Chimeric antigen receptor (CAR) modified T Cells in acute myeloid leukemia: limitations and expectations.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis despite the advent of novel therapies. Consequently, a major need exists for new therapeutic options, particularly for patients with relapsed/refractory (R/R) AML. In recent years, it has been possible to individualize the treatment of a subgroup of patients, particularly with the emergence of multiple targeted therapies. Nonetheless, a considerable number of patients remain without therapeutic options, and overall prognosis remains poor because of a high rate of disease relapse. In this sense, cellular therapies, especially chimeric antigen receptor (CAR)-T cell therapy, have dramatically shifted the therapeutic options for other hematologic malignancies, such as diffuse large B cell lymphoma and acute lymphoblastic leukemia. In contrast, effectively treating AML with CAR-based immunotherapy poses major biological and clinical challenges, most of them derived from the unmet need to identify target antigens with expression restricted to the AML blast without compromising the viability of the normal hematopoietic stem cell counterpart. Although those limitations have hampered CAR-T cell therapy translation to the clinic, there are several clinical trials where target antigens, such as CD123, CLL-1 or CD33 are being used to treat AML patients showing promising results. Moreover, there are continuing efforts to enhance the specificity and efficacy of CAR-T cell therapy in AML. These endeavors encompass the exploration of novel avenues, including the development of dual CAR-T cells and next-generation CAR-T cells, as well as the utilization of gene editing tools to mitigate off-tumor toxicities. In this review, we will summarize the ongoing clinical studies and the early clinical results reported with CAR-T cells in AML, as well as highlight CAR-T cell limitations and the most recent approaches to overcome these barriers. We will also discuss how and when CAR-T cells should be used in the context of AML.

Testing the latent structure, factorial equivalence, and external correlates of the brief self-control scale in a community sample of Spanish adults.

The Brief Self-Control Scale (BSCS) is a 13-item personality measure capturing how people differ in their capacity to exert self-control. Although the BSCS was originally regarded as a one-dimensional scale, subsequent psychometric studies have provided support for the empirical distinction of two and four interrelated but distinct components of self-control. Using a large sample of Spanish adults (n = 1,558; 914 female, 58.7%), we performed a comprehensive data-driven comparison of the most well-established item-level latent structures for the BSCS. Results showed that the differentiation between general self-discipline and impulse control offered a better fit to the observed data than did the unidimensional representation of self-control. This two-dimensional structure for the BSCS scores was also supported in terms of its internal consistency, measurement invariance across gender and age groups, and meaningful correlations with wellbeing-related indicators and Big Five personality traits. Plausible implications of these findings are discussed.

Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies.

Purpose: CAR-T cell therapy has proven to be a disruptive treatment in the hematology field, however, less than 50% of patients maintain long-term response and early predictors of outcome are still inconsistently defined. Here, we aimed to optimize the detection of CD19 CAR-T cells in blood and to identify phenotypic features as early biomarkers associated with toxicity and outcomes. Experimental design: In this study, monitoring by flow cytometry and digital PCR (dPCR), and immunophenotypic characterization of circulating CAR-T cells from 48 patients treated with Tisa-cel or Axi-cel was performed. Results: Validation of the flow cytometry reagent for the detection of CAR-T cells in blood revealed CD19 protein conjugated with streptavidin as the optimal detection method. Kinetics of CAR-T cell expansion in blood confirmed median day of peak expansion at seven days post-infusion by both flow cytometry and digital PCR. Circulating CAR-T cells showed an activated, proliferative, and exhausted phenotype at the time of peak expansion. Patients with increased expansion showed more severe CRS and ICANs. Immunophenotypic characterization of CAR-T cells at the peak expansion identified the increased expression of co-inhibitory molecules PD1 and LAG3 and reduced levels of the cytotoxicity marker CD107a as predictors of a better long-term disease control. Conclusions: These data show the importance of CAR-T cells in vivo monitoring and identify the expression of PD1LAG3 and CD107a as early biomarkers of long-term disease control after CAR-T cell therapy.

Robotic versus Laparoscopic Partial Nephrectomy in the New Era: Systematic Review.

(1) Background: In recent years there have been advances in imaging techniques, in addition to progress in the surgery of renal tumors directed towards minimally invasive techniques. Thus, nephron-sparing surgery has become the gold standard for the treatment of T1 renal masses. The aim of this study is to investigate the benefits of robotic partial nephrectomy in comparison with laparoscopic nephrectomy. (2) Methods: We performed a systematic review according to the PRISMA criteria during September 2022. We included clinical trials, and cohort and case-control studies published between 2000 and 2022. This comprised studies performed in adult patients with T1 renal cancer and studies comparing robotic with open and laparoscopic partial nephrectomy. A risk of bias assessment was performed according to the Newcastle-Ottawa scale. (3) Results: We observed lower hot ischemia times in the robotic surgery groups, although at the cost of an increase in total operative time, without appreciating the differences in terms of serious surgical complications (Clavien III-V). (4) Conclusions: Robotic partial nephrectomy is a safe procedure, with a shorter learning curve than laparoscopic surgery and with all the benefits of minimally invasive surgery.

All-trans retinoic acid works synergistically with the γ-secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells.

B-cell maturation antigen (BCMA) is the lead antigen for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). A challenge is inter- and intra-patient heterogeneity in BCMA expression on MM cells and BCMA downmodulation under therapeutic pressure. Accordingly, there is a desire to augment and sustain BCMA expression on MM cells in patients that receive BCMA-CAR T-cell therapy. We used all-trans retinoic acid (ATRA) to augment BCMA expression on MM cells and to increase the efficacy of BCMA-CAR T cells in pre-clinical models. We show that ATRA treatment leads to an increase in BCMA transcripts by quantitative reverse transcription polymerase chain reaction and an increase in BCMA protein expression by flow cytometry in MM cell lines and primary MM cells. Analyses with super-resolution microscopy confirmed increased BCMA protein expression and revealed an even distribution of non-clustered BCMA molecules on the MM cell membrane after ATRA treatment. The enhanced BCMA expression on MM cells after ATRA treatment led to enhanced cytolysis, cytokine secretion and proliferation of BCMA-CAR T cells in vitro, and increased efficacy of BCMA-CAR T-cell therapy in a murine xenograft model of MM in vivo (NSG/MM.1S). Combination treatment of MM cells with ATRA and the γ- secretase inhibitor crenigacestat further enhanced BCMA expression and the efficacy of BCMA-CAR T-cell therapy in vitro and in vivo. Taken together, the data show that ATRA treatment leads to enhanced BCMA expression on MM cells and consecutively, enhanced reactivity of BCMA-CAR T cells. The data support the clinical evaluation of ATRA in combination with BCMA-CAR T-cell therapy and potentially, other BCMA-directed immunotherapies.

Renal Failure Management in Patients with Metastatic Renal Cancer Receiving Nivolumab: Evaluation from Two Points of View.

INTRODUCTION: Immunotherapy is recommended as category 1 in first-line treatment in metastatic renal cancer (mRC), however the evidence on the management of toxicities in patients with chronic renal failure is limited. Description of the Cases: Case 1: Patient with mRC and renal failure on hemodialysis. After 25 months of treatment with Nivolumab, he presented a partial response, without toxicities. Case 2: Patient with mRC undergoing treatment with Nivolumab-Ipilimumab, who after 6 cycles was admitted for acute renal failure, compatible with grade 4 nephrotoxicity, requiring definitive suspension of treatment, corticosteroid therapy and hemodialysis. CONCLUSIONS: Nivolumab is a safe and effective therapy in hemodialysis patients, not increasing adverse events, nor requiring dose adjustment. Immunotherapy nephrotoxicity must be adequately managed in daily clinical practice in an interdisciplinary way with the nephrologist.

Renal Failure Management in Patients with Metastatic Renal Cancer Receiving Nivolumab: Evaluation from Two Points of View

Introduction: Immunotherapy is recommended as category 1 in first-line treatment in metastatic renal cancer (mRC), however the evidence on the management of toxicities in patients with chronic renal failure is limited. Description of the Cases: Case 1: Patient with mRC and renal failure on hemodialysis. After 25 months of treatment with Nivolumab, he presented a partial response, without toxicities. Case 2: Patient with mRC undergoing treatment with Nivolumab-Ipilimumab, who after 6 cycles was admitted for acute renal failure, compatible with grade 4 nephrotoxicity, requiring definitive suspension of treatment, corticosteroid therapy and hemodialysis. Conclusions: Nivolumab is a safe and effective therapy in hemodialysis patients, not increasing adverse events, nor requiring dose adjustment. Immunotherapy nephrotoxicity must be adequately managed in daily clinical practice in an interdisciplinary way with the nephrologist (AU)

Introducción: La inmunoterapia está recomendadacon categoría 1 en primera línea de tratamiento en cáncerrenal metastásico (CRm), sin embargo la evidencia sobre elmanejo de toxicidades en pacientes con insuficiencia renalcrónica es limitada.Descripción de los Casos: Caso 1: Paciente con CRme insuficiencia renal en hemodiálisis. Tras 25 meses detratamiento con Nivolumab, presenta respuesta parcial, sintoxicidades. Caso 2: Paciente con CRm en tratamiento conNivolumab-Ipilimumab, que tras 6 ciclos precisa ingresopor fracaso renal agudo, compatible con nefrotoxicidadgrado 4, requiriendo suspensión definitiva del tratamiento,corticoterapia y hemodiálisis.Conclusiones: El uso de Nivolumab es seguro y eficaz en pacientes en hemodiálisis, no incrementando losefectos adversos, ni precisando ajuste de dosis. Es fundamental conocer el manejo de la nefrotoxicidad por inmunoterapia en la práctica clínica diaria y establecer un enfoque multidisciplinar con nefrología. (AU)

Combined treatment of graft versus host disease using donor regulatory T cells and ruxolitinib.

Donor derived regulatory T lymphocytes and the JAK1/2 kinase inhibitor ruxolitinib are currently being evaluated as therapeutic options in the treatment of chronic graft versus host disease (cGvHD). In this work, we aimed to determine if the combined use of both agents can exert a synergistic effect in the treatment of GvHD. For this purpose, we studied the effect of this combination both in vitro and in a GvHD mouse model. Our results show that ruxolitinib favors the ratio of thymic regulatory T cells to conventional T cells in culture, without affecting the suppressive capacity of these Treg. The combination of ruxolitinib with Treg showed a higher efficacy as compared to each single treatment alone in our GvHD mouse model in terms of GvHD incidence, severity and survival without hampering graft versus leukemia effect. This beneficial effect correlated with the detection in the bone marrow of recipient mice of the infused donor allogeneic Treg after the adoptive transfer.

Nighttime Kidney Transplant From Donor With Controlled Cardiac Death: Greater Functionality at the Cost of More Complications?

BACKGROUND: Kidney transplantation surgery from controlled cardiac death donor (Maastricht III) is frequently performed at night, without taking into account the accumulated fatigue that the surgical team may experience. The objective of the study is to assess whether surgical complications and the functionality of the graft in the short and long term are affected by the time of day in which kidney transplantation from controlled cardiac death donors is performed. METHODS: A retrospective observational study was carried out. Patient were classified according to the start of surgery, daytime hours (8:00 AM to 7:59 PM), and nighttime hours (8:00 PM to 7:59 AM). Baseline and intraoperative parameters, postoperative complications, and parameters related to graft functionality were analyzed. RESULTS: A total of 77 patients were included: 37 patients had kidney transplantations performed during the daytime (48.05%), and 40 patients had kidney transplantations performed at nighttime (51.95%). No statistically significant differences were found between the baseline characteristics of both groups except for sex (55.0% men in daytime vs 78.4% men in nighttime, P = .03) and time on pretransplant dialysis (33.1 months in daytime vs 13.8 months in nighttime, P = .008). The incidence of surgical complications and the functionality of the graft was similar in both groups; however, the surgical time was shorter in night transplants (163.2 minutes in daytime vs 136.5 minutes at nighttime, P = .0006) CONCLUSION: The performance of kidney transplants at night is not associated, either in the short or long term, with an increase in surgical complications or conditions leading to the deterioration in the functionality of the graft.

Delayed administration of ixazomib modifies the immune response and prevents chronic graft-versus-host disease.

In this study, we aimed to modify the immune response in the long term after allogeneic bone marrow transplantation (allo-BMT) by using the proteasome inhibitor ixazomib (IXZ) at the late stages of the post-transplant period. This approach facilitated the immune reconstitution after transplantation. IXZ significantly prolonged survival and decreased the risk of chronic graft-versus-host disease (cGvHD) in two different murine models without hampering the graft-versus-leukemia (GvL) effect, as confirmed by bioluminescence assays. Remarkably, the use of IXZ was related to an increase of regulatory T cells both in peripheral blood and in the GvHD target organs and a decrease of effector donor T cells. Regarding B cells, IXZ treated mice had faster recovery of B cells in PB and of pre-pro-B cells in the bone marrow. Mice receiving ixazomib had a lower number of neutrophils in the GvHD target organs as compared to the vehicle group. In summary, delayed administration of IXZ ameliorated cGvHD while preserving GvL and promoted a pro-tolerogenic immune response after allo-BMT.

Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab.

Multiple myeloma (MM) is incurable, so there is a significant unmet need for effective therapy for patients with relapsed or refractory disease. This situation has not changed despite the recent approval of the anti-CD38 antibody daratumumab, one of the most potent agents in MM treatment. The efficiency of daratumumab might be improved by combining it with synergistic anti-MM agents. We therefore investigated the potential of the histone deacetylase (HDAC) inhibitor ricolinostat to up-regulate CD38 on MM cells, thereby enhancing the performance of CD38-specific therapies. Using quantitative reverse transcription polymerase chain reaction and flow cytometry, we observed that ricolinostat significantly increases CD38 RNA levels and CD38 surface expression on MM cells. Super-resolution microscopy imaging of MM cells by direct stochastic optical reconstruction microscopy confirmed this rise with molecular resolution and revealed homogeneous distribution of CD38 molecules on the cell membrane. Particularly important is that combining ricolinostat with daratumumab induced enhanced lysis of MM cells. We also evaluated next-generation HDAC6 inhibitors (ACY-241, WT-161) and observed similar increase of CD38 levels suggesting that the upregulation of CD38 expression on MM cells by HDAC6 inhibitors is a class effect. This proof-of-concept illustrates the potential benefit of combining HDAC6 inhibitors and CD38-directed immunotherapy for MM treatment.

Performance and well-being of native and immigrant students. Comparative analysis based on PISA 2018.

INTRODUCTION: The emotional, cultural, and economic changes involved in the process of coping with migration can be particularly difficult during adolescence. How education systems respond to the challenges posed by the flow of immigration has profound implications for society. One of the ways that students can demonstrate their adaptation to the education system is by their academic performance. In addition, in many education systems well-being has been shown to be directly related to performance. Therefore, this study aims at examine the differences between native and immigrant students in mathematics and science skills, and in well-being indicators evaluated in PISA 2018. METHOD: We performed multivariate analysis of variance (MANOVA) based on the results of PISA 2018 evaluation, obtained from the official OECD database. The sample was 7099 Spanish students (49.5% girls; 50.5% boys), with a mean age of 15.83 years old (SD = 0.29). A little under half (42%) were native students, 35.5% were first generation-immigrant students, and 22.7% were second-generation immigrant students. RESULTS: The native students demonstrated higher levels of mathematics and science skills than the two groups of immigrant students, and had significantly higher means in positive affect, self-efficacy-resilience, and feeling of belonging at school. Although life satisfaction was no different between the immigrant and native groups, the second-generation immigrants showed higher rates of positive affect, and a greater sense of belonging to the school than the first-generation immigrants. CONCLUSIONS: We suggest future lines of research and the need to produce explanatory models that consider the complexity of migratory processes.

Overcoming Chimeric Antigen Receptor (CAR) Modified T-Cell Therapy Limitations in Multiple Myeloma.

Multiple myeloma (MM) remains an incurable disease regardless of recent advances in the field. Therefore, a substantial unmet need exists to treat patients with relapsed/refractory myeloma. The use of novel agents such as daratumumab, elotuzumab, carfilzomib, or pomalidomide, among others, usually cannot completely eradicate myeloma cells. Although these new drugs have had a significant impact on the prognosis of MM patients, the vast majority ultimately become refractory or can no longer be treated due to toxicity of prior treatment, and thus succumb to the disease. Cellular therapies represent a novel approach with a unique mechanism of action against myeloma with the potential to defeat drug resistance and achieve long-term remissions. Genetic modification of cells to express a novel receptor with tumor antigen specificity is currently being explored in myeloma. Chimeric antigen receptor gene-modified T-cells (CAR T-cells) have shown to be the most promising approach so far. CAR T-cells have shown to induce durable complete remissions in other advanced hematologic malignancies like acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). With this background, significant efforts are underway to develop CAR-based therapies for MM. Currently, several antigen targets, including CD138, CD19, immunoglobulin kappa (Ig-Kappa) and B-cell maturation antigen (BCMA), are being used in clinical trials to treat myeloma patients. Some of these trials have shown promising results, especially in terms of response rates. However, the absence of a plateau is observed in most studies which correlates with the absence of durable remissions. Therefore, several potential limitations such as lack of effectiveness, off-tumor toxicities, and antigen loss or interference with soluble proteins could hamper the efficacy of CAR T-cells in myeloma. In this review, we will focus on clinical outcomes reported with CAR T-cells in myeloma, as well as on CAR T-cell limitations and how to overcome them with next generation of CAR T-cells.

Sociodemographic Characteristics and Stress of People from Spain Confined by COVID-19.

This study responds to the need to explore the individual characteristics that may help us to understand the levels of stress involved in the significant COVID-19-related restrictions to people's daily lives. In order to understand levels of stress and stress control during the COVID-19 confinement, 1269 people from Spain (17.5% men) aged between 18 and 70 completed the Perceived Stress Scale (PSS-14). The results indicated that people aged under 40, and especially those under 25, women, and those on low incomes reported higher rates of confinement stress. The nature of where people live, and their working situation during confinement also contributed to people's stress response, although with lower levels of impact. In this context, our study suggests that the levels of stress in those who combine remote working with in situ working were lower than those who had other working conditions. Our study contributes significant information to understanding the effects of confinement, and its results may be used to inform intervention tools and programs.

Selection of Tumor-Specific Cytotoxic T Lymphocytes in Acute Myeloid Leukemia Patients Through the Identification of T-Cells Capable to Establish Stable Interactions With the Leukemic Cells: "Doublet Technology".

The relevance of the immune system in cancer has long been studied. Autologous adoptive T cell therapies, based on the use of tumor infiltrating lymphocytes (TILs), have made great progress in recent years for the treatment of solid tumors, especially melanoma. However, further work is needed to isolate tumor-reactive T cells among patients diagnosed with hematologic malignancies. The dynamics of the interaction between T cells and antigen presenting cells (APC) dictate the quality of the immune responses. While stable joints between target cells and T lymphocytes lead to the induction of T cell activation and immune response, brief contacts contribute to the induction of immune-tolerance. Taking advantage of the strong interaction between target cell and activated T-cells, we show the feasibility to identify and isolate tumor-specific cytotoxic T lymphocytes (CTLs) from acute myeloid leukemia (AML) patients by flow cytometry. Using this technology, CTLs bound through T cell receptor (TCR) to tumor cells can be identified in peripheral blood and bone marrow and subsequently selected and isolated by FACS-based cell sorting. These CTLs display higher percentage of effector cells and marked cytotoxic activity against AML blasts. In conclusion, we have developed a new procedure to identify and select specific cytotoxic T cells in patients diagnosed with acute myeloid leukemia.

Cannabinoid derivatives exert a potent anti-myeloma activity both in vitro and in vivo.

Although hematopoietic and immune system show high levels of the cannabinoid receptor CB2, the potential effect of cannabinoids on hematologic malignancies has been poorly determined. Here we have investigated their anti-tumor effect in multiple myeloma (MM). We demonstrate that cannabinoids induce a selective apoptosis in MM cell lines and in primary plasma cells of MM patients, while sparing normal cells from healthy donors, including hematopoietic stem cells. This effect was mediated by caspase activation, mainly caspase-2, and was partially prevented by a pan-caspase inhibitor. Their pro-apoptotic effect was correlated with an increased expression of Bax and Bak, a decrease of Bcl-xL and Mcl-1, a biphasic response of Akt/PKB and an increase in the levels of ceramide in MM cells. Inhibition of ceramide synthesis partially prevented apoptosis, indicating that these sphingolipids play a key role in the pro-apoptotic effect of cannabinoids in MM cells. Remarkably, blockage of the CB2 receptor also inhibited cannabinoid-induced apoptosis. Cannabinoid derivative WIN-55 enhanced the anti-myeloma activity of dexamethasone and melphalan overcoming resistance to melphalan in vitro. Finally, administration of cannabinoid WIN-55 to plasmacytoma-bearing mice significantly suppressed tumor growth in vivo. Together, our data suggest that cannabinoids may be considered as potential therapeutic agents in the treatment of MM.

The Dynamics of the Human Leukocyte Antigen Head Domain Modulates Its Recognition by the T-Cell Receptor.

Generating the immune response requires the discrimination of peptides presented by the human leukocyte antigen complex (HLA) through the T-cell receptor (TCR). However, how a single amino acid substitution in the antigen bonded to HLA affects the response of T cells remains uncertain. Hence, we used molecular dynamics computations to analyze the molecular interactions between peptides, HLA and TCR. We compared immunologically reactive complexes with non-reactive and weakly reactive complexes. MD trajectories were produced to simulate the behavior of isolated components of the various p-HLA-TCR complexes. Analysis of the fluctuations showed that p-HLA binding barely restrains TCR motions, and mainly affects the CDR3 loops. Conversely, inactive p-HLA complexes displayed significant drop in their dynamics when compared with its free versus ternary forms (p-HLA-TCR). In agreement, the free non-reactive p-HLA complexes showed a lower amount of salt bridges than the responsive ones. This resulted in differences between the electrostatic potentials of reactive and inactive p-HLA species and larger vibrational entropies in non-elicitor complexes. Analysis of the ternary p-HLA-TCR complexes also revealed a larger number of salt bridges in the responsive complexes. To summarize, our computations indicate that the affinity of each p-HLA complex towards TCR is intimately linked to both, the dynamics of its free species and its ability to form specific intermolecular salt-bridges in the ternary complexes. Of outstanding interest is the emerging concept of antigen reactivity involving its interplay with the HLA head sidechain dynamics by rearranging its salt-bridges.

Myelomatous plasma cells display an aberrant gene expression pattern similar to that observed in normal memory B cells.

Memory B cells (MBCs) remain in a quiescent state for years, expressing pro-survival and anti-apoptotic factors while repressing cell proliferation and activation genes. During their differentiation into plasma cells (PCs), their expression pattern is reversed, with a higher expression of genes related to cell proliferation and activation, and a lower expression of pro-survival genes. To determine whether myelomatous PCs (mPCs) share characteristics with normal PCs and MBCs and to identify genes involved in the pathophysiology of multiple myeloma (MM), we compared gene expression patterns in these three cell sub-types. We observed that mPCs had features intermediate between those of MBCs and normal PCs, and identified 3455 genes differentially expressed in mPCs relative to normal PCs but with a similar expression pattern to that in MBCs. Most of these genes are involved in cell death and survival, cell growth and proliferation and protein synthesis. According to our findings, mPCs have a gene expression pattern closer to a MBC than a PC with a high expression of genes involved in cell survival. These genes should be physiologically inactivated in the transit from MBC to PC, but remain overexpressed in mPCs and thus may play a role in the pathophysiology of the disease.