Subject(s)
Antibodies, Monoclonal/therapeutic use , CD47 Antigen/antagonists & inhibitors , Epitopes/therapeutic use , Neoplasms/drug therapy , Receptors, Antigen, T-Cell/metabolism , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Macrophages/drug effects , Mice , Neoplasms/metabolism , Phagocytosis/drug effectsABSTRACT
The inadequate transport of drugs into the tumor tissue caused by its abnormal vasculature is a major obstacle to the treatment of cancer. Anti-vascular endothelial growth factor (anti-VEGF) drugs can cause phenotypic alteration and maturation of the tumor's vasculature. However, whether this consistently improves delivery and subsequent response to therapy is still controversial. Clinical results indicate that not all patients benefit from antiangiogenic treatment, necessitating the development of criteria to predict the effect of these agents in individual tumors. We demonstrate that, in anti-VEGF-refractory murine tumors, vascular changes after VEGF ablation result in reduced delivery leading to therapeutic failure. In these tumors, the impaired response after anti-VEGF treatment is directly linked to strong deposition of fibrillar extracellular matrix (ECM) components and high expression of lysyl oxidases. The resulting condensed, highly crosslinked ECM impeded drug permeation, protecting tumor cells from exposure to small-molecule drugs. The reduced vascular density after anti-VEGF treatment further decreased delivery in these tumors, an effect not compensated by the improved vessel quality. Pharmacological inhibition of lysyl oxidases improved drug delivery in various tumor models and reversed the negative effect of VEGF ablation on drug delivery and therapeutic response in anti-VEGF-resistant tumors. In conclusion, the vascular changes after anti-VEGF therapy can have a context-dependent negative impact on overall therapeutic efficacy. A determining factor is the tumor ECM, which strongly influences the effect of anti-VEGF therapy. Our results reveal the prospect to revert a possible negative effect and to potentiate responsiveness to antiangiogenic therapy by concomitantly targeting ECM-modifying enzymes.
Subject(s)
Antibodies, Monoclonal/pharmacology , Extracellular Matrix/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Animals , Cell Line, Tumor , Disease Models, Animal , Drug Resistance, Neoplasm , Female , Humans , Mice , Models, Biological , Molecular Targeted Therapy , Neoplasms/drug therapy , Permeability , Protein-Lysine 6-Oxidase/metabolism , Sarcoma/drug therapy , Sarcoma/metabolism , Sarcoma/pathology , Xenograft Model Antitumor AssaysABSTRACT
CD19-directed chimeric antigen receptor (CAR) T cells are clinically effective in a limited set of leukemia patients. However, CAR T-cell therapy thus far has been largely restricted to targeting extracellular tumor-associated antigens (TAA). Herein, we report a T-cell receptor-mimic (TCRm) CAR, termed WT1-28z, that is reactive to a peptide portion of the intracellular onco-protein Wilms Tumor 1(WT1), as it is expressed on the surface of the tumor cell in the context of HLA-A*02:01. T cells modified to express WT1-28z specifically targeted and lysed HLA-A*02:01+ WT1+ tumors and enhanced survival of mice engrafted with HLA-A*02:01+, WT1+ leukemia or ovarian tumors. This in vivo functional validation of TCRm CAR T cells provides the proof-of-concept necessary to expand the range of TAA that can be effectively targeted for immunotherapy to include attractive intracellular targets, and may hold great potential to expand on the success of CAR T-cell therapy.
Subject(s)
Leukemia/therapy , Receptors, Antigen, T-Cell/immunology , WT1 Proteins/immunology , Animals , Cell Line , Female , HLA-A Antigens/analysis , Humans , Immunotherapy , Interleukin-12/biosynthesis , Mice , Ovarian Neoplasms/therapy , Recombinant Fusion Proteins/immunology , Retroviridae/genetics , Transcriptome , WT1 Proteins/analysisABSTRACT
Inhibition of human mitochondrial peptide deformylase (HsPDF) depolarizes the mitochondrial membrane, reduces mitochondrial protein translation and causes apoptosis in Burkitt's lymphoma. We showed that HsPDF mRNA and protein levels were overexpressed in cancer cells and primary acute myeloid leukemia samples. Myc regulates mitochondria and metabolism; we also demonstrated c-myc regulated the expression of HsPDF, likely indirectly. Inhibition of HsPDF by actinonin blocked mitochondrial protein translation and caused apoptotic death of myc-positive Burkitt's lymphoma, but not myc-negative B cells. Inhibition of mitochondrial translation by chloramphenicol or tetracycline, structurally different inhibitors of the mitochondrial ribosome, which is upstream of deformylase activity, followed by treatment with actinonin, resulted in reversal of the biochemical events and abrogation of the apoptosis induced by actinonin. This reversal was specific to inhibitors of HsPDF. Inhibition of HsPDF resulted in a mitochondrial unfolded protein response (increased transcription factors CHOP and CEB/P and the mitochondrial protease Lon), which may be a mechanism mediating cell death. Therefore, HsPDF may be a therapeutic target for these hematopoietic cancers, acting via a new mechanism.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Apoptosis , Hematologic Neoplasms/enzymology , Hematologic Neoplasms/pathology , Hematopoiesis , Mitochondria/enzymology , Proto-Oncogene Proteins c-myc/metabolism , Amidohydrolases/genetics , Amidohydrolases/metabolism , Apoptosis/drug effects , Apoptosis/genetics , Burkitt Lymphoma/enzymology , Burkitt Lymphoma/genetics , Burkitt Lymphoma/pathology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Glycolysis/drug effects , Hematologic Neoplasms/genetics , Hematopoiesis/drug effects , Humans , Hydroxamic Acids/toxicity , Leukemia, Myeloid/enzymology , Leukemia, Myeloid/genetics , Leukemia, Myeloid/pathology , Mitochondria/drug effects , Unfolded Protein Response/drug effectsABSTRACT
Clinical therapeutic studies using (225)Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of (225)Ac. The purpose of this study was to determine the amount of (225)Ac and non-equilibrium progeny in the mouse kidney after the injection of (225)Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with (225)Ac-huM195 antibody and kidneys excised. One kidney was used for gamma ray spectroscopic measurements by a high-purity germanium (HPGe) detector. The second kidney was used to generate frozen tissue sections which were examined by digital autoradiography (DAR). Two measurements were performed on each kidney specimen: (1) immediately post-resection and (2) after sufficient time for any non-equilibrium excess (213)Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess (213)Bi reaching the kidney (γ-ray spectroscopy) and its sub-regional distribution (DAR). The average absorbed dose to whole kidney, determined by spectroscopy, was 0.77 (SD 0.21) Gy kBq(-1), of which 0.46 (SD 0.16) Gy kBq(-1) (i.e. 60%) was due to non-equilibrium excess (213)Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from non-equilibrium excess (213)Bi (0.31 (SD 0.11) Gy kBq(-1)) represented â¼46% of the total. For the medulla the dose contribution from excess (213)Bi (0.81 (SD 0.28) Gy kBq(-1)) was â¼80% of the total. Based on these estimates, for human patients we project a kidney-absorbed dose of 0.28 Gy MBq(-1) following administration of (225)Ac-huM195 with non-equilibrium excess (213)Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the success of (225)Ac radioimmunotherapy.
Subject(s)
Actinium/chemistry , Antibodies/administration & dosage , Antibodies/chemistry , Bismuth/metabolism , Kidney/metabolism , Kidney/radiation effects , Radioisotopes/metabolism , Actinium/adverse effects , Animals , Autoradiography , Biological Transport , Female , Humans , Kidney/pathology , Mice , Mice, Inbred BALB C , Radiation Dosage , RadiometrySubject(s)
Cancer Vaccines/administration & dosage , Fusion Proteins, bcr-abl/chemistry , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Adult , Aged , Amino Acid Sequence , CD4-Positive T-Lymphocytes/immunology , Cancer Vaccines/therapeutic use , Enzyme-Linked Immunosorbent Assay , Female , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Male , Middle Aged , Molecular Sequence Data , Pilot ProjectsABSTRACT
Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML) for which a number of targeted therapies have been developed. The "targets" have included both genotypic and phenotypic features of the disease. The application of monoclonal antibodies (MAbs) to this disease to date have been limited to a relatively small number of studies where this therapy has been used to supplement effective approaches to the disease. The preliminary results have been promising, and further development of this modality as an effective adjunct to existing treatment regimens will most certainly occur in the near future.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Aminoglycosides/therapeutic use , Animals , Antibodies, Monoclonal, Humanized , Antigens, CD/immunology , Antigens, Differentiation, Myelomonocytic/immunology , Gemtuzumab , HL-60 Cells , Humans , Mice , Sialic Acid Binding Ig-like Lectin 3 , Treatment OutcomeABSTRACT
CD307 is a differentiation antigen expressed in B-lineage cells. One soluble and two membrane-bound forms have been predicted and an enzyme-linked immunosorbent assay (ELISA) for soluble CD307 established. Our goal was to determine if CD307 is expressed on the surface of cells from patients with multiple myeloma (MM), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and other B-cell malignancies and if soluble CD307 levels are elevated in the blood of patients with these B-cell malignancies. Cells and blood were collected from patients. Expression of CD307 was measured by flow cytometry and blood levels of soluble CD307 by ELISA. High soluble CD307 levels were detected in 21/43 (49%) of patients with MM, 36/46 (78%) with CLL and 9/24 (38%) with MCL. Soluble CD307 levels correlated with plasma cell percentages in bone marrow aspirates in MM and total white blood cells in CLL. CD307 on the cell membrane was detected by flow cytometry in 8/8 MM, 23/29 CLL and 4/5 MCL samples. Because CD307 is present on malignant cells from patients with MM, CLL and MCL, CD307 may be a useful therapeutic target for the treatment of these diseases.
Subject(s)
Biomarkers, Tumor , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Lymphoma, Mantle-Cell/blood , Multiple Myeloma/blood , Receptors, Cell Surface/metabolism , Adolescent , Adult , Aged , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Female , Flow Cytometry , Humans , Male , Middle Aged , Receptors, FcABSTRACT
Wilms tumor protein 1 (WT1) is a transcription factor overexpressed in several types of leukemia and solid tumors. For this reason, WT1 is an attractive target for immunotherapy. Four peptide nonamers from WT1 have been identified by others to generate a WT1-specific cytotoxic response in the context of human leukocyte antigen (HLA)-A0201 and A2402. However, as WT1 is a self-antigen, breaking tolerance is a potential obstacle to vaccination. Here, we use a strategy to circumvent tolerance by designing synthetic immunogenic analog peptides that could crossreact to the native peptides (a heteroclitic response). A number of synthetic peptides derived from nonamer sequences of the WT1 protein were designed in which single amino-acid substitutions were introduced at HLA-A0201 major histocompatibility complex (MHC)-binding positions. Several of new peptides could stabilize MHC class I A0201 molecules better than native sequences. Some analogs were also able to elicit WT1-specific T-cell recognition and cytotoxic T-cell lymphocytes more effectively than native sequences. Importantly, T cells stimulated with the new analogs crossreacted with the native WT1 peptide sequence and were able to kill HLA-matched chronic myeloid leukemia cell lines. In conclusion, analog heteroclitic WT1 peptides with increased immunogenicity can be synthesized and are potential cancer vaccine candidates.
Subject(s)
Cancer Vaccines/immunology , HLA-A Antigens/immunology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Peptide Fragments/immunology , T-Lymphocytes/immunology , WT1 Proteins/genetics , Amino Acid Sequence , CD8 Antigens/immunology , Cell Line, Tumor , Epitopes/immunology , HLA-A Antigens/metabolism , HLA-A2 Antigen , Humans , Immune Tolerance/immunology , Interferon-gamma/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Peptide Fragments/chemical synthesis , Peptide Fragments/metabolism , Protein Binding/immunology , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , WT1 Proteins/metabolismABSTRACT
Targeted radiotherapy of the bone marrow using radiolabeled monoclonal antibodies is a therapeutic approach of considerable potential for the treatment of acute leukemia in addition to or as a substitute for total body irradiation. The data currently available, of about 300 patients, suggest that radioimmunotherapy (RIT) with beta-emitters in acute leukemia is feasible and safe using a variety of antibodies (anti-CD33, anti-CD45, anti-CD66) and radionuclides (131I, 90Y, 188Re). It appears to reduce the risk of relapse in high-risk acute myelogenous leukemia (AML) patients transplanted early in the course of their disease (<15% blasts) to 20-30%. Furthermore, it has shown the potential to safely intensify reduced-intensity conditioning regimens (nonrelapse mortality of 25% compared to relapse rate of 55% within 2 years). Significant improvements in the results of refractory patients will probably depend on the successful further development of RIT with alpha-emitters or the use of a cocktail of antibodies labeled with alpha- and beta-emitters, in a first dose escalation study of 213Bi-labeled anti-CD33 in refractory AML (partial) remission could be achieved in 5/18 patients. Randomized trials to evaluate the therapeutic efficacy of RIT in the context of stem cell transplantation have been initiated and the results are keenly anticipated.
Subject(s)
Immunoconjugates/therapeutic use , Leukemia/radiotherapy , Alpha Particles , Antibodies, Monoclonal/pharmacology , Antigens, CD/biosynthesis , Antigens, Differentiation, Myelomonocytic/biosynthesis , Beta Particles , Cell Adhesion Molecules/biosynthesis , Clinical Trials as Topic , Dose-Response Relationship, Radiation , Humans , Leukocyte Common Antigens/biosynthesis , Quality Control , Radioimmunotherapy , Radioisotopes/therapeutic use , Radiometry , Rhenium/therapeutic use , Sialic Acid Binding Ig-like Lectin 3 , Stem Cell Transplantation , Yttrium Radioisotopes/therapeutic useABSTRACT
The monoclonal antibodies M195 and HuM195 target CD33, a glycoprotein found on myeloid leukemia cells. When labeled with iodine-131 ((131)I), these antibodies can eliminate large disease burdens and produce prolonged myelosuppression. We studied whether (131)I-labeled M195 and HuM195 could be combined safely with busulfan and cyclophosphamide (BuCy) as conditioning for allogeneic BMT. A total of 31 patients with relapsed/refractory acute myeloloid leukemia (AML) (n=16), accelerated/myeloblastic chronic myeloid leukemia (CML) (n=14), or advanced myelodysplastic syndrome (n=1) received (131)I-M195 or (131)I-HuM195 (122-437 mCi) plus busulfan (16 mg/kg) and cyclophosphamide (90-120 mg/kg) followed by infusion of related-donor bone marrow (27 first BMT; four second BMT). Hyperbilirubinemia was the most common extramedullary toxicity, occurring in 69% of patients during the first 28 days after BMT. Gamma camera imaging showed targeting of the radioisotope to the bone marrow, liver, and spleen, with absorbed radiation doses to the marrow of 272-1470 cGy. The median survival was 4.9 months (range 0.3-90+ months). Three patients with relapsed AML remain in complete remission 59+, 87+, and 90+ months following bone marrow transplantation (BMT). These studies show the feasibility of adding CD33-targeted radioimmunotherapy to a standard BMT preparative regimen; however, randomized trials will be needed to prove a benefit to intensified conditioning with radioimmunotherapy.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Transplantation/methods , Leukemia, Myeloid/therapy , Transplantation Conditioning/methods , Adolescent , Adult , Antibodies, Monoclonal/pharmacokinetics , Antigens, CD/immunology , Antigens, Differentiation, Myelomonocytic/immunology , Bone Marrow Transplantation/mortality , Busulfan/therapeutic use , Child , Child, Preschool , Cyclophosphamide/therapeutic use , Female , Humans , Immunoconjugates/pharmacokinetics , Immunoconjugates/therapeutic use , Iodine Radioisotopes/pharmacokinetics , Iodine Radioisotopes/therapeutic use , Leukemia, Myeloid/mortality , Male , Middle Aged , Radiation Dosage , Sialic Acid Binding Ig-like Lectin 3 , Survival Analysis , Tissue Distribution , Transplantation, Homologous , Treatment OutcomeABSTRACT
In recent years, radioimmunotherapy (RIT) with beta(-) particle emitting radionuclides targeting the CD20 antigen on B cells in the treatment of non-Hodgkin's lymphoma has provided the most compelling human clinical data for the success of RIT. CD19, like CD20, is an antigen expressed on the surface of cells of the B lineage, and CD19 may provide an alternative target for radioimmunotherapy of B cell neoplasms. CD19 has been largely overlooked as a target for conventional 131I RIT, because the antigen rapidly internalizes upon binding of antibody, resulting in catabolism and significant release of 131I. Such modulation may be an advantage to RIT with radiometals such as 90Y, 177Lu, 213Bi and 225Ac. Herein, we have compared beta(-) particle RIT with antibodies targeting either CD19 or CD20. The anti-CD19 and anti-CD20 antibodies, B4 or C2B8, respectively, were appended with the SCN-CHX-A''-DTPA bifunctional chelating agent and labeled with 90Y. In the tumor model used, there were three times as many CD20 target sites on lymphoma cells as compared to CD19 sites (62000 vs 20000 binding sites, respectively). We compared the efficacy of the 90Y-labeled antibodies to reduce lymphoma in a nude mouse xenograft solid tumor model, after measurable lymphoma appeared. Reduction in tumor size began at day 3 in all three 90Y-treated groups, but tumor began to recur in many animals 9 days after the treatments. There was one cure in each specific treatment group. In contrast, the tumor in the two control groups showed no regression. There was a significant prolongation of median survival time from xenograft (P < 0.0001) in all the 90Y-labeled antibody construct-treated groups (32 days for 0.15 mCi 90Y-B4; 26 days for 0.20 mCi 90Y-C2B8, and 23 days for 0.15 mCi 90Y-C2B8) in comparison to the two control groups (11 days for 0.02 mg of C2B8 and 9 days for untreated growth controls). Specificity of the radioimmunotherapy was also shown. In conclusion, 90Y-labeled anti-CD19 antibody has efficacy comparable to 90Y-labeled anti-CD20 antibody in the treatment of mice bearing human lymphoma xenografts. These data suggest that CD19-targeted RIT merits further study.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antigens, CD19/immunology , Antigens, CD20/immunology , Antigens, Neoplasm/immunology , Burkitt Lymphoma/radiotherapy , Radioimmunotherapy , Yttrium Radioisotopes/therapeutic use , Animals , Antibodies, Monoclonal/immunology , Antibody Affinity , Burkitt Lymphoma/immunology , Burkitt Lymphoma/pathology , Female , Humans , Mice , Mice, Nude , Tumor Cells, Cultured/immunology , Tumor Cells, Cultured/transplantation , Xenograft Model Antitumor Assays , Yttrium Radioisotopes/administration & dosageABSTRACT
A single, high linear energy transfer alpha particle can kill a target cell. We have developed methods to target molecular-sized generators of alpha-emitting isotope cascades to the inside of cancer cells using actinium-225 coupled to internalizing monoclonal antibodies. In vitro, these constructs specifically killed leukemia, lymphoma, breast, ovarian, neuroblastoma, and prostate cancer cells at becquerel (picocurie) levels. Injection of single doses of the constructs at kilobecquerel (nanocurie) levels into mice bearing solid prostate carcinoma or disseminated human lymphoma induced tumor regression and prolonged survival, without toxicity, in a substantial fraction of animals. Nanogenerators targeting a wide variety of cancers may be possible.
Subject(s)
Actinium/therapeutic use , Immunoconjugates/therapeutic use , Neoplasms/radiotherapy , Radioimmunotherapy/methods , Actinium/administration & dosage , Actinium/pharmacokinetics , Alpha Particles/therapeutic use , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Female , Half-Life , Heterocyclic Compounds, 1-Ring , Humans , Immunoconjugates/administration & dosage , Immunoconjugates/pharmacokinetics , Linear Energy Transfer , Lymphoma/radiotherapy , Male , Mice , Mice, Nude , Neoplasm Transplantation , Prostate-Specific Antigen/blood , Prostatic Neoplasms/radiotherapy , Survival Rate , Tumor Cells, CulturedABSTRACT
The t(15;17) translocation in acute promyelocytic leukemia (APL) yields a PML/RAR-alpha fusion messenger RNA species that can be detected by reverse transcription-polymerase chain reaction (RT-PCR) amplification. Breakpoints within intron 3 of PML produce a short PML/RAR-alpha isoform, whereas breakpoints within intron 6 result in a longer form. Using RT-PCR, serial evaluations were performed on the bone marrow of 82 patients with APL (median follow-up, > 63 months) who received retinoic acid (RA) induction followed by postremission treatment with chemotherapy, RA, and biologic agents. Sixty-four patients attained a clinical complete remission and had at least 2 RT-PCR assays performed after completing therapy. Forty of 47 patients (85%) with newly diagnosed APL who were induced using RA had residual disease detectable by RT-PCR before additional therapy. After 3 cycles of consolidation therapy, residual disease was found in only 4 of 40 evaluable patients (10%). Among newly diagnosed patients who had 2 or more negative RT-PCR assays, only 3 of 41 (7%) had a relapse, whereas all 4 patients (100%) who had 2 or more positive results had a relapse. Among 63 newly diagnosed patients, those who expressed the short isoform appeared to have shorter disease-free and overall survival durations than patients who expressed the long isoform. These data indicate that 2 or more negative RT-PCR assays on bone marrow, performed at least 1 month apart after completing therapy, are strongly associated with long-term remissions. Conversely, a confirmed positive test is highly predictive of relapse.
Subject(s)
Leukemia, Promyelocytic, Acute/diagnosis , Neoplasm Proteins/genetics , Neoplasm, Residual/genetics , Oncogene Proteins, Fusion/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Bone Marrow/metabolism , Child , Follow-Up Studies , Humans , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/therapy , Middle Aged , Neoplasm, Residual/diagnosis , Predictive Value of Tests , Prognosis , Prospective Studies , Protein Isoforms/genetics , RNA, Messenger/analysis , Recurrence , Remission Induction , Reverse Transcriptase Polymerase Chain Reaction , Survival AnalysisABSTRACT
Alpha emitting radionuclides are of considerable interest for targeted radioimmunotherapy. Generator supplied 213Bi emitting 8.5 MeV alpha particles with a 45.6 min half-life has been conjugated to a monoclonal antibody (HuM195-CHX-A-DTPA) for targeted therapy of leukemia in a clinical trial. The clinical dose preparation of pharmaceutical formulation by a pair of skilled radiochemists took 25 min, which corresponds, to an overall decay loss of 30% of the initial 213Bi activity eluted from the generator. In order to allow more widespread and practical clinical use of targeted 213Bi alpha particle therapy, we developed a new procedure that is simpler, more rapid and adaptable to a hospital pharmacy. The new 10 min process includes a tandem elution and labeling, and an anion exchange column purification method that can be reproducibly used.
Subject(s)
Alpha Particles , Immunoconjugates/isolation & purification , Radiopharmaceuticals/isolation & purification , Alpha Particles/therapeutic use , Antibodies, Monoclonal/isolation & purification , Antibodies, Monoclonal/therapeutic use , Bismuth/isolation & purification , Bismuth/therapeutic use , Chromatography, Ion Exchange/methods , Clinical Trials as Topic , Half-Life , Humans , Immunoconjugates/therapeutic use , Leukemia, Myeloid, Acute/therapy , Radioisotopes/isolation & purification , Radioisotopes/therapeutic use , Radiopharmaceuticals/therapeutic useABSTRACT
PURPOSE: To determine the safety and efficacy of arsenic trioxide (ATO) in patients with relapsed acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Forty patients experiencing first (n = 21) or > or = second (n = 19) relapse were treated with daily infusions of ATO to a maximum of 60 doses or until all leukemic cells in bone marrow were eliminated. Patients who achieved a complete remission (CR) were offered one consolidation course of ATO that began 3 to 4 weeks later. Patients who remained in CR were eligible to receive further cycles of ATO therapy on a maintenance study. RESULTS: Thirty-four patients (85%) achieved a CR. Thirty-one patients (91%) with CRs had posttreatment cytogenetic tests negative for t(15;17). Eighty-six percent of the patients who were assessable by reverse transcriptase polymerase chain reaction converted from positive to negative for the promyelocytic leukemia/retinoic acid receptor-alpha transcript by the completion of their consolidation therapy. Thirty-two patients received consolidation therapy, and 18 received additional ATO as maintenance. Eleven patients underwent allogeneic (n = 8) or autologous (n = 3) transplant after ATO treatment. The 18-month overall and relapse-free survival (RFS) estimates were 66% and 56%, respectively. Twenty patients (50%) had leukocytosis (> 10,000 WBC/microL) during induction therapy. Ten patients developed signs or symptoms suggestive of the APL syndrome and were effectively treated with dexamethasone. Electrocardiographic QT prolongation was common (63%). One patient had an absolute QT interval of > 500 msec and had an asymptomatic 7-beat run of torsades de pointe. Two patients died during induction, neither from drug-related causes. CONCLUSION: This study establishes ATO as a highly effective therapy for patients with relapsed APL.
Subject(s)
Antineoplastic Agents/therapeutic use , Arsenicals/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Adolescent , Adult , Arsenic Trioxide , Arsenicals/adverse effects , Electrocardiography , Female , Humans , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/pathology , Leukocytosis/chemically induced , Male , Middle Aged , Nervous System Diseases/chemically induced , Oxides/adverse effects , Pilot Projects , Platelet Count , Remission Induction , Reverse Transcriptase Polymerase Chain Reaction , Survival Analysis , SyndromeABSTRACT
Bisumth-213, a short-lived alpha particle emitting radionuclide, is generated from the decay of 225Ac, which has a half-life of 10 days. The development of a clinical 225Ac/213Bi generator and the preparation of a 213Bi radiolabeled antibody for radioimmunotherapy of leukemia have been reported. The 225Ac decay scheme is complex; therefore a thorough understanding of the impact of both the parent 225Ac and its daughters on radiolabeling, purification, and quantification is necessary for optimal use of the generator system. This paper reports: (i) unique new methods to measure 221Fr, 213Bi, and 209Pb, the prominent daughters of 225Ac; and (ii) a quantitative evaluation of 225Ac/213Bi generator breakthrough and the radionuclidic purity of 213Bi labeled radiopharmaceutical dose formulations. A quantitative multi-dimensional proportional scanning method was employed to distinguish and measure specific daughter radionuclides. This method combines thin layer chromatography in two perpendicular directions with attenuated collimation as a function of time for data collection and analysis. Francium-221 and 213Bi eluted differentially from the generator, and 221Fr contributed minimally to unchelated 213Bi in the reaction and final products. Lead-209 was present in the reaction solution, but not strongly bound by the chelating moiety either (i) under the 213Bi labeling reaction conditions or (ii) following chelated 213Bi decay. As a consequence of incorporating several new procedures to the operation of the generator, 225Ac breakthrough in the final product was further reduced and represented a trivial contaminant in the final drug formulations.
Subject(s)
Actinium/isolation & purification , Bismuth/isolation & purification , Radioisotopes/isolation & purification , Radiopharmaceuticals/isolation & purification , Actinium/therapeutic use , Francium/isolation & purification , Humans , Lead Radioisotopes/isolation & purification , Leukemia/radiotherapy , Radiochemistry/methods , Radioimmunotherapy , Radiopharmaceuticals/therapeutic useABSTRACT
A theoretical drawback to alpha-particle therapy with 213Bi is the short range of the particle track coupled with the short half-life of the radionuclide, thereby potentially limiting effective cytotoxicity to rapidly accessible, disseminated individual tumor cells (e.g., as in leukemia). In this work, a prostate carcinoma spheroid model was used to evaluate the feasibility of targeting micrometastatic clusters of tumor cells using 213Bi-labeled anti-prostate-specific membrane antigen (PSMA) antibody, J591. In prostate cancer, vascular dissemination of tumor cells or tumor cell clusters to the marrow constitutes an important step in the progression of this disease to widespread skeletal involvement, an incurable state. Such prevascularized clusters are ideal targets for radiolabeled antibodies because the barriers to antibody penetration that are associated with the capillary basal lamina have not yet formed. Beta- and gamma-emitting radionuclides such as 131I, which are widely used in radioimmunotherapy, are not expected to be effective when targeting single cells or small cell clusters. This is because the range of the emissions is one to two orders of magnitude greater than the target size, and the energy deposited per traversal is insufficient to produce any significant radiobiological effect. Spheroids of the prostate cancer cell line, LNCaP-LN3, were used as a model of prevascularized micrometastases; their response to an anti-PSMA antibody, J591, radiolabeled with the alpha-particle emitter 213Bi (T(1/2), 45.6 min.) has been measured. The time course of spheroid volume reductions was found to be sensitive to the initial spheroid volume. J591 labeled with 0.9 MBq/ml 213Bi resulted in a 3-log reduction in spheroid volume on day 33, relative to control, for spheroids with an initial diameter of 130 microm; 1.8 MBq/ml were required to achieve a similar response for spheroids with an initial diameter of 180 microm. Equivalent spheroid responses were observed after 12 Gy of acute external beam photon irradiation. Monte Carlo-based microdosimetric analyses of the 213Bi decay distribution in individual spheroids of 130-microm diameter yielded an average alpha-particle dose of 3.7 Gy to the spheroids, resulting in a relative biological effectiveness factor of 3.2 over photon irradiation. The activity concentrations used in the experiments were clinically relevant, and this work supports the possibility of using 213Bi-labeled antibodies not only for disseminated single tumor cells, as found in patients with leukemia, but also for micrometastatic tumor deposits up to 180 microm in diameter (1200 cells).