Progress in the treatment of non-Hodgkin's lymphomas

The authors analyze the progress achieved in the treatment of low-grade as well as of high-grade non-Hodgkin's lymphomas. The challenging task in the treatment of low-grade or indolent lymphomas still is to decide whether watchful waiting is sufficient or whether chemotherapy is necessary and how aggressive this treatment should be. Among the new chemotherapeutic agents the role of purine analogues should be emphasized, fludarabin is especially important in the treatment of chronic lymphocytic leukemia and follicular lymphoma, while pentostatin and cladribine have revolutionized the treatment of hairy cell leukemia. Treatment with monoclonal antibodies, radioimmunoconjugates as well as autologous or allogeneic stem cell transplantation are potential new therapeutic options in the treatment of low-grade non-Hodgkin's lymphomas. In the case of aggressive non-Hodgkin's lymphomas risk-adapted strategies help the choice between standard or more intensive treatment options. In patients with relapsed high-grade lymphomas stem cell transplantation is indicated. In patients with marginal zone lymphoma the combination of hyperCVAD protocol + stem cell transplantation greatly improves prognosis.     

Grand rounds at the National Institutes of Health: HDAC inhibitors as radiation modifiers, from bench to clinic

Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumour. Patients afflicted with this disease unfortunately have a very poor prognosis, and fewer than 5% of patients survive for 5 years from the time of diagnosis. Therefore, improved therapies to treat this disease are sorely needed. One such class of drugs that have generated great enthusiasm for the treatment of numerous malignancies, including GBM, is histone deacetylase (HDAC) inhibitors. Pre-clinical data have demonstrated the efficacy of various HDAC inhibitors as anticancer agents, with the greatest effects shown when HDAC inhibitors are used in combination with other therapies. As a result of encouraging pre-clinical data, numerous HDAC inhibitors are under investigation in clinical trials, either as monotherapies or in conjunction with other treatments such as chemotherapy, biologic therapy or radiation therapy. In fact, two actively studied HDAC inhibitors, vorinostat and depsipeptide, were recently approved for the treatment of refractory cutaneous T cell lymphoma. In this review, we first present a patient with GBM, and then discuss the pathogenesis, epidemiology and current treatment options of GBM. Finally, we examine the translation of pre-clinical studies that have demonstrated HDAC inhibitors as potent radiosensitizers in in vitro and in vivo models, to a phase II clinical trial combining the HDAC inhibitor, valproic acid, along with temozolomide and radiation therapy for the treatment of GBM.     

Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B-cell lymphoma

Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapy outcomes. Here, we examined the therapeutic effects of chidamide, a new histone deacetylase (HDAC) inhibitor, on the cell and mouse models of rituximab/chemotherapy resistant B-cell lymphoma. In Raji-4RH/RL-4RH cells, the rituximab/chemotherapy resistant B-cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest. The primary B-cell lymphoma cells from Rituximab/chemotherapy relapsed patients were sensitive to chidamide. Interestingly, chidamide triggered the cell death with the activation of autophagy in RRCLs, likely due to the lack of the pro-apoptotic proteins. Based on the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as chidamide target genes, which control the autophagy and the cell cycle, respectively. Moreover, the combination of chidamide with the chemotherapy drug cisplatin increased growth inhibition on the RRCL in a synergistic manner, and significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, these results provide a theoretic and mechanistic basis for further evaluation of the chidamide-based treatment in rituximab/chemotherapy relapsed and refractory B-cell lymphoma patients.Subject terms: Targeted therapies, B-cell lymphoma     

Recent advances in cellular therapy for malignant lymphoma

Cellular therapies for malignant lymphoma include autologous or allogeneic hematopoietic stem cell transplantation (HSCT) and adaptive cellular therapy using EBV-specific T cells, cytokine-induced killer (CIK) cells, NKT cells, NK cells, chimeric antigen receptor T (CAR-T) cells and chimeric antigen receptor NK (CAR-NK) cells. In this review we discusses recent advances of these cellular therapies and consider ways to optimize these therapies. Not only a single strategy using one of these cellular therapies, but also multi-disciplinary treatment combines with antibodies, such as an anti-tumor antibody and an immune checkpoint antibody, may be more effective for relapsed and refractory lymphoma.     

Novel antigens of CAR T cell therapy: New roads; old destination

Chimeric antigen receptor T cell (CAR-T) therapy has so far proved itself as a reliable therapeutic option for the treatment of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), and mantle cell lymphoma (MCL). However, this picture is not as colorful when it comes to the treatment of solid tumors mainly due to the lack of definitive tumor antigens, as well as the immunosuppressive tumor microenvironments and poor CAR-T infiltration. The recent developments in bioinformatics and cell biology, such as single-cell RNA sequencing, have offered silver linings in the subject of tumor antigen discovery. In the current review, we summarize the development of some CAR-T therapies that target novel tumor antigens, rather than the traditionally CAR-T-targeted ones, and briefly discuss the clinical antitumor achievements of those evaluated in patients, so far. Furthermore, we propose some tumor antigens that might someday be therapeutically beneficial while targeted by CAR-Ts based on the experimental evaluations of their specific monoclonal antibodies.     

Downregulation of STAT3 phosphorylation enhances tumoricidal effect of IL-15-activated dendritic cell against doxorubicin-resistant lymphoma and leukemia via TNF-α

Although disputed by some, increasing evidence suggests that TNF-α synergies with traditional chemotherapeutic drugs to exert a heightened antitumor effect. The present study investigated the antitumor efficacy of recombinant IL-15 in combination with the STAT3 inhibitor cucurbitacin-I in a doxorubicin-resistant murine lymphoma model. The significance of the work is to understand and design effective strategies in doxorubicin resistant lymphomas. TNF-α is downregulated in dendritic cells from mice with Dalton's lymphoma and shows an inverse relationship with disease progression. Doxorubicin-resistant DL cells have elevated levels of Bcl-2 and Mcl-1 and increased phosphorylation of STAT3. These cells are refractory to dendritic cell derived TNF-α. Doxorubicin resistant Dalton's lymphoma is susceptible to dendritic cell derived TNF-α upon stimulation with the STAT3 inhibitor cucurbitacin-I, which downregulates STAT3 and other survival molecules. The combined treatment of low dose of cucurbitacin-I and rIL-15 is ineffective in mice with doxorubicin resistant Dalton's lymphoma, but a similar therapy prolongs the survival of mice transplanted with parental Dalton's lymphoma. Doxorubicin resistant Dalton's lymphoma responds to therapy with high doses of cucurbitacin-I and rIL-15. Dendritic cell derived from mice responded positively to the therapy and regained their tumoricidal properties with respect to growth inhibition and killing of DL tumor cells. Similar to DL, DC derived from CML patients are impaired in TNF-α expression and are unable to restrict the growth of drug-resistant lymphoma and leukemia cells. This combination approach could be used as a new therapeutic strategy for aggressive and highly metastatic doxorubicin resistant lymphoma.     

Efficacy and toxicity for CD22/CD19 chimeric antigen receptor T-cell therapy in patients with relapsed/refractory aggressive B-cell lymphoma involving the gastrointestinal tract

Gastrointestinal (GI) tract is the most common site of extranodal involvement in non-Hodgkin lymphoma. Life-threatening complications of GI may occur because of tumor or chemotherapy. Chimeric antigen receptor (CAR) T-cell therapy has been successfully used to treat refractory/relapse B-cell lymphoma, however, little is known about the efficacy and safety of CAR-T cell therapy for GI lymphoma. Here, we reported the efficacy and safety of CAR-T cell therapy in 14 patients with relapsed/refractory aggressive B-cell lymphoma involving the GI tract. After a sequential anti-CD22/anti-CD19 CAR-T therapy, 10 patients achieved an objective response, and seven patients achieved a complete response. CAR transgene and B-cell aplasia persisted in the majority of patients irrespective of response status. Six patients with partial response or stable disease developed progressive disease; two patients lost target antigens. Cytokine release syndrome (CRS) and GI adverse events were generally mild and manageable. The most common GI adverse events were diarrhea (4/14), vomiting (3/14) and hemorrhage (2/14). No perforation occurred during follow-up. Infection is a severe complication in GI lymphoma. Two patients were infected with bacteria that are able to colonize at GI; one died of sepsis early after CAR-T cells infusion. In conclusion, our study showed promising efficacy and safety of CAR-T cell therapy in refractory/relapsed B-cell lymphoma involving the GI tract. However, the characteristics of CAR-T–related infection in GI lymphoma should be further clarified to prevent and control infection.     

Promising immunotherapy: Highlighting cytokine-induced killer cells

For many years, cancer therapy has appeared to be a challenging issue for researchers and physicians. By the introduction of novel methods in immunotherapy, the prospect of cancer therapy even more explained than before. Cytokine-induced killer (CIK) cell-based immunotherapy demonstrated to have potentiality in improving clinical outcomes and relieving major side effects of standard treatment options. In addition, given the distinctive features such as high safety, low toxicity effects on healthy cells, numerous clinical trials conducted on CIK cells. Due to the shortcomings that observed in CIK cell immunotherapy alone, arising a tendency to make modifications (combined modality therapy or combination therapy) including the addition of various types of cytokines, genetic engineering, combination with immune checkpoints, and so on. In this review, we have tried to bring forth the latest immunotherapy methods and their overview. We have discussed the combination therapies with CIK cells and the conducted clinical trials. This helps the future studies to use integrated therapies with CIK cells as a promising treatment of many types of cancers.     

Brentuximab vedotin

Brentuximab vedotin (SGN-35; Adcetris®) is an anti-CD30 antibody conjugated via a protease-cleavable linker to the potent anti-microtubule agent monomethyl auristatin E (MMAE). Following binding to CD30, brentuximab vedotin is rapidly internalized and transported to lysosomes where MMAE is released and binds to tubulin, leading to cell cycle arrest and apoptosis. Several trials have shown durable antitumor activity with a manageable safety profile in patients with relapsed/refractory Hodgkin lymphoma, systemic anaplastic large cell lymphoma, or primary cutaneous CD30-positive lymphoproliferative disorders. Peripheral sensory neuropathy is a significant adverse event associated with brentuximab vedotin administration. Neuropathy symptoms are cumulative and dose-related. Multiple ongoing trials are currently evaluating brentuximab vedotin alone or in combination with other agents in relapsed/refractory patients, as well as patients with newly diagnosed disease.     

Brentuximab vedotin

Brentuximab vedotin (SGN-35; Adcetris®) is an anti-CD30 antibody conjugated via a protease-cleavable linker to the potent anti-microtubule agent monomethyl auristatin E (MMAE). Following binding to CD30, brentuximab vedotin is rapidly internalized and transported to lysosomes where MMAE is released and binds to tubulin, leading to cell cycle arrest and apoptosis.

Several trials have shown durable antitumor activity with a manageable safety profile in patients with relapsed/refractory Hodgkin lymphoma, systemic anaplastic large cell lymphoma, or primary cutaneous CD30-positive lymphoproliferative disorders. Peripheral sensory neuropathy is a significant adverse event associated with brentuximab vedotin administration. Neuropathy symptoms are cumulative and dose-related. Multiple ongoing trials are currently evaluating brentuximab vedotin alone or in combination with other agents in relapsed/refractory patients, as well as patients with newly diagnosed disease.