scholarly journals Conventional and pretargeted radioimmunotherapy using bismuth-213 to target and treat non-Hodgkin lymphomas expressing CD20: a preclinical model toward optimal consolidation therapy to eradicate minimal residual disease

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4231-4239 ◽  
Author(s):  
Steven I. Park ◽  
Jaideep Shenoi ◽  
John M. Pagel ◽  
Don K. Hamlin ◽  
D. Scott Wilbur ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Residual Disease ◽  
Preclinical Model ◽  
Optimal Method ◽  
Normal Tissues ◽  
Specific Localization ◽  
Path Lengths ◽  
Anti Cd20 ◽  
Minimal Residual ◽  
Α Particles

Abstract Radioimmunotherapy (RIT) with α-emitting radionuclides is an attractive approach for the treatment of minimal residual disease because the short path lengths and high energies of α-particles produce optimal cytotoxicity at small target sites while minimizing damage to surrounding normal tissues. Pretargeted RIT (PRIT) using antibody-streptavidin (Ab-SA) constructs and radiolabeled biotin allows rapid, specific localization of radioactivity at tumor sites, making it an optimal method to target α-emitters with short half-lives, such as bismuth-213 (213Bi). Athymic mice bearing Ramos lymphoma xenografts received anti-CD20 1F5(scFv)4SA fusion protein (FP), followed by a dendrimeric clearing agent and [213Bi]DOTA-biotin. After 90 minutes, tumor uptake for 1F5(scFv)4SA was 16.5% ± 7.0% injected dose per gram compared with 2.3% ± .9% injected dose per gram for the control FP. Mice treated with anti-CD20 PRIT and 600 μCi [213Bi]DOTA-biotin exhibited marked tumor growth delays compared with controls (mean tumor volume .01 ± .02 vs. 203.38 ± 83.03 mm3 after 19 days, respectively). The median survival for the 1F5(scFv)4SA group was 90 days compared with 23 days for the control FP (P < .0001). Treatment was well tolerated, with no treatment-related mortalities. This study demonstrates the favorable biodistribution profile and excellent therapeutic efficacy attainable with 213Bi-labeled anti-CD20 PRIT.

scholarly journals Minimal residual disease may predict bone marrow relapse in patients with hairy cell leukemia treated with 2-chlorodeoxyadenosine

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1556-1560 ◽  
Author(s):  
S Wheaton ◽  
MS Tallman ◽  
D Hakimian ◽  
L Peterson
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Hematoxylin And Eosin ◽  
Anti Cd20 ◽  
Minimal Residual

Minimal residual disease (MRD) can be detected in bone marrow core biopsies of patients with hairy cell leukemia (HCL) after treatment with 2-chlorodeoxyadenosine (2-CdA) using immunohistochemical (IHC) techniques. The purpose of this study was to determine whether the presence of MRD predicts bone marrow relapse. We studied paraffin- embedded bone marrow core biopsies from 39 patients with HCL in complete remission (CR) 3 months after a single cycle of 2-CdA. Biopsies performed 3 months posttherapy and annually thereafter were examined by routine hematoxylin and eosin (H&E) staining and IHC using the monoclonal antibodies (MoAbs) anti-CD45RO, anti-CD20, and DBA.44. At 3 months after therapy, 5 of 39 (13%) patients had MRD detectable by IHC that was not evident by routine H&E staining. Two of the five patients (40%) with MRD at 3 months have relapsed, whereas only 2 of 27 (7%) patients with no MRD and at least 1 year of follow up relapsed (P = .11). Over the 3-year follow-up period, two additional patients developed MRD. Overall, three of six (50%) patients with MRD detected at any time after therapy have relapsed, whereas only 1 of 25 (4%) patients without MRD has relapsed (P = .016). These data suggest that the presence of MRD after treatment with 2-CdA may predict relapse.

PHOX2B Is a Novel and Specific Marker for Minimal Residual Disease Testing in Neuroblastoma

2008 ◽  
Vol 26 (33) ◽  
pp. 5443-5449 ◽  
Author(s):  
Janine Stutterheim ◽  
Annemieke Gerritsen ◽  
Lily Zappeij-Kannegieter ◽  
Ilona Kleijn ◽  
Rob Dee ◽  
...  
Keyword(s):  
Real Time ◽  
Minimal Residual Disease ◽  
Quantitative Pcr ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Specific Marker ◽  
Real Time Quantitative Pcr ◽  
Normal Tissues ◽  
Specificity And Sensitivity ◽  
Minimal Residual

Purpose Polymerase chain reaction (PCR)–based detection of minimal residual disease (MRD) in neuroblastoma can be used to monitor therapy response and to evaluate stem cell harvests. Commonly used PCR markers, tyrosine hydroxylase (TH) and GD2 synthase, have expression in normal tissues, thus limiting MRD detection. To identify a more specific MRD marker, we tested PHOX2B. Patients and Methods To determine PHOX2B, TH, and GD2 synthase expression in normal tissues, it was measured by real-time quantitative PCR in samples of normal bone marrow (BM; n = 51), peripheral blood (PB; n = 37), and peripheral-blood stem cells (PBSCs; n = 24). Then, 289 samples of 101 Dutch patients and 47 samples of 43 German patients were tested for PHOX2B and TH; these samples included 52 tumor, 214 BM, 32 BM, and 38 PBSC harvests. Of the 214 BM samples, 167 were compared with cytology, and 47 BM samples were compared with immunocytology (IC). Results In contrast to TH and GD2 synthase, PHOX2B was not expressed in any of the normal samples. In patient samples, PHOX2B was detected in 32% cytology-negative and in 14% IC-negative samples and in 94% of cytology-positive and in 90% of IC-positive BM samples. Overall, PHOX2B was positive in 43% compared with 31% for TH. In 24% of all samples, TH expression was inconclusive, which is similar to expression found in normal tissues. In 42% of these samples, PHOX2B expression was positive. Conclusion PHOX2B is superior to TH and GD2 synthase in specificity and sensitivity for MRD detection of neuroblastoma by using real-time quantitative PCR. We propose to include PHOX2B in additional prospective MRD studies in neuroblastoma alongside TH and other MRD markers.

scholarly journals Daratumumab eradicates minimal residual disease in a preclinical model of pediatric T-cell acute lymphoblastic leukemia

Blood ◽  
2019 ◽  
Vol 134 (8) ◽  
pp. 713-716 ◽  
Author(s):  
Fotini Vogiatzi ◽  
Dorothee Winterberg ◽  
Lennart Lenk ◽  
Swantje Buchmann ◽  
Gunnar Cario ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Preclinical Model ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Minimal Residual

scholarly journals Detection and therapy of neuroblastoma minimal residual disease using [64/67Cu]Cu-SARTATE in a preclinical model of hepatic metastases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jason L. J. Dearling ◽  
Ellen M. van Dam ◽  
Matthew J. Harris ◽  
Alan B. Packard
Keyword(s):  
Tumor Cell ◽  
Minimal Residual Disease ◽  
Radionuclide Therapy ◽  
Residual Disease ◽  
Ex Vivo ◽  
Control Group ◽  
Preclinical Model ◽  
Tumor Cell Inoculation ◽  
Cell Inoculation ◽  
Minimal Residual

Abstract Background A major challenge to the long-term success of neuroblastoma therapy is widespread metastases that survive initial therapy as minimal residual disease (MRD). The SSTR2 receptor is expressed by most neuroblastoma tumors making it an attractive target for molecularly targeted radionuclide therapy. SARTATE consists of octreotate, which targets the SSTR2 receptor, conjugated to MeCOSar, a bifunctional chelator with high affinity for copper. Cu-SARTATE offers the potential to both detect and treat neuroblastoma MRD by using [64Cu]Cu-SARTATE to detect and monitor the disease and [67Cu]Cu-SARTATE as the companion therapeutic agent. In the present study, we tested this theranostic pair in a preclinical model of neuroblastoma MRD. An intrahepatic model of metastatic neuroblastoma was established using IMR32 cells in nude mice. The biodistribution of [64Cu]Cu-SARTATE was measured using small-animal PET and ex vivo tissue analysis. Survival studies were carried out using the same model: mice (6–8 mice/group) were given single doses of saline, or 9.25 MBq (250 µCi), or 18.5 MBq (500 µCi) of [67Cu]Cu-SARTATE at either 2 or 4 weeks after tumor cell inoculation. Results PET imaging and ex vivo biodistribution confirmed tumor uptake of [64Cu]Cu-SARTATE and rapid clearance from other tissues. The major clearance tissues were the kidneys (15.6 ± 5.8% IA/g at 24 h post-injection, 11.5 ± 2.8% IA/g at 48 h, n = 3/4). Autoradiography and histological analysis confirmed [64Cu]Cu-SARTATE uptake in viable, SSTR2-positive tumor regions with mean tumor uptakes of 14.1–25.0% IA/g at 24 h. [67Cu]Cu-SARTATE therapy was effective when started 2 weeks after tumor cell inoculation, extending survival by an average of 13 days (30%) compared with the untreated group (mean survival of control group 43.0 ± 8.1 days vs. 55.6 ± 9.1 days for the treated group; p = 0.012). No significant therapeutic effect was observed when [67Cu]Cu-SARTATE was started 4 weeks after tumor cell inoculation, when the tumors would have been larger (control group 14.6 ± 8.5 days; 9.25 MBq group 9.5 ± 1.6 days; 18.5 MBq group 15.6 ± 4.1 days; p = 0.064). Conclusions Clinical experiences of peptide-receptor radionuclide therapy for metastatic disease have been encouraging. This study demonstrates the potential for a theranostic approach using [64/67Cu]Cu-SARTATE for the detection and treatment of SSTR2-positive neuroblastoma MRD.

scholarly journals An abbreviated therapy-dosimetric equation for the companion diagnostic/therapeutic [64/67Cu]Cu-SARTATE

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eric Laffon ◽  
Henri de Clermont ◽  
Roger Marthan
Keyword(s):  
Minimal Residual Disease ◽  
Pediatric Patients ◽  
Residual Disease ◽  
Initial Therapy ◽  
Preclinical Model ◽  
Potential Interest ◽  
Companion Diagnostic ◽  
Minimal Residual

AbstractIn a preclinical model of neuroblastoma, Dearling et al. recently demonstrated the potential interest for a theranostic approach of [64/67Cu]Cu-SARTATE for the detection and treatment of SSTR2-positive neuroblastoma lesions in pediatric patients whose widespread metastases survive initial therapy as minimal residual disease (MRD). MRD may be detected by [64Cu]Cu-SARTATE and subsequently treated by [67Cu]Cu-SARTATE. Since therapeutic dosimetry estimation of the latter agent from the uptake of the former one in the initial diagnostic scan was not addressed, the present theoretical commentary proposes the derivation of an abbreviated therapy-dosimetric equation for the companion diagnostic/therapeutic [64/67Cu]Cu-SARTATE that might be of interest for future clinical theranostic practice.

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