Amino acid metabolism is a critical regulator of the immune response, and its modulating becomes a promising approach in various forms of immunotherapy. Insufficient concentrations of essential amino acids restrict T-cells activation and proliferation. However, only arginases, that degrade L-arginine, as well as enzymes that hydrolyze L-tryptophan are substantially increased in cancer. Two arginase isoforms, ARG1 and ARG2, have been found to be present in tumors and their increased activity usually correlates with more advanced disease and worse clinical prognosis. Nearly all types of myeloid cells were reported to produce arginases and the increased numbers of various populations of myeloid-derived suppressor cells and macrophages correlate with inferior clinical outcomes of cancer patients. Here, we describe the role of arginases produced by myeloid cells in regulating various populations of immune cells, discuss molecular mechanisms of immunoregulatory processes involving L-arginine metabolism and outline therapeutic approaches to mitigate the negative effects of arginases on antitumor immune response. Development of potent arginase inhibitors, with improved pharmacokinetic properties, may lead to the elaboration of novel therapeutic strategies based on targeting immunoregulatory pathways controlled by L-arginine degradation.

Figure 1 Timeline of the procedures performed in patients with CDI, which coincidentally occurred during COVID-19 early stage infection. Created with BioRender.com. CDI, Clostridioides difficile infection; ESBL, extended-spectrum beta-lactamase, FMT, faecal microbiota transplant.

In recent years, the introduction of chimeric antigen receptor (CAR) T-cell therapies into clinics has been a breakthrough in treating relapsed or refractory malignancies in hematology and oncology. To date, Food and Drug Administration (FDA) has approved six CAR-T therapies for specific non-Hodgkin lymphomas, B-cell acute lymphoblastic leukemia, and multiple myeloma. All registered treatments and most clinical trials are based on so-called 2nd generation CARs, which consist of an extracellular antigen-binding region, one costimulatory domain, and a CD3z signaling domain. Unfortunately, despite remarkable overall treatment outcomes, a relatively high percentage of patients do not benefit from CAR-T therapy (overall response rate varies between 50 and 100%, with following relapse rates as high as 66% due to limited durability of the response). Moreover, it is associated with adverse effects such as cytokine release syndrome and neurotoxicity. Advances in immunology and molecular engineering have facilitated the construction of the next generation of CAR-T cells equipped with various molecular mechanisms. These include additional costimulatory domains (3rd generation), safety switches, immune-checkpoint modulation, cytokine expression, or knockout of therapy-interfering molecules, to name just a few. Implementation of next-generation CAR T-cells may allow overcoming current limitations of CAR-T therapies, decreasing unwanted side effects, and targeting other hematological malignancies. Accordingly, some clinical trials are currently evaluating the safety and efficacy of novel CAR-T therapies. This review describes the CAR-T cell constructs concerning the clinical application, summarizes completed and ongoing clinical trials of next-generation CAR-T therapies, and presents future perspectives.

During recent years considerable progress has been made in the treatment of multiple myeloma. However, despite the current improvements in the prognosis of this malignancy, it always ends with relapse, and therefore new therapy approaches for destroying resistant cancer cells are needed. Presently, there is great hope being placed in the use of immunotherapy against refractory/relapsed multiple myeloma which is unresponsive to any other currently known drugs. The most promising one is CAR-T cell therapy which has already shown tremendous success in treating other malignancies such as acute lymphoblastic leukaemia (ALL) and could potentially be administered to multiple myeloma patients. CAR-T cells equipped with receptors against BCMA (B-cell maturation antigen), which is a surface antigen that is highly expressed on malignant cells, are now of great interest in this field with significant results in clinical trials. Furthermore, CAR-T cells with other receptors and combinations of different strategies are being intensively studied. However, even with CAR-T cell therapy, the majority of patients eventually relapse, which is the greatest limitation of this therapy. Serious adverse events such as cytokine release syndrome or neurotoxicity should also be considered as possible side effects of CAR-T cell therapy. Here, we discuss the results of CAR-T cell therapy in the treatment of multiple myeloma, where we describe its main advantages and disadvantages. Additionally, we also describe the current results that have been obtained on using combinations of CAR-T cell therapies with other drugs for the treatment of multiple myeloma.

The number of allogeneic hematopoietic stem cell transplantations conducted worldwide is constantly rising. Together with that, the absolute number of complications after the procedure is increasing, with graft-versus-host disease (GvHD) being one of the most common. The standard treatment is steroid administration, but only 40–60% of patients will respond to the therapy and some others will be steroid-dependent. There is still no consensus regarding the best second-line option, but fecal microbiota transplantation (FMT) has shown encouraging preliminary and first clinically relevant results in recent years and seems to offer great hope for patients. The reason for treatment of steroid-resistant acute GvHD using this method derives from studies showing the significant immunomodulatory role played by the intestinal microbiota in the pathogenesis of GvHD. Depletion of commensal microbes is accountable for aggravation of the disease and is associated with decreased overall survival. In this review, we present the pathogenesis of GvHD, with special focus on the special role of the gut microbiota and its crosstalk with immune cells. Moreover, we show the results of studies and case reports to date regarding the use of FMT in the treatment of steroid-resistant acute GvHD.