Beatriz Coutinho de Oliveira

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy represents a breakthrough in the treatment of relapsed and refractory B-cell malignancies, such as chronic lymphocytic leukemia (CLL), inducing long-term, sometimes curative, responses. However, fewer than 30% of CLL patients achieve such outcomes. It has been shown that a smaller subset of T cells capable of expansion and persistence is crucial for treatment effectiveness. Notably, a pre-existing mutation in the epigenetic regulator TET2, combined with CAR vector-induced disruption of the other intact allele, significantly enhanced the potency of the CAR-engineered T-cell clone in one CLL patient. This finding aligns with independent research, suggesting that the CAR gene’s genomic insertion site influences tumor-targeting capability. Thus, it is plausible that vector-induced gene disruptions affect CAR T-cell function. This review synthesizes existing knowledge on vector integration into the host genome and its impact on clinical outcomes in CAR T-cell therapy patients. Our aim is to inform the development of improved therapies and enhance their overall efficacy.

Significant populations in tropical and sub-tropical locations all over the world are severely impacted by a group of neglected tropical diseases called leishmaniases. This disease is caused by roughly 20 species of the protozoan parasite from the Leishmania genus. Disease prevention strategies that include early detection, vector control, treatment of affected individuals, and vaccination are all essential. The diagnosis is critical for selecting methods of therapy, preventing transmission of the disease, and minimizing symptoms so that the affected individual can have a better quality of life. Nevertheless, the diagnostic methods do eventually have limitations, and there is no established gold standard. Some disadvantages include the existence of cross-reactions with other species, and limited sensitivity and specificity, which are mostly determined by the type of antigen used to perform the tests. A viable alternative for a more precise diagnosis is the application of recombinant antigens, which have been generated using bioinformatics approaches and have shown increased diagnostic accuracy. This approach proves valuable as it spans from epitope selection to predicting the interactions within the antibody–antigen complex through docking analysis. As a result, identifying potential new antigens using bioinformatics resources becomes an effective technique since it may result in an earlier and more accurate diagnosis. Consequently, the primary aim of this review is to conduct a comprehensive overview of the most significant in silico tools developed over time, with a focus on evaluating their efficacy and exploring their potential applications in optimizing the selection of highly specific molecules for a more effective diagnosis of leishmaniasis.

Cutaneous Leishmaniasis (CL) is a Neglected Tropical Disease characterized by skin ulcers caused by Leishmania spp. protozoans and there is no safe and effective vaccine to reduce its negative consequences. In a previous work by our group, we identified T cell epitopes of Leishmania (Viannia) braziliensis which stimulated patients’ T cells in vitro. In the present work, the peptides were tested as two pools for their ability to rescue memory T cells during natural infection by Leishmania. We analyzed the frequency of central memory (TCM, CD45RA-CD62L+) and effector memory (TEM, CD45RA + CD62L-) cells during active CL and post-treatment. In parallel, we investigated cell proliferation levels and the cytokines produced after stimulation. Interestingly, we observed higher frequencies (%) in CD4+ TEM during CL, and CD8+ TEM and CD8+ TCM during CL and post-treatment. Cell proliferation was increased, and a significant difference in expression was observed on T-bet and RORγT. Besides that, IFN-γ, IL-2, and IL-10 were detected in patient samples. Collectively, this dataset suggests that during CL there is an increase in the frequency of TCM and TEM, especially in the CD8 compartment. These results indicate a potentially immunogenic profile of the peptide pools, which can support the development of anti-Leishmania formulations.

The leishmaniases are a collection of vector-borne parasitic diseases caused by a number of different Leishmania species that are distributed worldwide. Clinical and laboratory research have together revealed several important immune components that control Leishmania infection and indicate the potential of immunization to prevent leishmaniasis. In this review we introduce previous and ongoing experimental research efforts to develop vaccines against Leishmania species. First, second and third generation vaccine strategies that have been proposed to counter cutaneous and visceral leishmaniasis (CL and VL, respectively) are summarized. One of the major bottlenecks in development is the transition from results in animal model studies to humans, and we highlight that although American tegumentary leishmaniasis (ATL; New World CL) can progress to destructive and disfiguring mucosal lesions, most research has been conducted using mouse models and Old World Leishmania species. We conclude that assessment of vaccine candidates in ATL settings therefore appears merited.

The leishmaniasis are neglected tropical diseases widespread throughout the globe which are caused by protozoans from the genus Leishmania and are transmitted by infected phlebotomine flies. The development of a safe and effective vaccine against these diseases has been seen as the best alternative to control and reduce the number of cases. To support vaccine development, this work has applied an in silico approach to search for high potential peptide epitopes able to bind to different Major Histocompatibility Complex Class I and Class II (MHC I and MHC II) molecules from different human populations. First, the predicted proteome of Leishmania braziliensis was compared and analysed by modern linear programs to find epitopes with the capacity to trigger an immune response. This approach resulted in thousands of epitopes derived from 8,000 proteins conserved among different Leishmania species. Epitopes from proteins similar to those found in host species were excluded and epitopes from proteins conserved between different Leishmania species and belonging to surface proteins were preferentially selected. The resulting epitopes were then clustered, to avoid redundancies, resulting in a total of 230 individual epitopes for MHC I and 2,319 for MHC II. These were used for molecular modeling and docking with MHC structures retrieved from the Protein Data Bank (PDB). Molecular docking then ranked epitopes based on their predicted binding affinity to both MHC I and II. Peptides corresponding to the top 10-ranked epitopes were synthesized and evaluated in vitro for their capacity to stimulate PBMC from post-treated cutaneous leishmaniasis patients, with PBMC from healthy donors used as control. From the ten peptides tested, 50% showed to be immunogenic and capable to stimulate the proliferation of lymphocytes from recovered individuals.

In this article, we describe that mononuclear complexes composed of (5-chloro-2-hydroxybenzylidene)aminobenzenesulfonamides (L1-3) of general formula (L2(M)2H2O, where M is Co, Cu, Zn, Ni or Mn) reduced epimastigote proliferation and were found cidal for trypomastigotes of Trypanosoma cruzi Y strain. Complexes C5 and C11 have IC50 of 2.7 ± 0.27 and 4.8 ± 0.47 µM, respectively, for trypomastigotes, when the positive control Nifurtimox, which is also an approved drug for Chagas disease, showed IC50 of 2.7 ± 0.25 µM. We tested whether these complexes inhibit the enzyme T. cruzi trypanothione reductase or acting as DNA binders. While none of these complexes inhibited trypanothione reductase, we observed some degree of DNA binding, albeit less pronounced than observed for cisplatin in this assay. Unfortunately, most of these complexes were also toxic for mouse splenocytes. Along with the present studies, we discuss a number of interesting structure-activity relationships and chemical features for these metal complexes, including computational calculations.