Immune checkpoint inhibitors in malignant lymphoma: Advances and perspectives

Abstract

Classical Hodgkin lymphoma (cHL) has been identified with universal genetic alterations of chromosome 9p24.1, which contains PD-L1/PD-L2 genes. The amplification of 9p24.1 is associated with the increased expression of PD-L1 and PD-L2 on RS cells, which promotes their immune evasion, and subsequently makes cHL sensitive to PD-1 blockade. Several PD-1 inhibitors have shown significant efficacies with overall response rate (ORR) of 70%−90% in relapse/refractory (r/r) cHL and have acquired the approvals for this indication. Recently, more and more studies are conducted to investigate PD-1 blockade in earlier disease course and in combination with neo-agents or chemotherapy. Unlike cHL, non-Hodgkin lymphoma (NHL) consists of numerous subtypes harboring highly biological heterogeneity. Only a few subtypes have been shown to have genetic alteration of 9p24.1 including primary mediastinal B cell lymphoma (PMBL), gray zone lymphoma (GZL) with features intermediate between diffuse large B cell lymphoma (DLBCL) and cHL, primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL). Epstein-Barr virus (EBV)-associated lymphomas have a virally mediated overexpression of PD-L1, also making them sensitive to PD-1 blockade. Therefore, PD-1 inhibitors are less effective in most r/r NHL than in r/r cHL. Further understanding of the biological features of NHL and immune checkpoint inhibitors (ICPi) combined therapy is the research focus in the future. In this review, we outlined the recent progress of ICPi in lymphoma originating from clinical studies.

B7 Family Members in Lymphoma: Promising Novel Targets for Tumor Immunotherapy?

“…Anti-PD-1 antibodies have been approved for use in various solid tumors and lymphomas ( 7 ). A multicenter, single-arm, phase II trial of sintilimab to treat relapsed or refractory classical Hodgkin’s lymphoma (cHL) was carried out in China and showed that the overall response rate (ORR) was 80.4% ( 5 , 8 ).…”

“…The finished clinical trials are summarized in Table 1 and ongoing ones in Table 2 . Avelumab is a fully human IgG1 mAb that selectively blocks PD-L1 and enhances anti-tumor T-cell activity ( 7 ). A phase I study of avelumab demonstrated that ORR and complete response (CR) were 54.8% and 6.5%, respectively, in patients with relapse/refractory cHL who had suffered progression following stem cell transplantation (SCT) or SCT-ineligible ( 7 ).…”

“…Avelumab is a fully human IgG1 mAb that selectively blocks PD-L1 and enhances anti-tumor T-cell activity ( 7 ). A phase I study of avelumab demonstrated that ORR and complete response (CR) were 54.8% and 6.5%, respectively, in patients with relapse/refractory cHL who had suffered progression following stem cell transplantation (SCT) or SCT-ineligible ( 7 ). A phase II trial demonstrated that the CR of avelumab was 24% and that the ORR was 38% in patients with relapsed or refractory ENKTL ( 14 ).…”

Current Immunotherapy Approaches in Non-Hodgkin Lymphomas

“…Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) binds to CD80 (B7-1) or CD86 (B7-2) and decreases activity of T cells by interrupting CD28-mediated co-stimulatory signaling. Aberrant overexpression of programmed death ligands 1 and 2 (PD-L1, PD-L2) or T-cell immunoglobulin and mucin domain 3 (TIM3) on malignant cells induce T-cell impairment, exhaustion, and apoptosis [ 64 , 65 , 66 ]. With the approval of several immune checkpoint inhibitors for the treatment of diverse solid cancers, it is now evident that the original proof-of-concept of inhibition of cancer-induced immunosuppression successfully translated into clinical practice.…”

“…In 2018, James P. Allison and Tasuku Honjo were awarded a Nobel Prize in Physiology and Medicine “for their discovery of cancer therapy by inhibition of negative immune regulation”. In hematologic malignancies, PD-1 blockade with nivolumab or pembrolizumab in R/R Hodgkin lymphoma became a flagship of immune checkpoint inhibition in lymphoproliferative disorders reaching ORR of 65% to 87% [ 66 ]. Curiously, in contrast to solid tumors and Hodgkin lymphoma, the implementation of checkpoint inhibitors into the treatment algorithms of NHL still remains a matter of investigation [ 68 ].…”