling pathways, thereby increasing phagocytosis of tumor cells; drugs with presented/published clinical trial data are shown. (a) The anti-CD47 drugs are ALX148 (engineered fusion protein - two high affinity CD47 binding domains of SIRPα linked to an inactive Fc), magrolimab (anti-CD47 humanized IgG4 mAb), SRF231 (anti-CD47 fully human IgG4 mAb), lemzoparlimab (anti-CD47 humanized IgG4 mAb), and IBI188 (anti-CD47 humanized IgG4 mAb). No compounds blocking the LILRB1/MHC-I axis have available clinical trial results (b). MK-4830 is an anti-LILRB2 fully human IgG4 mAb (c). The NK checkpoints (Panel B) include (a) TIGIT/CD155+CD112, (b) PVRIG/CD112, (c) Inhibitory KIRs/MHC-I, and (d) NKG2A-CD94/HLA-E. Drugs are being developed to interrupt these signaling pathways, thereby increasing natural cytotoxicity of tumor cells; drugs with presented/published clinical trial data are shown. Tiragolumab, vibostolimab, and etigilimab are anti-TIGIT humanized IgG1 mAbs (a). COM701 is an anti-PVRIG humanized IgG4 mAb (b). Lirilumab is an anti-KIR2D fully human IgG4 mAb (c). Monalizumab is an anti-NKG2A-CD94 humanized IgG4 mAb (d). Created with BioRender.com. Abbreviations: B2MG, beta-2-microglobulin; Fc, immunoglobulin fragment crystallizable region; HLA, human leukocyte antigen; Ig, immunoglobulin; KIR, killer cell immunoglobulin-like receptor; LILRB1, leukocyte immunoglobulin-like receptor B1; LILRB2, leukocyte immunoglobulin-like receptor B2; mAb, monoclonal antibody; MHC, major histocompatibility complex; NKG2A, NK group 2 member A; PVRIG, poliovirus receptor related immunoglobulin domain containing; SIRPα, signal-regulatory protein-α; TIGIT, T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motifs domain.