The progress of novel strategies on immune-based therapy in relapsed or refractory diffuse large B-cell lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) can be cured with standard front-line immunochemotherapy, whereas nearly 30-40% of patients experience refractory or relapse. For several decades, the standard treatment strategy for fit relapsed/refractory (R/R) DLBCL patients has been high-dose chemotherapy followed by autologous hematopoietic stem cell transplant (auto-SCT). However, the patients who failed in salvage treatment or those ineligible for subsequent auto-SCT have dismal outcomes. Several immune-based therapies have been developed, including monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engaging antibodies, chimeric antigen receptor T-cells, immune checkpoint inhibitors, and novel small molecules. Meanwhile, allogeneic SCT and radiotherapy are still necessary for disease control for fit patients with certain conditions. In this review, to expand clinical treatment options, we summarize the recent progress of immune-related therapies and prospect the future indirections in patients with R/R DLBCL.

Keywords: Diffuse large B-cell lymphoma; Immunotherapy; Radiotherapy; Refractory; Relapsed.

Fig. 1

Monoclonal antibodies applied in R/R DLBCLs. Many monoclonal antibodies can be used in R/R DLBCLs. Among these, Tafasitamab showed an apparent synergistic effect with Lenalidomide (a). Tafasitamab shows direct cytotoxicity, ADCC and ADCP. Lenalidomide shows direct cytotoxicity, enhances ADCC and stimulates interferon-ϒ secretion, lowering the NK cell activation threshold and increasing NK cell proliferation by promoting interleukin-2 production (b). Obinutuzumab is a type II anti-CD20 monoclonal antibody with no CD20 internalization and a stronger antitumor effect than Rituximab (type I anti-CD20 monoclonal antibody) (c). ADCC antibody-dependent cell mediated cytotoxicity, ADCP antibody-dependent cell-mediated phagocytosis, CDC complement dependent cytotoxicity

Fig. 2

Antibody–drug conjugates used in R/R DLBCLs. This picture shows the mechanisms and processes of antibody–drug conjugates in lymphoma patients. Once the antibody binds the target antigen on the tumor cell surface. The complex is rapidly endocytosed and transported to lysosomes, where the effector molecule MMAE is released into the cytoplasm leading to cell toxicity. ADC antibody–drug conjugate

Fig. 3

How do bispecific antibodies work. Bispecific antibodies (BsAbs) are engineered to simultaneously bind a cytotoxic cell and a target (a lymphoma cell) to be destroyed. The Fc region binds to cells expressing Fc receptors, like a macrophage, natural killer, or dendritic cell. BsAbs are artificial proteins composed of fragments of two monoclonal antibodies and can bind to two types of antigens (a). BsAbs function by bringing targeted tumor cells close to T-cells to allow killing via perforin and granzyme release (b). ADCC antibody dependent cell-mediated cytotoxicity, FCR Fc receptor, VH heavy chain variable region, VL light chain variable region, TAA tumor associated antigen

Fig. 4

The usage and progress of CAR-T cell therapy. In CAR T-cell therapy, the patient's T cells are collected and sent to a lab. In the lab, they are genetically modified to recognize target lymphoma cells. These genetically modified T cells are named CAR-T cells. After that, the CAR-T cells are expanded in the lab until there are enough to treat the lymphoma cells. Then, CAR-T cells are returned to the patient, like a blood transfusion. When they recognize the lymphoma cells in the body, the CAR-T cells are activated and kill the lymphoma cells (a). There are currently five generations of CAR-T cell products. The first-generation, composed of scFv and CD3ξ, is a single chain approach based on the scFv, which joins the antibody's heavy and light variable gene segments with a flexible linker. Second-generation CARs contain the scFv and CD3ξ components present in the first-generation together with a costimulatory domain, which markedly increases T-cell proliferation and interleukin -2 secretion. Axi-cel contains a CD28 costimulatory domain, while Tisa-cel and Liso-cel contain the 4-1BB costimulatory domain. The third-generation CARs contain both CD28 and 4-1BB and have superior expansion and longer persistence than the second-generation CARs. Fourth-generation CARs incorporate a transgenic cytokine sequence and counteract the immunosuppressive microenvironment in tumors. The fifth-generation CARs encode a truncated cytoplasmic domain of IL-2Rb and a STAT3- binding YXXQ motif together with scFv targeting CD19, CD3z, and CD28 domains, which show better proliferation and cytokine polyfunctionality compared to second-generation CARs (b). NK cells do not require HLA matching like T cells. It makes “off-the-shelf” NK cell therapy a viable option. CAR NK cells will release perforin and granzymes to kill tumor cells (c). Most CAR-T therapies consist of autologous T cells, whereas CAR-NK cell therapies can be generated from allogeneic donors

Fig. 5

The mechanism and usage of immune checkpoint inhibitors. PD-1/PD-L1 binding inhibits T cell killing of lymphoma cells. Blocking PD-1 and PD-L1 allows T cell killing, APC-T cell interaction, and T cell stimulation in a lymphoma microenvironment (a). When SIRPα interacts with its ligand CD47 on tumor cells, SIRPα undergoes tyrosine phosphorylation and recruits the protein tyrosine phosphatases. These phosphatases inhibit the ability of prophagocytic receptors to trigger phagocytosis when ligands are present on tumor cells. Blocking CD47-SIRPα signaling with an anti-CD47 or SIRPα monoclonal antibody enhances macrophage-mediated phagocytosis of lymphoma cells (b). Anti-CD47 monoclonal antibody synergises with Rituximab when lymphoma cells double express CD20 and CD47 proteins (c)

Fig. 6

The application of small molecules agents in R/R DLBCLs. Several biomarkers are potentially targeted in R/R DLBCLs, including BCR (PI3K, MTOR), BCL2, XPO1, NF-κB, and CARD11-BCL10-MALT1 inhibitors

Fig. 7

The recommended therapies for R/R DLBCLs. This chat shows the recommended therapies with patients of R/R DLBCL in different clinical states. DLBCL diffuse large B-cell lymphoma, CAR-T chimeric antigen receptor T cells, RT radiotherapy, BSC best supportive care, CR complete response, PR partial response, SD stable disease, PD progressive disease, HDT high-dose chemotherapy, SCT, stem cell transplantation. ¶ second-line chemotherapy for transplant eligible: DHAP ± R, GDP ± R, ICE ± R, ESHAP ± R, GemOx ± R, MINE ± R, § second-line therapy for transplant ineligible: CAR-T (Liso-cel), Pola ± B ± R, Tafa + Len, CEOP ± R, DA-EPOCH ± R, GDP ± R, GemOx ± R, Rituximab, BV, BTKi, Len ± R, † second-line chemotherapy for relapse within 12 months or refractory disease: alternative systemic therapy, Ж, Bridging therapy: DHAP ± R, GDP ± R, ICE ± R, Pola ± B ± R, RT, ξ CAR-T products: Axi-cel, Liso-cel, € CAR-T products: Axi-cel, Liso-cel, Tisa-cel, ₤ ≥ Third-line chemotherapy: alternative systemic therapy