Steven I. Park

Anti-CD45 Pretargeted Radioimmunotherapy using Bismuth-213: High Rates of Complete Remission and Long-Term Survival in a Mouse Myeloid Leukemia Xenograft Model

Pretargeted radioimmunotherapy (PRIT) using an anti-CD45 antibody (Ab)-streptavidin (SA) conjugate and DOTA-biotin labeled with β-emitting radionuclides has been explored as a strategy to decrease relapse and toxicity. α-emitting radionuclides exhibit high cytotoxicity coupled with a short path length, potentially increasing the therapeutic index and making them an attractive alternative to β-emitting radionuclides for patients with acute myeloid leukemia. Accordingly, we have used (213)Bi in mice with human leukemia xenografts. Results demonstrated excellent localization of (213)Bi-DOTA-biotin to tumors with minimal uptake into normal organs. After 10 minutes, 4.5% ± 1.1% of the injected dose of (213)Bi was delivered per gram of tumor. α-imaging demonstrated uniform radionuclide distribution within tumor tissue 45 minutes after (213)Bi-DOTA-biotin injection. Radiation absorbed doses were similar to those observed using a β-emitting radionuclide ((90)Y) in the same model. We conducted therapy experiments in a xenograft model using a single-dose of (213)Bi-DOTA-biotin given 24 hours after anti-CD45 Ab-SA conjugate. Among mice treated with anti-CD45 Ab-SA conjugate followed by 800 μCi of (213)Bi- or (90)Y-DOTA-biotin, 80% and 20%, respectively, survived leukemia-free for more than 100 days with minimal toxicity. These data suggest that anti-CD45 PRIT using an α-emitting radionuclide may be highly effective and minimally toxic for treatment of acute myeloid leukemia.

Radioimmunotherapy for treatment of B-cell lymphomas and other hematologic malignancies.

Purpose of reviewRadioimmunotherapy has emerged as one of the most promising treatment options for hematologic malignancies. This review will present the latest information on radioimmunotherapy for treatment of hematologic malignancies in various clinical settings and assess its long-term safety profile. Recent findingsRecent data suggest that radioimmunotherapy with 131I-tositumomab or 90Y-ibritumomab tiuxetan not only induces high response rates but also results in durable remissions in patients with relapsed or refractory indolent non-Hodgkins lymphomas. Even more notable response rates have been observed when radioimmunotherapy is used as front-line treatment in patients with indolent non-Hodgkins lymphomas. The use of radioimmunotherapy has been evaluated in the treatment of aggressive lymphomas with promising results, but it remains investigational. Standard doses of radioimmunotherapy given as a conditioning regimen for hematopoietic stem-cell transplant or myeloablative doses of radioimmunotherapy given in conjunction with stem-cell support have yielded encouraging outcomes with durable remissions and a low incidence of treatment-related mortality. SummaryThe safety and efficacy of radioimmunotherapy has been demonstrated for patients with B-cell lymphomas and other hematologic malignancies in various clinical settings. A number of randomized phase III clinical trials are currently underway to further define radioimmunotherapys role in the treatment of lymphomas.

Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates

Pretargeted radioimmunotherapy (PRIT) is designed to enhance the directed delivery of radionuclides to malignant cells. Through a series of studies in 19 nonhuman primates (Macaca fascicularis), the potential therapeutic advantage of anti-CD45 PRIT was evaluated. Anti-CD45 PRIT demonstrated a significant improvement in target-to-normal organ ratios of absorbed radiation compared with directly radiolabeled bivalent antibody (conventional radioimmunotherapy [RIT]). Radio-DOTA-biotin administered 48 hours after anti-CD45 streptavidin fusion protein (FP) [BC8 (scFv)(4)SA] produced markedly lower concentrations of radiation in nontarget tissues compared with conventional RIT. PRIT generated superior target:normal organ ratios in the blood, lung, and liver (10.3:1, 18.9:1, and 9.9:1, respectively) compared with the conventional RIT controls (2.6:1, 6.4:1, and 2.9:1, respectively). The FP demonstrated superior retention in target tissues relative to comparable directly radiolabeled bivalent anti-CD45 RIT. The time point of administration of the second step radiolabeled ligand (radio-DOTA-biotin) significantly impacted the biodistribution of radioactivity in target tissues. Rapid clearance of the FP from the circulation rendered unnecessary the addition of a synthetic clearing agent in this model. These results support proceeding to anti-CD45 PRIT clinical trials for patients with both leukemia and lymphoma.

A pretargeted nanoparticle system for tumor cell labeling

Nanoparticle-based cancer diagnostics and therapeutics can be significantly enhanced by selective tissue localization, but the strategy can be complicated by the requirement of a targeting ligand conjugated on nanoparticles, that is specific to only one or a limited few types of neoplastic cells, necessitating the development of multiple nanoparticle systems for different diseases. Here, we present a new nanoparticle system that capitalizes on a targeting pretreatment strategy, where a circulating fusion protein (FP) selectively prelabels the targeted cellular epitope, and a biotinylated iron oxide nanoparticle serves as a secondary label that binds to the FP on the target cell. This approach enables a single nanoparticle formulation to be used with any one of existing fusion proteins to bind a variety of target cells. We demonstrated this approach with two fusion proteins against two model cancer cell lines: lymphoma (Ramos) and leukemia (Jurkat), which showed 72.2% and 91.1% positive labeling, respectively. Notably, TEM analysis showed that a large nanoparticle population was endocytosed via attachment to the non-internalizing CD20 epitope.

Five-year follow-up of brentuximab vedotin combined with ABVD or AVD for advanced stage classical Hodgkin lymphoma

Today, the large majority of patients with Hodgkin lymphoma are cured. However, treatment of patients with advanced-stage disease with optimal chemotherapy, such as doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), fails to cure as many as 15% to 25% of patients, necessitating secondary intensified treatment, which incurs major toxicity and is only successful in;50% of patients. Genuine improvement in these outcomes will require identification of novel effective agents that can be integrated with standard chemotherapy during primary treatment. One candidate agent is brentuximab vedotin (ADCETRIS, Seattle Genetics, Inc), an antibody drug conjugate that employs a protease cleavable covalent linker to combine a chimeric monoclonal antibody directed against the CD30 antigen found universally on the surface of Hodgkin Reed-Sternberg cells with monomethyl auristatin E, amicrotubule disrupting agent. Brentuximab vedotin has substantial effectiveness (complete response rate 34%; overall response rate 75%) against otherwise treatment-resistant classical Hodgkin lymphoma and confers only modest toxicity, primarily confined to reversible neuropathy, suggesting that it may be safely combined with standard primary chemotherapy. We previously conducted a phase 1 clinical trial with an expansion cohort testing the safety and effectiveness of the addition of brentuximab vedotin to ABVD or the same combination with omission of bleomycin. The addition of brentuximab vedotin was associated with excellent outcomes, including complete response in 45 of 47 assessable patients (95%). The addition of brentuximab vedotin was well tolerated, permitting full doses of 1.2 mg/kg every 2 weeks to be delivered without compromising the dosing of the other therapeutic chemotherapy agents; however, excessive pulmonary toxicity emerged when brentuximab vedotinwas added toABVD, indicating that brentuximab vedotin andbleomycin cannot be safely combined.At the conclusion of the original trial, we initiated a long-term follow-up study to determine the ultimate impact of the addition of brentuximab vedotin toABVDor doxorubicin, vinblastine, and dacarbazine (AVD). Inbrief, 51patientswith previouslyuntreated advanced-stage (stage IIA bulky, n5 3; IIB, n5 8; IIIA, n5 8; IVA, n5 9; IVB, n5 23) classical Hodgkin lymphoma were treated with ABVD (n 5 25) or AVD (n 5 26) plus brentuximab vedotin. Patients’ initial characteristics are summarized in Table 1. Brentuximab vedotin was given IV every 2weeks on the sameday as theABVDorAVD, and the dosewas escalated from 0.6 mg/kg to 1.2 mg/kg in planned cohorts (0.6 mg/kg, n 5 6; 0.9 mg/kg, n 5 13; 1.2 mg/kg, n 5 6). All 26 patients treated with AVD started their brentuximab vedotin at the full planned dose of 1.2 mg/kg every 2 weeks (n5 26). Additional details, including use of supportive medications such as neutrophil growth factors, are fully described in the original publication about this trial. Radiation, permitted at the treating physician’s discretion, was delivered to 4 patients (8%) at the conclusion of primary chemotherapy. Three of these 4 patients had bulkymediastinal tumors, and all 4 patients were treated with AVD plus brentuximab vedotin. None experienced pulmonary toxicity. After completion of the original trial, patients were enrolled in this long-term follow-up study. Periodically, each patient’s current vital and relapse status was determined and, if relapse had occurred, the date and planned treatment of relapsewere recorded, afterwhich onlyvital status and presence or absence of lymphoma were subsequently ascertained. Survival estimates were calculated using the method of Kaplan and Meier, and graphical plots were displayed using GraphPad Prism 7.0 software. Failure-free survival (FFS) was the interval from diagnosis to death from any cause, disease progression after initiation of primary treatment, or date of last follow-up. Overall survival (OS) was the interval from diagnosis to death from any cause or date of last followup. This study was approved by the respective institutional research ethics boards of each of the participating centers. Seattle Genetics, Inc provided funding to support the conduct of the study and was provided a copy of this manuscript in advance of publication but did not otherwise participate in its execution or interpretation. Two patients died because of pulmonary toxicity during treatment with ABVD plus brentuximab vedotin, and 1 patient initially treated with ABVD plus brentuximab withdrew consent after 1 cycle of treatment, leaving 48 patients available for the long-term follow-up

Complex karyotype in patients with mantle cell lymphoma predicts inferior survival and poor response to intensive induction therapy

Risk stratification of newly diagnosed patients with mantle cell lymphoma (MCL) primarily is based on the MCL International Prognostic Index (MIPI) and Ki‐67 proliferative index. Single‐center studies have reported inferior outcomes in patients with a complex karyotype (CK), but this remains an area of controversy.

Hodgkin Lymphoma With Multiple Autoimmune Disorders: Case Report and Review of the Literature

This is a case report and review of the literature of Hodgkin lymphoma (HL) and multiple autoimmune disorders. We report a case of a patient who presented initially with refractory immune thrombocytopenia (ITP) and was subsequently diagnosed with HL and was also found to have other autoimmune disorders (Hashimoto thyroiditis and primary biliary cirrhosis [PBC]). Her ITP and PBC improved with therapy for HL. In some patients with autoimmune disorders such as ITP and PBC presenting around the time of HL diagnosis, these conditions may be paraneoplastic and may improve with lymphoma therapy. For patients presenting with autoimmune disease and lymphadenopathy, it is important to have a high index of suspicion for HL and pursue an excisional biopsy, if feasible; a suboptimal biopsy could result in a missed diagnosis.