CAR-T Cells Shoot for New Targets: Novel Approaches to Boost Adoptive Cell Therapy for B Cell-Derived Malignancies

Chimeric antigen receptor (CAR)-T cell therapy is undeniably a promising tool in combating various types of hematological malignancies. However, it is not yet optimal and a significant number of patients experience a lack of response or relapse after the treatment. Therapy improvement requires careful analysis of the occurring problems and a deeper understanding of the reasons that stand behind them. In this review, we summarize the recent knowledge about CAR-T products’ clinical performance and discuss diversified approaches taken to improve the major shortcomings of this therapy. Especially, we prioritize the challenges faced by CD19 CAR-T cell-based treatment of B cell-derived malignancies and revise the latest insights about mechanisms mediating therapy resistance. Since the loss of CD19 is one of the major obstacles to the success of CAR-T cell therapy, we present antigens that could be alternatively used for the treatment of various types of B cell-derived cancers

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) results from a clonal expansion of abnormal lymphoid progenitors of B cell (BCP-ALL) or T cell (T-ALL) origin that invade bone marrow, peripheral blood, and extramedullary sites. Leukemic cells, apart from their oncogene-driven ability to proliferate and avoid differentiation, also change the phenotype and function of innate and adaptive immune cells, leading to escape from the immune surveillance. In this review, we provide an overview of the genetic heterogeneity and treatment of BCP- and T-ALL. We outline the interactions of leukemic cells in the bone marrow microenvironment, mainly with mesenchymal stem cells and immune cells. We describe the mechanisms by which ALL cells escape from immune recognition and elimination by the immune system. We focus on the alterations in ALL cells, such as overexpression of ligands for various inhibitory receptors, including anti-phagocytic receptors on macrophages, NK cell inhibitory receptors, as well as T cell immune checkpoints. In addition, we describe how developing leukemia shapes the bone marrow microenvironment and alters the function of immune cells. Finally, we emphasize that an immunosuppressive microenvironment can reduce the efficacy of chemo- and immunotherapy and provide examples of preclinical studies showing strategies for improving ALL treatment by targeting these immunosuppressive interactions

Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy

Lysosomes are conservative organelles with an indispensable role in cellular degradation and the recycling of macromolecules. However, in light of recent findings, it has emerged that the role of lysosomes in cancer cells extends far beyond cellular catabolism and includes a variety of cellular pathways, such as proliferation, metastatic potential, and drug resistance. It has been well described that malignant transformation leads to alterations in lysosomal structure and function, which, paradoxically, renders cancer cells more sensitive to lysosomal destabilization. Furthermore, lysosomes are implicated in the regulation and execution of cell death in response to diverse stimuli and it has been shown that lysosome-dependent cell death can be utilized to overcome apoptosis and drug resistance. Thus, the purpose of this review is to characterize the role of lysosome in cancer therapy and to describe how these organelles impact treatment resistance. We summarized the characteristics of typical inducers of lysosomal cell death, which exert its function primarily via alterations in the lysosomal compartment. The review also presents other anticancer agents with the predominant mechanism of action different from lysosomal destabilization, the activity of which is influenced by lysosomal signaling, including classical chemotherapeutics, kinase inhibitors, monoclonal antibodies, as well as photodynamic therapy

Additional file 4: Figure S3. of Long-lasting reduction in clonogenic potential of colorectal cancer cells by sequential treatments with 5-azanucleosides and topoisomerase inhibitors

Combinatorial treatments increase CRC cell apoptosis. Annexin V-FITC/PI-double staining of HCT116, DLD-1, and HT-29 cells after sequential treatments with 1 μM 5-aza-dC and 25 μM etoposide (n = 3). Figure 1a shows the treatment scheme. Data are presented as means ± SD. *P < 0.05 compared with DNA demethylating agent treatment group and topoisomerase inhibitor treatment group. (PDF 177 kb

Additional file 5: Figure S4. of Long-lasting reduction in clonogenic potential of colorectal cancer cells by sequential treatments with 5-azanucleosides and topoisomerase inhibitors

5-Aza-dC reduces CRC cell proliferation. Cell proliferation of DLD-1 cells within 7 days of exposure to 1 μM 5-aza-dC alone. Green histograms: tested cells; white histograms: unstained cells; grey histograms: the cells stained on the day of analysis. The percentage of cells in gates represents non-proliferating cells. Cell proliferation was assessed by CellTrace Far Red Cell Proliferation Kit (Molecular Probes, Thermo Fisher Scientific) according to the manufacturer’s protocol. Briefly, the cells were stained with CellTrace Far Red (1 μM) for 20 min at 37 °C. Data was acquired on a FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA) and analyzed using Flowing Software 2.5.1 software (Perttu Terho, Turku, Finland). (PDF 46 kb

Additional file 3: Figure S2. of Long-lasting reduction in clonogenic potential of colorectal cancer cells by sequential treatments with 5-azanucleosides and topoisomerase inhibitors

Combinatorial treatments increase apoptosis-associated DNA fragmentation in CRC cells. Representative histograms of HCT116, DLD-1, and HT-29 cells after sequential treatments with 1 μM 5-aza-dC and 5-50 μM etoposide. Figure 1a shows the treatment scheme. (PDF 208 kb

Additional file 1: Table S1. of Long-lasting reduction in clonogenic potential of colorectal cancer cells by sequential treatments with 5-azanucleosides and topoisomerase inhibitors

Comprehensive summary of CRC cell viability results after sequential treatments with 5-azanucleosides and topoisomerase inhibitors. Data are presented as means ± SD normalized to untreated control. *P < 0.05 compared with DNA demethylating agent treatment group and topoisomerase inhibitor treatment group. Combinatorial Index (CI) values for each drug combination were determined. N/D - no data. (PDF 45.3 kb

Additional file 2: Figure S1. of Long-lasting reduction in clonogenic potential of colorectal cancer cells by sequential treatments with 5-azanucleosides and topoisomerase inhibitors

Pretreatment with 5-aza-dC enhances the cytotoxicity of etoposide in DKs-8 cells. Cell viability of DKs-8 cells after sequential treatments with 1 μM 5-aza-dC and 5-50 μM etoposide. Figure 1a shows the treatment scheme. Data are presented as means ± SD normalized to untreated control. *P < 0.05 compared with DNA demethylating agent treatment group and topoisomerase inhibitor treatment group. (PDF 33.6 kb