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Leukemia Research Reports 2022Treatment of non-Hodgkin lymphoma (NHL) in general has improved over the years with the emergence of the monoclonal antibodies (MAB) therapy. NHL is divided into B cell...
Treatment of non-Hodgkin lymphoma (NHL) in general has improved over the years with the emergence of the monoclonal antibodies (MAB) therapy. NHL is divided into B cell NHL and T cell NHL. Treatment of NHL was based on the subtype of NHL and its staging. NHL is divided into aggressive and indolent NHL (iNHL). Subtypes of iNHL include: Follicular lymphoma (FL), Marginal zone lymphoma (MZL), Chronic lymphocytic leukemia/small-cell lymphocytic lymphoma (CLL/SLL), Gastric mucosa-associated lymphoid tissue (MALT) lymphoma, Lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, Nodal marginal zone lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL). Chemotherapy was the main stay treatment of iNHL until the emergence of Rituximab, anti-CD20 MAB targeting CD-20 surface cell antigens that are present on B-cells lymphoma and not on precursor cells, mainly efficacious in B cell iNHL, It became the mainstay treatment in follicular lymphoma (FL) as a single agent modality or in combination with chemotherapy. The anti-CD20 Rituximab played an important role in the development of the treatment of iNHL to become FDA approved in 1997. It was also proven effective in multiple other types of lymphoma. MAB through targeting the cell surface antigen leads to a direct or immune mediated cytotoxicity. This carries few side effects, including allergic reactions. Other than that, a resistance mechanism to rituximab emerged by inducing a failure in the apoptosis mechanism. Alternative mechanisms of resistance included the presence of soluble antigens that could act by binding to the antibody present before the drug itself can bind the lymphoma cell. Thus, the interest in immunotherapy grew further to explore the possibility of conjugating an immune mediated drug to a radio-sensitizing agent in order to enhance the selectivity of the drug. Here came the development of 90Y-ibritumomab tiuxetan and 131I-tositumomab. After it, humanized anti-CD20 emerged ofatumumab, IMMU106 (veltuzumab) in 2005, and ocrelizumab which are considered as second generation anti-CD20 and 3 generation anti-CD20 include AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutuzumab). Also multiple other agents emerged targeting different surface cell antigens like CD52 (alemtuzumab), CD22 (unconjugated epratuzumab and calicheamicin conjugated CMC-544 [inotuzumab ozogamicin]), CD80 (galiximab), CD2 (MEDI-507 [siplizumab]), CD30 (SGN-30 and MDX-060 [iratumumab], Brentuximab vedotin), CD40 (SGN-40), and CD79b (Polatuzumab). Other agents include MAB targeting T-Cells like mogamulizumab, Denileukin Diftitox and BiTEs or bispecific T cell engagers like Mosunetuzumab, Glofitamab, and Epcoritamab. Moreover, further studies came up to evaluate the role of immunotherapy in combination chemotherapy as a pathway to evade the resistance mechanisms. Side effects of the treatment were mainly infusion related adverse reactions, myelosuppression in conjugated forms leading to immunosuppression and subsequently to infectious complications. Another important aspect in immunotherapy is the half-lives of the medication which is an important factor that can influence the evaluation of the response. The MAB treatment showed important benefit in the treatment of iNHL and it continuously shows how rapidly it can develop to provide optimum care and benefit to patients with iNHL.
PubMed: 35663281
DOI: 10.1016/j.lrr.2022.100325 -
Journal of Nuclear Medicine : Official... Jul 2023In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to...
In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to Food and Drug Administration approval. For instance, the theranostic armamentarium for the referring hematooncologist now includes Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia. During the last decade, the concept of theranostics in hematooncology has been further expanded by C-X-C motif chemokine receptor 4-directed molecular imaging. Beyond improved detection rates of putative sites of disease, C-X-C motif chemokine receptor 4-directed PET/CT also selects candidates for radioligand therapy using β-emitting radioisotopes targeting the identical chemokine receptor on the lymphoma cell surface. Such image-piloted therapeutic strategies provided robust antilymphoma efficacy, along with desired eradication of the bone marrow niche, such as in patients with T- or B-cell lymphoma. As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications.
Topics: Humans; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Precision Medicine; Positron Emission Tomography Computed Tomography; Lymphoma, B-Cell; Radioimmunotherapy; Yttrium Radioisotopes
PubMed: 37290799
DOI: 10.2967/jnumed.122.265199 -
Cancers Jan 2022Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20... (Review)
Review
Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) I-tositumomab and Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody-drug conjugate (ADC) for the treatment of lymphomas, anti-CD30 brentuximab vedotin, paved the path for the preclinical development and clinical testing of several other ADCs, including polatuzumab vedotin and loncastuximab tesirine. Other modalities of TDD are based on new formulations of "old" cytostatic agents and their passive trapping in the lymphoma tissue by means of the enhanced permeability and retention (EPR) effect. Currently, the diagnostic and restaging procedures in aggressive lymphomas are based on nuclear imaging, namely PET. A theranostic approach that combines diagnostic or restaging lymphoma imaging with targeted treatment represents an appealing innovative strategy in personalized medicine. The future of theranostics will require not only the capability to provide suitable disease-specific molecular probes but also expertise on big data processing and evaluation. Here, we review the concept of targeted drug delivery in malignant lymphomas from RIT and ADC to a wide array of passively and actively targeted nano-sized investigational agents. We also discuss the future of molecular imaging with special focus on monoclonal antibody-based and monoclonal antibody-derived theranostic strategies.
PubMed: 35158894
DOI: 10.3390/cancers14030626 -
Theranostics 2021Radioimmunotherapy (RIT) is FDA-approved for the clinical management of liquid malignancies, however, its use for solid malignancies remains a challenge. The putative... (Review)
Review
Radioimmunotherapy (RIT) is FDA-approved for the clinical management of liquid malignancies, however, its use for solid malignancies remains a challenge. The putative benefit of RIT lies in selective targeting of antigens expressed on the tumor surface using monoclonal antibodies, to systemically deliver cytotoxic radionuclides. The past several decades yielded dramatic improvements in the quality, quantity, recent commercial availability of alpha-, beta- and Auger Electron-emitting therapeutic radiometals. Investigators have created new or improved existing bifunctional chelators. These bifunctional chelators bind radiometals and can be coupled to antigen-specific antibodies. In this review, we discuss approaches to develop radiometal-based RITs, including the selection of radiometals, chelators and antibody platforms (i.e. full-length, F(ab'), Fab, minibodies, diabodies, scFv-Fc and nanobodies). We cite examples of the performance of RIT in the clinic, describe challenges to its implementation, and offer insights to address gaps toward translation.
Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Agents, Immunological; Chelating Agents; Click Chemistry; Clinical Trials as Topic; Dose Fractionation, Radiation; Drug Delivery Systems; Forecasting; Humans; Immunoglobulin Fab Fragments; Lymphoma, Non-Hodgkin; Mice; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms, Experimental; Organ Specificity; Precision Medicine; Radiation Tolerance; Radioimmunotherapy; Radiopharmaceuticals; Receptor Protein-Tyrosine Kinases; Single-Chain Antibodies; Single-Domain Antibodies; Yttrium Radioisotopes
PubMed: 33995659
DOI: 10.7150/thno.57177 -
Pharmacological Research Jan 2023New therapies for relapsed/refractory diffuse large B-cell lymphoma (r/rDLBCL) have emerged in recent years, but there have been no comprehensive quantitative... (Meta-Analysis)
Meta-Analysis Review
New therapies for relapsed/refractory diffuse large B-cell lymphoma (r/rDLBCL) have emerged in recent years, but there have been no comprehensive quantitative comparisons of the efficacy of these therapies. In this study, the efficacy characteristics of 11 types of treatment strategy and 63 treatment regimens were compared by model based meta-analysis. We found that compared with monotherapy, association therapy had significant benefits in terms of overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). However, whereas treatment regimens involving chemotherapy contributed to significant improvements in ORR and PFS, OS was not improved. In terms of treatment strategy, we identified chemotherapy in association with immunotherapy sequential autologous stem cell transplantation (ASCT), the association of two different types of immunotherapies, chemotherapy sequential ASCT, chemotherapy in association with immunotherapy, and chemotherapy in association with two types of immunotherapies as showing better efficacy. With respect to specific treatment regimens, we found that the following had better efficacy: rituximab in association with inotuzumab ozogamicin; rituximab in association with carmustine, etoposide, cytarabine, and melphalan sequential ASCT (R-BEAM+ASCT); lenalidomide in association with rituximab, etoposide, cisplatin, cytarabine, and methylprednisolone; iodine-131 tositumomab in association with BEAM sequential ASCT; and chemotherapy sequential chimeric antigen receptor T-cell immunotherapy, with median OS of 48.2, 34.2, 27.8, 25.8, and 25 months, respectively. Moreover, with respect to association therapy, there was a strong correlation between the 6-month PFS and 2-year OS. The findings of this study provide the necessary quantitative information for clinical practice and clinical trial design for the treatment of r/rDLBCL.
Topics: Humans; Rituximab; Etoposide; Hematopoietic Stem Cell Transplantation; Antineoplastic Combined Chemotherapy Protocols; Transplantation, Autologous; Neoplasm Recurrence, Local; Lymphoma, Large B-Cell, Diffuse; Cytarabine
PubMed: 36470547
DOI: 10.1016/j.phrs.2022.106592 -
Blood Advances Sep 2023Although TP53 is commonly mutated in transformed follicular lymphoma, mutations are reported in <5% of pretreatment follicular lymphoma (FL) specimens. We assayed... (Randomized Controlled Trial)
Randomized Controlled Trial
Although TP53 is commonly mutated in transformed follicular lymphoma, mutations are reported in <5% of pretreatment follicular lymphoma (FL) specimens. We assayed archival follicular B-cell non-Hodgkin lymphoma specimens from a completed clinical trial, Southwest Oncology Group S0016, a phase 3 randomized intergroup trial of CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone) chemotherapy plus R-CHOP (rituximab-CHOP) compared with CHOP chemotherapy plus 131-iodine tositumomab (radioimmunotherapy [RIT]-CHOP). Subclonal TP53 mutations (median allele frequency 0.02) were found in 25% of diagnostic FL specimens and in 27% of a separate validation cohort. In the R-CHOP arm, pathogenic TP53 mutations were not associated with progression-free survival (PFS) (10-year PFS 43% vs 44%). In contrast, among patients with no detectable pathogenic TP53 mutation, RIT-CHOP was associated with a longer PFS than with R-CHOP (10-year PFS 67% vs 44%; hazard ratio = 0.49; P = .008). No relationship was detected between PFS and the extent of activation-induced cytidine deaminase (AICDA)-mediated heterogeneity. In summary, subclonal TP53 mutations are common in FL and are a distinct phenomenon from AICDA-mediated genetic heterogeneity. The absence of a detectable subclonal mutation in TP53 defined a population that particularly benefited from RIT.
Topics: Humans; Lymphoma, Follicular; Radioimmunotherapy; Neoplasm Recurrence, Local; Rituximab; Lymphoma, Non-Hodgkin; Vincristine; Cyclophosphamide; Prednisone; Doxorubicin; Mutation; Tumor Suppressor Protein p53
PubMed: 37379264
DOI: 10.1182/bloodadvances.2022009467 -
Exploration of Targeted Anti-tumor... 2024Radioimmunotherapy (RIT) is a therapy that combines a radioactive nucleotide with a monoclonal antibody (mAb). RIT enhances the therapeutic effect of mAb and reduces... (Review)
Review
Radioimmunotherapy (RIT) is a therapy that combines a radioactive nucleotide with a monoclonal antibody (mAb). RIT enhances the therapeutic effect of mAb and reduces toxicity compared with conventional treatment. The purpose of this review is to summarize the current progress of RIT for treating non-Hodgkin's lymphoma (NHL) based on recent preclinical and clinical studies. The efficacy of RIT targeting the B-lymphocyte antigen cluster of differentiation 20 (CD20) has been demonstrated in clinical trials. Two radioimmunoconjugates targeting CD20, yttrium-90 (Y)-ibritumomab-tiuxetan (Zevalin) and iodine-131 (I)-tositumomab (Bexxar), have been approved in the USA Food and Drug Administration (FDA) for treating relapsed/refractory indolent or transformed NHL in 2002 and 2003, respectively. Although these two radioimmunoconjugates are effective and least toxic, they have not achieved popularity due to increasing access to novel therapies and the complexity of their delivery process. RIT is constantly evolving with the identification of novel targets and novel therapeutic strategies using newer radionuclides such as alpha-particle isotopes. Alpha-particles show very short path lengths and high linear energy transfer. These characteristics provide increased tumor cell-killing activities and reduced non-specific bystander responses on normal tissue. This review also discusses reviewed pre-targeted RIT (PRIT) and immuno-positron emission tomography (PET). PRIT potentially increases the dose of radionuclide delivered to tumors while toxicities to normal tissues are limited. Immuno-PET is a molecular imaging tracer that combines the high sensitivity of PET with the specific targeting capability of mAb. Immuno-PET strategies targeting CD20 and other antigens are currently being developed. The theragnostic approach by immuno-PET will be useful in monitoring the treatment response.
PubMed: 38464386
DOI: 10.37349/etat.2024.00213 -
Journal of Nuclear Medicine : Official... Jan 2023We studied the feasibility of using the α-emitting Bi-anti-CD20 therapy with direct bioluminescent tracking of micrometastatic human B-cell lymphoma in a SCID mouse...
We studied the feasibility of using the α-emitting Bi-anti-CD20 therapy with direct bioluminescent tracking of micrometastatic human B-cell lymphoma in a SCID mouse model. A highly lethal SCID mouse model of minimal-tumor-burden disseminated non-Hodgkin lymphoma (NHL) was established using human Raji lymphoma cells transfected to express the luciferase reporter. In vitro and in vivo radioimmunotherapy experiments were conducted. Single- and multiple-dose regimens were explored, and results with Bi-rituximab were compared with various controls, including no treatment, free Bi radiometal, unlabeled rituximab, and Bi-labeled anti-HER2/ (non-CD20-specific antibody). Bi-rituximab was also compared in vivo with the low-energy β-emitter I-tositumomab and the high-energy β-emitter Y-rituximab. In vitro studies showed dose-dependent target-specific killing of lymphoma cells with Bi-rituximab. Multiple in vivo studies showed significant and specific tumor growth delays with Bi-rituximab versus free Bi, Bi-labeled control antibody, or unlabeled rituximab. Redosing of Bi-rituximab was more effective than single dosing. With a single dose of therapy given 4 d after intravenous tumor inoculation, disease in all untreated controls, and in all mice in the 925-kBq Y-rituximab group, progressed. With 3,700 kBq of Bi-rituximab, 75% of the mice survived and all but 1 survivor was cured. With 2,035 kBq of I-tositumomab, 75% of the mice were tumor-free by bioluminescent imaging and 62.5% survived. Cure of micrometastatic NHL is achieved in most animals treated 4 d after intravenous tumor inoculation using either Bi-rituximab or I-tositumomab, in contrast to the lack of cures with unlabeled rituximab or Y-rituximab or if there was a high tumor burden before radioimmunotherapy. α-emitter-labeled anti-CD20 antibodies are promising therapeutics for NHL, although a longer-lived α-emitter may be of greater efficacy.
Topics: Mice; Humans; Animals; Rituximab; Mice, SCID; Antibodies, Monoclonal; Lymphoma, B-Cell; Antineoplastic Agents; Lymphoma, Non-Hodgkin; Lymphoma; Radioimmunotherapy; Antigens, CD20
PubMed: 35981897
DOI: 10.2967/jnumed.122.263962