Targeted Cancer Therapy Using Radiolabeled Monoclonal Antibodies

2005 ◽  
Vol 4 (4) ◽  
pp. 393-405 ◽  
Author(s):  
Wolfgang A. Bethge ◽  
Brenda M. Sandmaier
Keyword(s):  
Monoclonal Antibodies ◽  
Solid Tumors ◽  
Path Length ◽  
Residual Disease ◽  
Allogeneic Transplantation ◽  
Hematologic Malignancies ◽  
Clinical Results ◽  
Host Cells ◽  
Beta Emitters ◽  
Targeted Radiation Therapy

Radioimmunotherapy (RIT) combines the advantages of targeted radiation therapy and specific immunotherapy using monoclonal antibodies. RIT can be used either to target tumor cells or to specifically suppress immunocompetent host cells in the setting of allogeneic transplantation. The choice of radionuclide used for RIT depends on its distinct radiation characteristics and the type of malignancy or cells targeted. Beta-emitters with their lower energy and longer path length are more suitable to target bulky, solid tumors whereas α-emitters with their high linear energy transfer and short path length are better suited to target hematopoietic cells (normal or malignant). Different approaches of RIT such as the use of stable radioimmunoconjugates or of pretargeting strategies are available. Encouraging results have been obtained with RIT in patients with hematologic malignancies. The results in solid tumors are somewhat less favorable but new strategies for patients with minimal residual disease using adjuvant and locoregional treatment are evolving. This report outlines basic principles of RIT, gives an overview of available radionuclides and radioimmunoconjugates, and discusses clinical results with special emphasis on their use in hematologic malignancies including use in conditioning regimens for bone marrow transplantation.

Fluorescence In Situ Hybridization Detected MRD and Chimerism in Patients with Hematologic Malignancies after allo-HSCT.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5214-5214
Author(s):  
Huiying Qiu ◽  
Yongquan Xue ◽  
Jinlan Jin ◽  
De Pei Wu
Keyword(s):  
Stem Cell ◽  
In Situ Hybridization ◽  
Stem Cell Transplantation ◽  
Fluorescence In Situ Hybridization ◽  
Cell Transplantation ◽  
Residual Disease ◽  
Hematologic Malignancies ◽  
Host Cells ◽  
Hematopoietic Stem

Abstract Objective Monitoring of minimal residual disease (MRD) and cellular chimerism in patients with hematopoietic malignancies after allogeneic hematopoietic stem cell transplantation(allo-HSCT). Methods From May 2001 to June 2005, seventy four patients were received allo-HSCT. Including 50 Males and 24 females. 41 patients received sibling HLA-matched BMT, 7 patients received un-related BMT, 9 patients received Nonmyeloablative stem cell transplantation (NST), 14 patients received related haploidentical transplantation and 3 patients received allo-PBSCT. Among them, 45 patients were diagnosed with CML, 13 patients with AML, 14 patients with ALL, one patient with Multiple myeloma and one patient with malignant lymphoma. Chimerism and MRD were monitored using X and Y specific centromeric probes or gene probes for BCR/ABL, MLL and AML1/ETO by fluorescence in situ hybridization (FISH),1000 cells were analysised. Results Among 18 patients, received sex-matched transplant, we did not found the former chromosome rearrangements in 14 patients after transplantation, MRD were detected in 17% and 10% of cells in two patients, MRD were decreased from 10% to 1% of cells after the reduction of the dose of immunotherapy in one patient four month later, the patient was still in remission one year after transplantation. Another patient died of sever GVHD after the reduction of immunotherapy. 2 patients were found to have the former chromosomal rearrangement 1 and 4 month after transplantation respectively who did not achieve remission after chemotherapy and died 3 and 5 months respectively after transplantation. Over 99% donor chimerisms were found in 44 patients on day 25, donor cells were at a low level (96.2%~98.7) in 7 patients on day 25, and increased over 99% on day 180, they were in remission without relapse. The donor chimerisms decreased gradually in 6 patients, host cells were found over 20 cells, 3 patients showed cytogenetic or hematologic bone marrow relapse, two patients died of sever GVHD after the reduction of cyclosporine A, Over 99% donor chimerisms was achieved in one patient. Conclusion FISH could play a pivotal role in the detection of MRD and chimerism. It is helpful to the evaluation of graft and relapse, to the guide of implement of early immunotherapy.

scholarly journals Challenges and Recent Advances in NK Cell-Targeted Immunotherapies in Solid Tumors

2021 ◽  
Vol 23 (1) ◽  
pp. 164
Author(s):  
Guang-Yu Lian ◽  
Thomas Shiu-Kwong Mak ◽  
Xue-Qing Yu ◽  
Hui-Yao Lan
Keyword(s):  
Solid Tumors ◽  
Antigen Processing ◽  
Nk Cell ◽  
Residual Disease ◽  
Hematologic Malignancies ◽  
Great Success ◽  
Direct Cytotoxicity ◽  
Early Tumor ◽  
Immunosuppressive Microenvironment ◽  
Preclinical And Clinical Studies

Natural killer (NK) cell is a powerful malignant cells killer, providing rapid immune responses via direct cytotoxicity without the need of antigen processing and presentation. It plays an essential role in preventing early tumor, metastasis and minimal residual disease. Although adoptive NK therapies achieved great success in clinical trials against hematologic malignancies, their accumulation, activation, cytotoxic and immunoregulatory functions are severely impaired in the immunosuppressive microenvironment of solid tumors. Now with better understandings of the tumor evasive mechanisms from NK-mediated immunosurveillance, immunotherapies targeting the key molecules for NK cell dysfunction and exhaustion have been developed and tested in both preclinical and clinical studies. In this review, we introduce the challenges that NK cells encountered in solid tumor microenvironment (TME) and the therapeutic approaches to overcome these limitations, followed by an outline of the recent preclinical advances and the latest clinical outcomes of NK-based immunotherapies, as well as promising strategies to optimize current NK-targeted immunotherapies for solid tumors.

Adoptive Cell Therapy for Gastrointestinal Cancers

2020 ◽  
Vol 04 (04) ◽  
pp. 345-350
Author(s):  
Ryan J. Slovak ◽  
Hyun S. Kim
Keyword(s):  
Cell Therapy ◽  
Clinical Research ◽  
Solid Tumors ◽  
Immune Cells ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Hematologic Malignancies ◽  
Gastrointestinal Cancers ◽  
Gastrointestinal Malignancies ◽  
Specific Antigens

AbstractThe reinfusion of autologous or allogeneic immune cells that have been educated and/or engineered ex vivo to respond to tumor-specific antigens is termed “adoptive cell therapy.” While adoptive cell therapy has made tremendous strides in the treatment of hematologic malignancies, its utilization for solid tumors has lagged somewhat behind. The purpose of this article is to concisely review the clinical research that has been done to investigate adoptive cell therapy as a treatment for gastrointestinal malignancies.

Therapeutic Monoclonal Antibodies in Clinical Practice against Cancer

2020 ◽  
Vol 20 (16) ◽  
pp. 1895-1907
Author(s):  
Navgeet Kaur ◽  
Anju Goyal ◽  
Rakesh K. Sindhu
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Clinical Practice ◽  
Therapeutic Agent ◽  
Hematologic Malignancies ◽  
Immune Checkpoints ◽  
Malignant Cells ◽  
Main Target ◽  
Therapeutic Monoclonal Antibodies ◽  
Cancerous Cells

The importance of monoclonal antibodies in oncology has increased drastically following the discovery of Milstein and Kohler. Since the first approval of the monoclonal antibody, i.e. Rituximab in 1997 by the FDA, there was a decline in further applications but this number has significantly increased over the last three decades for various therapeutic applications due to the lesser side effects in comparison to the traditional chemotherapy methods. Presently, numerous monoclonal antibodies have been approved and many are in queue for approval as a strong therapeutic agent for treating hematologic malignancies and solid tumors. The main target checkpoints for the monoclonal antibodies against cancer cells include EGFR, VEGF, CD and tyrosine kinase which are overexpressed in malignant cells. Other immune checkpoints like CTLA-4, PD-1 and PD-1 receptors targeted by the recently developed antibodies increase the capability of the immune system in destroying the cancerous cells. Here, in this review, the mechanism of action, uses and target points of the approved mAbs against cancer have been summarized.

scholarly journals CAR-T cells and BiTEs in solid tumors: challenges and perspectives

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Julien Edeline ◽  
Roch Houot ◽  
Aurélien Marabelle ◽  
Marion Alcantara
Keyword(s):  
T Cells ◽  
Solid Tumors ◽  
Specific Antigen ◽  
Hematologic Malignancies ◽  
Antibody Fragments ◽  
New Drugs ◽  
Car T Cells ◽  
Cell Specificity ◽  
Car T ◽  
Early Phase Clinical Trials

AbstractChimeric antigen receptor (CAR)-modified T cells and BiTEs are both immunotherapies which redirect T cell specificity against a tumor-specific antigen through the use of antibody fragments. They demonstrated remarkable efficacy in B cell hematologic malignancies, thus paving the way for their development in solid tumors. Nonetheless, the use of such new drugs to treat solid tumors is not straightforward. So far, the results from early phase clinical trials are not as impressive as expected but many improvements are under way. In this review we present an overview of the clinical development of CAR-T cells and BiTEs targeting the main antigens expressed by solid tumors. We emphasize the most frequent hurdles encountered by either CAR-T cells or BiTEs, or both, and summarize the strategies that have been proposed to overcome these obstacles.

scholarly journals Predicting Responses to Checkpoint Inhibitors in Lymphoma: Are We Up to the Standards of Solid Tumors?

2020 ◽  
Vol 14 ◽  
pp. 117955492097636
Author(s):  
Ah-Reum Jeong ◽  
Edward D Ball ◽  
Aaron Michael Goodman
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
B Cell ◽  
Solid Tumors ◽  
Cell Lymphoma ◽  
Checkpoint Inhibitors ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Checkpoint Blockade ◽  
Programmed Cell Death 1

Treatment of cancer has transformed with the introduction of checkpoint inhibitors. However, the majority of solid tumor patients do not respond to checkpoint blockade. In contrast, the response rate to programmed cell death 1 (PD-1) blockade in relapsed/refractory classical Hodgkin lymphoma (cHL) is 65% to 84% which is the highest among all cancers. Currently, checkpoint inhibitors are only approved for cHL and primary mediastinal B-cell lymphoma as the responses to single-agent checkpoint blockade in other hematologic malignancies is disappointingly low. Various established biomarkers such as programmed cell death 1 ligand 1 (PD-L1) protein surface expression, mismatch repair (MMR) status, and tumor mutational burden (TMB) are routinely used in clinical decision-making in solid tumors. In this review, we will explore these biomarkers in the context of hematologic malignancies. We review characteristic 9p24.1 structural alteration in cHL and primary mediastinal B-cell lymphoma (PMBCL) as a basis for response to PD-1 inhibition, as well as the role of antigen presentation pathways. We also explore the reported frequencies of MMR deficiency in various hematologic malignancies and investigate TMB as a predictive marker.

scholarly journals Transplantation of allogeneic CD34+ peripheral blood stem cells in patients with advanced hematologic malignancy

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4132-4138 ◽  
Author(s):  
WI Bensinger ◽  
CD Buckner ◽  
K Shannon-Dorcy ◽  
S Rowley ◽  
FR Appelbaum ◽  
...  
Keyword(s):  
Stem Cells ◽  
Body Weight ◽  
Peripheral Blood ◽  
Hematologic Malignancy ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
Hematologic Malignancies ◽  
Peripheral Blood Stem Cells ◽  
Cd34 Cells ◽  
Blood Stem Cells

Abstract Sixteen patients with advanced hematologic malignancies were transplanted with HLA-identical allogeneic peripheral blood stem cells (PBSCs) that were selected for CD34+ cells by an avidin-biotin immunoadsorption technique. The median age of patients was 48 years (range, 37 to 67). Patients received 12.0 or 13.2 Gy of total body irradiation followed by 120 mg/kg of cyclophosphamide. Normal donors received 16 mg/kg of granulocyte-colony stimulating factor on days 1 to 6 followed by PBSC harvests on days 4 to 7. PBSC harvests were processed each day on a single avidin-blotin column containing an antibody to the CD34 antigen and processed cells were infused without cryopreservation daily for 4 consecutive days. Prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine alone for 5 patients and CSA plus methotrexate for 11 patients. A median of 18.64 (6.74 to 34.97) x 10(8) CD34+ cells/kg patient body weight were collected from each donor. A median of 8.96 (2.62 to 17.34) x 10(8) CD34+ cells/kg patient body weight were recovered after avidin-biotin adsorption which represented a median CD34+ cell yield of 53% (18% to 77%) with a median purity of 62% (34% to 82%). There was a reduction in CD3+ cells from a median of 557.26 (227.73 to 677.77) x 106/kg to 0.73 x 10(4)/kg (0.40 to 3.65), in CD4+ cells from 351.72 (194.47 to 520.11) x 10(6)/kg to 0.40 (0.15 to 1.03) x 10(4)/kg and in CD8+ cells from 169.74 (53.34 to 325.83) x 10(6)/ kg to 0.32 (0.12 to 2.71) x 10(4)/kg representing a median 2.8 (2.19 to 3.14) log reduction in T cells. One patient died of infection on day 3 posttransplant and was unevaluable for recovery of neutrophils. The median day to recovery of 500 neutrophils/mL was 15 (8 to 26) in the remaining 15 patients. Six of 16 patients falled to achieve a platelet count of 20,000/mL before death on days 3 to 97 of transplant-related complications. The median day to achieving platelets of 20,000 mL in the remaining 10 patients was 11 (7 to 31). Eight of 16 patients (50%) died between 3 and 97 days posttransplant, 7 of transplant-related causes, and 1 of progressive disease. Grade 2–4 acute GVHD occurred in 12 out of 14 (86%) and grades 3–4 in 6 out of 14 (43%) evaluable patients. Six of 8 evaluable patients developed clinical chronic GVHD and 1 developed subclinical chronic GVHD. Bone marrow and/or peripheral blood chimerism studies in 12 evaluable patients showed 97% to 100% donor type in 11 patients with 1 patient in relapse showing 40% donor cells 60 to 90 days posttransplant. Four of 16 patients (25%) are alive and disease-free 312 to 576 days after transplant. There were no episodes of graft failure or rejection. This study shows that allogeneic transplantation using CD34+ selected PBSC results in prompt and sustained engraftment. CD34+ selection, as employed in this preliminary study, however, resulted in an apparently higher rate of acute and chronic GVHD. However, The sample size is quite small and precludes a more definitive conclusion regarding GVHD.

scholarly journals Nonmyeloablative allogeneic transplantation achieves clinical and molecular remission in cutaneous T-cell lymphoma

2020 ◽  
Vol 4 (18) ◽  
pp. 4474-4482 ◽  
Author(s):  
Wen-Kai Weng ◽  
Sally Arai ◽  
Andrew Rezvani ◽  
Laura Johnston ◽  
Robert Lowsky ◽  
...  
Keyword(s):  
T Cell ◽  
High Throughput Sequencing ◽  
Residual Disease ◽  
Chronic Gvhd ◽  
Survival Rates ◽  
Stage Iv ◽  
Allogeneic Transplantation ◽  
Cell Receptor ◽  
Advanced Stage ◽  
Molecular Remission

Abstract The majority of patients with refractory, advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) have a life expectancy of <5 years. Here, we report a phase 2 study of a novel nonmyeloablative allogeneic transplantation strategy tailored for this patient population. This study has completed the enrollment, and 35 patients (13 MF, 22 SS) have undergone transplant as planned. The majority (80%) of the patients had stage IV disease and received multiple previous systemic therapies. All patients had active disease at the time of conditioning using total skin electron beam therapy, total lymphoid irradiation, and antithymocyte globulin, and received allograft infusion as outpatients. Cyclosporine or tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. Patients tolerated the transplant well, with 1- and 2-year nonrelapse mortality of 3% and 14%, respectively. The day +180 cumulative incidence of grade 2 to 4 acute GVHD was 16%, and the 2-year incidence of moderate/severe chronic GVHD was 32%. With a median posttransplant follow-up of 5.4 years, the 2-, 3-, and 5-year overall survival rates were 68%, 62%, and 56%. Using high-throughput sequencing of the T-cell receptor for minimal residual disease monitoring, we observed that 43% achieved molecular remission, which was associated with a lower incidence of disease progression or relapse (9% vs 87%; P = .02). Our study also showed that patients who were aged ≥65 years at the time of allotransplant had similar clinical outcomes compared with younger patients. Thus, we have developed an alternative and potentially curative nonmyeloablative allogeneic transplant regimen for patients with advanced stage MF/SS. This trial was registered at www.clinicaltrials.gov as #NCT00896493.

scholarly journals Subinhibitory Concentrations of Antimicrobial Agents Reduce the Uptake of Legionella pneumophila into Acanthamoeba castellanii and U937 Cells by Altering the Expression of Virulence-Associated Antigens

1998 ◽  
Vol 42 (11) ◽  
pp. 2870-2876 ◽  
Author(s):  
P. Christian Lück ◽  
Jürgen W. Schmitt ◽  
Arne Hengerer ◽  
Jürgen H. Helbig
Keyword(s):  
Monoclonal Antibodies ◽  
Membrane Protein ◽  
Outer Membrane ◽  
Outer Membrane Protein ◽  
Legionella Pneumophila ◽  
Antimicrobial Agents ◽  
Acanthamoeba Castellanii ◽  
Host Cells ◽  
Uncharacterized Protein ◽  
Subinhibitory Concentrations

ABSTRACT We determined the MICs of ampicillin, ciprofloxacin, erythromycin, imipenem, and rifampin for two clinical isolates of Legionella pneumophila serogroup 1 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay and by quantitative culture. To test the influence of subinhibitory concentrations (sub-MICs) of antimicrobial agents on Legionella uptake into Acanthamoeba castellanii and U937 macrophage-like cells, both strains were pretreated with 0.25 MICs of the antibiotics for 24 h. In comparison to that for the untreated control, subinhibitory concentrations of antibiotics significantly reducedLegionella uptake into the host cells. Measurement of the binding of monoclonal antibodies against several Legionellaantigens by enzyme-linked immunoassays indicated that sub-MIC antibiotic treatment reduced the expression of the macrophage infectivity potentiator protein (Mip), the Hsp 60 protein, the outer membrane protein (OmpM), an as-yet-uncharacterized protein of 55 kDa, and a few lipopolysaccharide (LPS) epitopes. In contrast, the expression of some LPS epitopes recognized by monoclonal antibodies 8/5 and 30/4 as well as a 45-kDa protein, a 58-kDa protein, and the major outer membrane protein (OmpS) remained unaffected.

Combination epigenetic and immunotherapy overcomes resistance to monoclonal antibodies in hematologic malignancies: A new therapeutic approach

2016 ◽  
Vol 44 (3) ◽  
pp. 157-160 ◽  
Author(s):  
Elliot M. Epner ◽  
Bikramajit Singh Saroya ◽  
Zainul S. Hasanali ◽  
Thomas P. Loughran
Keyword(s):  
Monoclonal Antibodies ◽  
Therapeutic Approach ◽  
Hematologic Malignancies
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