100,365 research outputs found
Acute Lymphoblastic Leukemia Immunotherapy Treatment: Now, Next, and Beyond
No full textAcute lymphoblastic leukemia (ALL) is a blood cancer that primarily affects children
but also adults. It is due to the malignant proliferation of lymphoid precursor cells that invade the bone marrow and can spread to extramedullary sites. ALL is divided into B cell (85%) and T cell lineages (10 to 15%); rare cases are associated with the natural killer (NK) cell lineage (<1%). To date, the survival rate in children with ALL is excellent while in adults continues to be poor. Despite the therapeutic progress, there are subsets of patients that still have high relapse rates after chemotherapy or hematopoietic stem cell transplantation (HSCT) and an unsatisfactory cure rate. Hence, the identification of more effective and safer therapy choices represents a primary issue. In this review, we will discuss novel therapeutic options including bispecific antibodies, antibody–drug conjugates, chimeric antigen receptor (CAR)-based therapies, and other promising treatments for both pediatric and adult patients
Recent perspective on CAR and Fcγ-CR T cell immunotherapy for cancers: Preclinical evidence versus clinical outcomes.
No full textThe chimeric antigen receptor Tcell (CAR-T cell) immunotherapy currently represents a hot research trend and it is expected to revolutionize the field of cancer therapy. Promising outcomes have been achieved using CAR-T cell therapy for haematological malignancies. Despite encouraging results, several challenges still pose eminent hurdles before being fully recognized. Directing CAR-T cells to target a single tumour associated antigen (TAA) as the case in haematological malignancies might be much simpler than targeting the extensive inhibitory microenvironments associated with solid tumours. This review focuses on the basic principles involved in development of CAR-T cells, emphasizing the differences between humoral IgG, T-cell receptors, CAR and Fcγ-CR constructs. It also highlights the complex inhibitory network that is usually associated with solid tumours, and tackles recent advances in the clinical studies that have provided great hope for the future use of CAR-T cell immunotherapy. While current Fcγ-CR T cell immunotherapy is in pre-clinical stage, is expected to provide a sound therapeutic approach to add to existing classical chemo- and radio-therapeutic modalities
FCγ Chimeric Receptor-Engineered T Cells: Methodology, Advantages, Limitations, and Clinical Relevance
No full textFor many years, disappointing results have been generated by many investigations, which have utilized a variety of immunologic strategies to enhance the ability of a patient’s immune system to recognize and eliminate malignant cells. However, in recent years, immunotherapy has been used successfully for the treatment of hematologic and solid malignancies. The impressive clinical responses observed in many types of cancer have convinced even the most skeptical clinical oncologists that a patient’s immune system can recognize and reject his tumor if appropriate strategies are implemented. The success immunotherapy is due to the development of at least three therapeutic strategies. They include tumor-associated antigen (TAA)-specific monoclonal antibodies (mAbs), T cell checkpoint blockade, and TAA-specific chimeric antigen receptors (CARs) T cell-based immunotherapy. However, the full realization of the therapeutic potential of these approaches requires the development of strategies to counteract and overcome some limitations. They include off-target toxicity and mechanisms of cancer immune evasion, which obstacle the successful clinical application of mAbs and CAR T cell-based immunotherapies. Thus, we and others have developed the Fc gamma chimeric receptors (Fcγ-CRs)-based strategy. Like CARs, Fcγ-CRs are composed of an intracellular tail resulting from the fusion of a co-stimulatory molecule with the T cell receptor ζ chain. In contrast, the extracellular CAR single-chain variable fragment (scFv), which recognizes the targeted TAA, has been replaced with the extracellular portion of the FcγRIIIA (CD16). Fcγ-CR T cells have a few intriguing features. First, given in combination with mAbs, Fcγ-CR T cells mediate anticancer activity in vitro and in vivo by an antibody-mediated cellular cytotoxicity mechanism. Second, CD16-CR T cells can target multiple cancer types provided that TAA-specific mAbs with the appropriate specificity are available. Third, the off-target effect of CD16-CR T cells may be controlled by withdrawing the mAb administration. The goal of this manuscript was threefold. First, we review the current state-of-the-art of preclinical CD16-CR T cell technology. Second, we describe its in vitro and in vivo antitumor activity. Finally, we compare the advantages and limitations of the CD16-CR T cell technology with those of CAR T cell methodology
Immunotherapy as a turning point in the treatment of acute myeloid leukemia
No full textAcute myeloid leukemia (AML) is a malignant disease of hematopoietic precursors at
the earliest stage of maturation, resulting in a clonalproliferation of myoblasts replacing normal
hematopoiesis. AML represents one of the most common types of leukemia, mostly affecting elderly
patients. To date, standard chemotherapy protocols are only effective in patients at low risk of relapse
and therapy-related mortality. The average 5-year overall survival (OS) is approximately 28%. Allogeneic hematopoietic stem cell transplantation (HSCT) improves prognosis but is limited by donor
availability, a relatively young age of patients, and absence of significant comorbidities. Moreover, it
is associated with significant morbidity and mortality. However, increasing understanding of AML
immunobiology is leading to the development of innovative therapeutic strategies. Immunotherapy
is considered an attractive strategy for controlling and eliminating the disease. It can be a real
breakthrough in the treatment of leukemia, especially in patients who are not eligible forintensive
chemotherapy. In this review, we focused on the progress of immunotherapy in the field of AML by
discussing monoclonal antibodies (mAbs), immune checkpoint inhibitors, chimeric antigen receptor
T cells (CAR-T cells), and vaccine therapeutic choices
EGFR+ Glioblastoma stem cells targeting by CD16158V-chimeric receptor T cells and cetuximab
No full textGlioblastoma multiforme (GBM) is the deadliest human brain tumor with a median survival following diagnosis of 14–16 months. Innovative therapeutic approaches are urgently needed. Cancer stem cells (CSC) from GBM resist current chemo- and radio therapies and can generate recurrent and aggressive tumors. To envisage innovative therapeutic approaches of potential clinical use, we engineered T cells with Fcγ-chimeric receptors (CRs) to elicit antibody-dependent cellular cytotoxicity (ADCC) in the presence of mAbs specific for tumor associated antigens (TAA). Indeed, in previous studies, we success fully redirected CD16158V-CR T cells against KRAS-mutated colorectal carcinoma cells. Since surface overexpression of epidermal growth factor receptor (EGFR) is frequently detectable in GBM, we assessed, in vitro, the anti-GBM potential of polymorphic CD16-CR T cells, in combination with anti-EGFR mAbs, on GBM-derived EGFR+ CSC. Our results indicate that CD16158V, but not CD16158F-CR engineered T cells in cubated with cetuximab, but not panitumumab, induced the elimination of GBM-derived CSC through a caspase-3 dependent mechanism, and produced high amounts of TNFα and IFNγ upon recognition of target cells. These data pave the way towards pre-clinical development of innovative GBM treatments, taking advantage of CD16158V-CR engineered T cells and therapeutic antibodie
CD16-158-valine chimeric receptor T cells overcome the resistance of KRAS-mutated colorectal carcinoma cells to cetuximab
No full textKRAS mutations hinder therapeutic efficacy of epidermal growth factor receptor (EGFR)-specific monoclonal antibodies cetuximab and panitumumab-based immunotherapy of EGFR+ cancers. Although cetuximab inhibits KRAS-mutated cancer cell growth in vitro by natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), KRAS-mutated colorectal carcinoma (CRC) cells escape NK cell immunosurveillance in vivo. To overcome this limitation, we used cetuximab and panitumumab to redirect Fc gamma chimeric receptor (CR) T cells against KRAS-mutated HCT116 colorectal cancer (CRC) cells. We compared four polymorphic Fc gamma-CR constructs including CD16(158F)-CR, CD16(158V)-CR, CD32(131H)-CR, and CD32(131R)-CR transduced into T cells by retroviral vectors. Percentages of transduced T cells expressing CD32(131H)-CR (83.5 +/- 9.5) and CD32(131R)-CR (77.7 +/- 13.2) were significantly higher than those expressing with CD16(158F)-CR (30.3 +/- 10.2) and CD16(158V)-CR (51.7 +/- 13.7) (p < 0.003). CD32(131R)-CR T cells specifically bound soluble cetuximab and panitumumab. However, only CD16(158V)-CR T cells released high levels of interferon gamma (IFN gamma = 1,145.5 pg/ml +/- 16.5 pg/ml, p < 0.001) and tumor necrosis factor alpha (TNF alpha = 614 pg/ml +/- 21 pg/ml, p < 0.001) upon incubation with cetuximab-opsonized HCT116 cells. Moreover, only CD16(158V)-CR T cells combined with cetuximab killed HCT116 cells and A549 KRAS-mutated cells in vitro. CD16(158V)-CR T cells also effectively controlled subcutaneous growth of HCT116 cells in CB17-SCID mice in vivo. Thus, CD16(158V)-CR T cells combined with cetuximab represent useful reagents to develop innovative EGFR+KRAS-mutated CRC immunotherapies
In vitro elimination of EGFR-overexpressing cancer cells by CD32A chimeric receptor T cells in combination with cetuximab or panitumumab
No full textCetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). While the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on natural killer (NK) cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32A) to a similar extent. This study compares the ability of T cells, engineered with a novel low-affinity CD32A131R -chimeric receptor (CR), and those engineered with the low-affinity CD16158F -CR T cells, in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. Following T cell transduction, the percentage of CD32A131R -CR T cells was 74 ± 10% while the percentage of CD16158F -CR T cells was 46 ± 15%. Only CD32A131R -CR T cells bound panitumumab. CD32A131R -CR T cells combined with the mAb 8.26 (anti-CD32) and CD16158F -CR T cells combined with the mAb 3 g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116FcγR+ cells, in a reverse ADCC assay in vitro. Cross-linking of CD32A131R -CR on T cells by cetuximab or panitumumab and CD16158F -CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and the secretion of IFNγ and TNFα. Neither cetuximab nor panitumumab induced Fcγ-CR T anti-tumor activity against KRAS-mutated HCT116, non-small-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. The ADCC of Fcγ-CR T cells was associated with the over-expression of EGFR on ECCs. In conclusion, CD32A131R -CR T cells are efficiently redirected by cetuximab or panitumumab against BC cells overexpressing EGFR. This article is protected by copyright. All rights reserved
Confronto terapeutico tra l'utilizzo di Fluorometolone 0,1% collirio vs Fluorometolone 1% collirio in associazione con Tetrizolina + Feniramina collirio nella cura della congiuntivite allergica: case report.
No full textChallenges in Multiple Myeloma Therapy in Older and Frail Patients
No full textEvery year, more than 150,000 cases of multiple myeloma (MM) are diagnosed worldwide, and over 100,000 deaths caused by this malignancy are recorded. MM incidence is increasing globally, particularly in high-income countries and in the male population aged ≥ 50. While advances in treatment strategies have led to the improvement of survival over the past decades, MM remains incurable in a large percentage of cases. Importantly, about one-third of patients diagnosed with MM are >75 years old and are characterized by relatively low fitness or frailty. These patients are more vulnerable to stressors and present lower resistance to cancer and related treatments. Therefore, patients’ fitness and frailty should become part of the standard assessment in MM, and flexible therapeutic options should apply. A careful review of studies investigating the management of frail patients with MM strongly supports the use of a dynamic evaluation of effectiveness and adverse events associated with current treatments in the context of patient-specific frailty and co-morbidities
Letter, [Author unclear] to Paulina T. Merritt
No full textHandwritten letter to Paulina Merritt from an unknown author, October 1, 1876.
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