Checkpoint inhibitors in hematological malignancies

Abstract

Inhibitory molecules such as PD-1, CTLA-4, LAG-3, or TIM-3 play a role to keep a balance in immune function. However, many cancers exploit such molecules to escape immune surveillance. Accumulating data support that their functions are dysregulated in lymphoid neoplasms, including plasma cell myeloma, myelodysplastic syndrome, and acute myeloid leukemia. In lymphoid neoplasms, aberrations in 9p24.1 (PD-L1, PD-L2, and JAK2 locus), latent Epstein-Barr virus infection, PD-L1 3'-untranslated region disruption, and constitutive JAK-STAT pathway are known mechanisms to induce PD-L1 expression in lymphoma cells. Clinical trials demonstrated that PD-1 blockade is an attractive way to restore host's immune function in hematological malignancies, particularly classical Hodgkin lymphoma. Numerous clinical trials exploring PD-1 blockade as a single therapy or in combination with other immune checkpoint inhibitors in patients with hematologic cancers are under way. Although impressive clinical response is observed with immune checkpoint inhibitors in patients with certain cancers, not all patients respond to immune checkpoint inhibitors. Therefore, to identify best candidates who would have excellent response to checkpoint inhibitors is of utmost importance. Several possible biomarkers are available, but consensus has not been made and pursuit to discover the best biomarker is ongoing.

Keywords: CTLA-4; Hematologic malignancies; Immune checkpoint; PD-1; PD-L1; PD-L2.

Fig. 1

T cell activation signals. The main signal is mediated by T cell receptor. Co-stimulatory signal is provided by CD28. Co-inhibitory signals are mediated by CTLA-4, PD-1, LAG-3, or TIM-3. TIM-3 T cell immunoglobulin and mucin domain-containing protein-3. LAG-3 lymphocyte activation gene-3, PD-1 programmed death-1, CTLA-4 cytotoxic T-lymphocyte antigen-4, TCR T cell receptor, HMGB1 high mobility group protein B1, MHC major histocompatibility complex, PD-L1 programmed death-ligand 1, PD-L2 programmed death-ligand 2

Fig. 2

From discovery for immunocheckpoints to FDA approval of immunocheckpoint inhibitors. CHL classical Hodgkin lymphoma, NSCLC non-small cell lung cancer, RCC renal cell carcinoma, SCCHN squamous cell carcinoma of the head and neck, UCC urothelial carcinoma