Radioimmunotherapy Of Lymphoma Research Articles

Cysteine-specific 89Zr-labeled anti-CD25 IgG allows immuno-PET imaging of interleukin-2 receptor-α on T cell lymphomas.

Positron emission tomography (PET) using radiolabeled Abs as imaging tracer is called immuno-PET. Immuno-PET can verify therapeutic Ab delivery and can noninvasively quantify global levels of target expression in tumors of living subjects. The interleukin-2 receptor α chain (IL-2Rα; CD25) is a promising target for immune therapy and radioimmunotherapy of lymphomas. Immuno-PET could facilitate this approach by visualizing CD25 expression in vivo. We prepared 89Zr-anti-CD25 IgG specifically labeled to sulfhydryl moieties by maleimide-deferoxamine conjugation. CD25(+) SUDHL1 human T-cell lymphoma cells showed high anti-human 89Zr-CD25 IgG binding that reached 32-fold of that of CD25(-) human lymphoma cells and was completely blocked by excess unlabeled Ab. In SUDHL1 tumor-bearing nude mice, pharmacokinetic studies demonstrated exponential reductions of whole blood and plasma activity following intravenous 89Zr-anti-CD25 IgG injection, with half-lives of 26.0 and 23.3 h, respectively. SUDHL1 tumor uptake of 89Zr-CD25 IgG was lower per weight in larger tumors, but blood activity did not correlate with tumor size or blood level of human CD25, indicating minimal influence by circulating soluble CD25 protein secreted from the lymphoma cells. 89Zr-CD25 IgG PET allowed high-contrast SUDHL1 lymphoma visualization at five days. Biodistribution studies confirmed high tumor 89Zr-CD25 IgG uptake (8.7 ± 0.9%ID/g) that was greater than blood (5.2 ± 1.6%ID/g) and organ uptakes (0.7 to 3.5%ID/g). Tumor CD25-specific targeting was confirmed by suppression of tumor uptake to 4.3 ± 0.2%ID by excess unlabeled CD25 IgG, as well as by low tumor uptake of 89Zr-labeled IgG2a isotype control Ab (3.6 ± 0.9%ID). Unlike CD25(+) lymphocytes from mouse thymus that showed specific uptake of anti-mouse 89Zr-CD25 IgG, EL4 mouse lymphoma cells had low CD25 expression and showed low uptake. In immunocompetent mice bearing EL4 tumors, anti-mouse 89Zr-CD25 IgG displayed low uptakes in normal organs as well as in the tumor. Furthermore, the biodistribution was not influenced by Ab blocking, indicating that specific uptake in nontumor tissues was minimal. 89Zr-CD25 IgG immuno-PET may thus be useful for imaging of T-cell lymphomas and noninvasive assessment of CD25 expression on target cells in vivo.

Immuno-PET Imaging and Radioimmunotherapy of Lymphomas.

Monoclonal antibodies (Ab) have revolutionized the management of lymphomas, the most common hematologic malignancy in adults. Indeed, incorporation of rituximab into the regimen for indolent non-Hodgkin's lymphomas (NHLs) has dramatically improved treatment response and disease outcome. Yet, newer Ab therapeutics against promising antigen targets need to be developed to treat refractory or relapsed patients. Treatment efficacy can be further enhanced by conjugating toxic molecules to the Abs. Radioimmunotherapy (RIT) harnesses Abs as vehicles for targeted delivery of therapeutic radionuclide payloads for direct killing of targeted tumor cells. Positron emission tomography (PET) with radiolabeled Abs (called immuno-PET) can facilitate the development of new Ab therapeutics and RIT by providing pharmacokinetic and pharmacodynamic information and by quantifying tumor antigen level relevant for treatment decision. Immuno-PET has recently gravitated toward labeling Abs with 89Zr, a radiometal with a 3.3 day half-life that is trapped following Ab internalization and thus provides high-resolution PET images with excellent contrast. Immuno-PET methods against major lymphoma antigens including CD20 and other promising targets are currently under development. With continued improvements, immuno-PET has the potential to be used in lymphoma management as an imaging biomarker for patient selection and assessment of treatment response.

Does the Number of Bifunctional Chelators Conjugated to a mAb Affect the Biological Activity of Its Radio-Labeled Counterpart? Discussion Using the Example of mAb against CD-20 Labeled with 90Y or 177Lu.

There has been considerable interest in developing a monoclonal antibody (mAb) against-CD-20 (for example, Rituximab) modified by bifunctional chelating agents (BCA) for non-Hodgkin's lymphoma radioimmunotherapy. Therefore, many researchers have modified this monoclonal antibody by attaching different BCA moieties and evaluated their biological activities in terms of in vitro study and in vivo study in healthy and tumor xenografted rodents. This mini-perspective reviews the in vitro studies, the immunoreactivity and physiological distribution studies: organ-to-blood and the tumor-to-organ ratio of conjugates with different numbers of chelators per mAb. We set up a null hypothesis that states there is no statistical significance between the biological activity of monoclonal antibody (Rituximab) and the number of conjugated bifunctional chelators. Overall, we have concluded that there is no strong evidence for this hypothesis. However, the literature data should be questioned due to the potential lack of uniform study methodology.

CD38-Targeted Theranostics of Lymphoma with 89Zr/177Lu-Labeled Daratumumab.

Lymphoma is a heterogeneous disease with varying clinical manifestations and outcomes. Many subtypes of lymphoma, such as Burkitt′s lymphoma and diffuse large B cell lymphoma, are highly aggressive with dismal prognosis even after conventional chemotherapy and radiotherapy. As such, exploring specific biomarkers for lymphoma is of high clinical significance. Herein, a potential marker, CD38, is investigated for differentiating lymphoma. A CD38‐targeting monoclonal antibody (mAb, daratumumab) is then radiolabeled with Zr‐89 and Lu‐177 for theranostic applications. As the diagnostic component, the Zr‐89‐labeled mAb is highly specific in delineating CD38‐positive lymphoma via positron emission tomography (PET) imaging, while the Lu‐177‐labeled mAb serves well as the therapeutic component to suppress tumor growth after a one‐time administration. These results strongly suggest that CD38 is a lymphoma‐specific marker and prove that 89Zr/177Lu‐labeled daratumumab facilitates immunoPET imaging and radioimmunotherapy of lymphoma in preclinical models. Further clinical evaluation and translation of this CD38‐targeted theranostics may be of significant help in lymphoma patient stratification and management.

Radioimmunotherapy of lymphoma: an underestimated therapy option

Radioimmunotherapy of lymphoma: an underestimated therapy option

The success and failure of radioimmunotherapy for lymphoma

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

An Update on Radioimmunotherapy for Lymphoma

SUMMARY Radioimmunotherapy is a promising treatment for B-cell lymphoma. 90Y-ibritumomab tiuxetan (Zevalin®) and 131I-tositumomab (Bexxar®) combine the potent antilymphoma effect of radiation with the specificity of antibody targeting. They have shown efficacy in follicular lymphoma in the setting of relapsed or refractory disease as consolidation regimens after first-line therapy, and in the front-line setting as single agents. Given their tolerability, they are actively being investigated as therapies or adjuncts for elderly patients with relapsed or high-risk diffuse large B-cell lymphoma. They have been added to autologous and allogeneic stem cell transplant preparatory regimens in early clinical trials with acceptable safety and efficacy. Early concerns over excess rates of treatment-related myelodysplastic syndrome and acute myelogenous leukemia have not come to fruition, but these questions remain to be fully answered. Ultimately, these are promising treatments for a variety of B-cell lymphomas. They are also models for the development of new radioimmunotherapies.

Standard Operating Procedure for In-house Preparation of 131 I-rituximab for Radioimmunotherapy of Non-Hodgkin′s Lymphoma

A Standard Operating Procedure (SOP) has been formulated for in-house preparation, quality control, dispensing and administration of 131I-rituximab appropriate for the safe, effective, radioimmunotherapy of non-Hodgkin lymphoma. A decade of experience of semi-automated radioiodination of rituximab in our hospital radiopharmaceutical laboratory was analysed. The methodology was then refined for safe, practical, affordable application to radioimmunotherapy of lymphoma in departments of nuclear medicine in developing countries. This SOP has the potential to be incorporated into good laboratory practice conditions appropriate for local regulatory agency requirements.

Radioimmunotherapy of lymphoma

Radioimmunotherapy of lymphoma

Radiothérapie vectorisée : les nouvelles molécules

Although the efficacy of radionuclide therapy has been demonstrated in several indications, the development of this new therapeutic modality is limited. However, promising results have been obtained, especially using different radiolabeled somatotatin analogs for neuroendocrine tumors or radioimmunotherapy for lymphoma. Toxicity is limited, particularly if patients are selected based on their background. The use of new vectors (bombesin, anti-PMSA monoclonal antibody), pretargeting system and innovative radionuclides (Copper-67, Astatine-211) suggests interesting perspectives, particularly to target small tumor masses or residual disease.

Radioimmunotherapy of Lymphoma: A Treatment Approach Ahead of Its Time or Past Its Sell-By Date?

The US Food and Drug Administration (FDA) registration of rituximab (anti-CD20 monoclonal antibody [mAb]) in 1997 was a landmark event, not only because that is when the first antibody for the treatment of cancer was licensed but also because a new era of targeted therapies in the treatment of B-cell malignancies had begun. Although responses with single-agent rituximab were rather modest, the addition of rituximab to chemotherapy (Rchemo) as immunochemotherapy has resulted in impressive improvements in response rates and outcome in patients with a range of B-cell malignances. In contrast, radioimmunotherapy (RIT) is the administration of mAb or mAb-derived constructs that are chemically conjugated to therapeutic radioisotopes targeted to tumors. A wide variety of different mAbs, delivery schedules, radioisotopes, and doses of radioactivity have been tested in RIT, resulting in impressive responses in the treatment of non-Hodgkin’s lymphoma (NHL). For more than a decade, targeting the CD20 antigen has dominated clinical RIT of lymphoma, and a number of pivotal clinical studies ultimately led to FDA approval of two radioimmunconjugates, iodine-131 (I)tositumomab (Bexxar; GlaxoSmithKline, Research Triangle Park, NC) and yttrium-90 (Y) –ibritumomab tiuxetan (Zevalin; Cell Therapeutics Inc, Seattle, WA). Y–ibritumomab tiuxetan was subsequently approved within the European Union in 2004, and in September 2009, it was approved by FDA as a first-line treatment for NHL. The recent approval by the FDA, applauded in the national press by the US Society of Nuclear Medicine, received little or no attention in the clinical community. Despite the fact that both drugs clearly have unique non–cross-reactive mechanisms of action with proven high clinical efficacy in patients resistant to both chemotherapy and rituximab and are arguably the most active drug approaches ever developed for NHL, this treatment modality has failed to be widely adopted by the hemato-oncology community. So what progress has been made with RIT and why is this “designer” targeted therapy so underused? During the last decade, the defining features of RIT using the two licensed radioimmunoconjugates applied to indolent lymphomas have emerged. These features include high response rates, durable remissions, and safe, predictable, and manageable toxicity. Both Itositumomab and Y–ibritumomab have demonstrated high clinical efficacy in heavily pretreated populations, including patients with disease refractory to both chemotherapy and rituximab underlying their unique mechanisms of action of RIT. An analysis of the long-term follow-up of patients who were heavily pretreated for indolent lymphoma with I-tositumomab demonstrated overall response rates (ORRs) of 47% to 68% and complete response (CR) rates of 20% to 38%. At the time of publication, with a median follow-up of 5.3 years, the 5-year progression-free survival (PFS) was 17%, and 81 (32%) of 250 patients had a time to progression of 1 year. For the durable response population, the median duration of response was 45.8 months and, impressively, the median duration of response had not been reached at 5 years for those who had achieved a CR. Interestingly, many of the patients who enjoyed these long durable responses had poor prognostic characteristics, including bone marrow involvement (41%), bulky disease 5 cm (49%), and transformed histology (23%). Forty-three percent of the patients had been treated with more than four prior therapies, and 36% had not responded to their most recent therapy. These durable responses have also been observed after Y–ibritumomab tiuxetan, with about 70% of patients who achieve a CR remaining in remission for years. RIT has also shown highly promising results in the first-line treatment of previously untreated follicular lymphoma as a single treatment or as consolidation therapy after initial chemotherapy. For 76 patients treated with I-tositumomab after a median follow-up of 5.1 years, the actuarial 5-year PFS for all patients was 59%, with a median PFS of 6.1 years. Hematologic toxicity was moderate, with no patients requiring transfusion or granulocyte colony-stimulating factor. Initial US-based phase II studies using RIT as consolidation therapy demonstrated high rates of conversion from partial response (PR) to CR, leading to impressive overall CR rates and PFS. However, these highly encouraging data from phase II studies have been insufficient to change practice, and the clinical community demanded phase III studies. More recently, results were published on a large, phase III randomized European and Canadian intergroup study (n 414) in previously untreated patients with follicular lymphoma. This study confirmed the high conversion rate from PR to CR (53.3% to 87.4%) seen in the early phase II US studies for patients treated with Y– ibritumomab tiuxetan. This high CR rate was almost identical in all subgroups of pretreatment chemotherapy, despite the difference in CR rate between the initial chemotherapy regimens such as chlorambucil (CR rate, 31%) and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone; CR rate, 56%). This consistently high CR among all of the groups after Y–ibritumomab tiuxetan suggests that JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 28 NUMBER 18 JUNE 2

New insights into the mechanisms of action of radioimmunotherapy in lymphoma

The exquisite sensitivity of haematological malignancies to targeted radiation alongside the impressive results achieved by the pioneers in this field suggests that radioimmunotherapy is likely to be a productive area for future clinical research. Recent experimental work has demonstrated that the combination of targeted radiation and antibody effector mechanisms are critical to long-term clearance of tumour. This review provides the background of clinical and biological insights into the mechanisms of action of radioimmunotherapy.

Radiotherapy in practice radioisotope therapy

This is a relatively short paperback book that the editor hopes will ‘overcome many of these obstacles (under utilization and limited accessibility) with contributions from experts in the field identifying the current role of radioisotope therapy in modern medicine and also providing a background in the physics and developmental biology that underpins their use'. It succeeds to some degree. The authors are all British and they know their field well. They do discuss the role of radioisotope therapy for a variety of conditions and the book does provide reasonably well much on the physics of radioisotope therapy. In asmuch as each of the chapters is written by a different contributor(s), there is some overlap and there is an unfortunate tendency to use acronyms and abbreviations, sometimes without defining them, at least in some of the chapters. This book will give a good review for someone who is studying for his board examination. However, if one is in the early part of his/her career or has very limited background of isotope therapy, this book will not be as easy to learn from as others. The chapters are well written, but most of them do not have a great deal of detail. The exceptions to this are the chapters on antibody-directed radioisotope therapy by Dearling and Pedley, and the chapter specifically on radioimmunotherapy for lymphoma by Illidge and Du. Both these chapters are filled with detail and excellent references. The final chapter on radioprotection and regulatory aspects of radioisotope therapy is certainly good from the UK/European point of view; there is a small section towards the end on non-UK legislation, but it is actually pretty brief. Also, I would have appreciated it if this chapter on radioprotection would have had a few pages on how to potentially deal with, at the hospital-based level, mass casualties from radiation bio-terrorism. A nuclear explosion obviously would have major consequences on the basis of the explosion itself, but much of the patient damage would be owing to secondary radioisotope contamination. The so-called ‘dirty bomb' would be predominately isotope contamination as the source of patient injury and chaos. Something on that topic would have been appropriate for this monograph. Finally, the index is suboptimal. Keeping such criticisms aside, this is a well-written monograph and it should be an excellent review for someone studying for boards. It can also serve as a useful reference for someone who is not actively carrying out such treatments but who is nonetheless interested in the topic. For a nuclear medical specialist, this book would be insufficient.

Focal Radiation Fibrosis After Radioimmunotherapy for Follicular Non-Hodgkin Lymphoma

A 75-year-old man with relapsed follicular non-Hodgkin lymphoma confined to a solitary lung mass was treated with radioimmunotherapy (RIT) using yttrium 90–ibritumomab tiuxetan. Imaging with positron emission tomography/computed tomography showed a complete response 3 months after RIT. Thirteen months after RIT, his positron emission tomography/computed tomography scan showed a fluorodeoxyglucose-avid infiltrate in the area of the previous lung mass. Bronchoscopy revealed the area to be obstructed with fibrosis, and cytologic washings and brushings did not show lymphoma. The patient remains asymptomatic, and the fluorodeoxyglucoseavid pulmonary infiltrate was unchanged 19 months after RIT. In view of the lack of respiratory symptoms or progressive imaging abnormalities, we believe radiation fibrosis is the most likely etiology. Radiation-induced lung injury after therapy with yttrium 90 was previously reported in the setting of intraarterial microspheres used to treat inoperable hepatic tumors. This is the first case in which radiation-induced radiographic changes are reported after RIT for lymphoma.

Microscopic Intratumoral Dosimetry of Radiolabeled Antibodies Is a Critical Determinant of Successful Radioimmunotherapy in B-Cell Lymphoma

Radioimmunotherapy is a highly effective treatment for some hematologic malignancies; however, the underlying mechanisms of tumor clearance remain poorly understood. We have previously shown that both targeted radiation using (131)I-labeled anti-MHC class II (MHCII) monoclonal antibody (mAb) plus mAb signaling with unlabeled anti-idiotype are required for the long-term clearance of tumor in syngeneic murine lymphoma models. In this study, we have investigated how the microdistribution of the targeted radiation component of this combination affects the long-term clearance of lymphoma. (131)I-labeled mAb targeting CD45 and MHCII antigens was found to deliver similar doses of radiation to tumor-bearing organ using conventional dosimetry ( approximately 1.0 Gy per MBq when (131)I was labeled to 500 mug mAb and given i.v. per mouse), but when used as radiation vectors in combination therapy only, (131)I-anti-MHCII plus anti-idiotype produced long-term survival. The profound differences in therapy did not seem to be dependent on levels of (131)I-mAb tumor-binding or antibody-dependent cytotoxicity. Instead, the microscopic intratumoral dosimetry seemed to be critical with the (131)I-anti-MHCII, delivering more concentrated and therefore substantially higher radiation dose to tumor cells. When the administered activity of (131)I-anti-CD45 was increased, a radiation dose response was shown in the presence of anti-idiotype and long-term survival was seen. We believe that these new insights should influence the selection of new antigen targets and the design of dosimetric methods in radioimmunotherapy of lymphoma.

Clinical applications of newer radionuclide therapies

When radio-iodine was first used in the treatment of metastasized thyroid carcinoma in 1943, its success in terms of tumour response, quality of life improvement and survival was considered a ‘miracle’, as in those days metastatic cancer was generally fatal. Inspired by this, many efforts have been made to apply radioisotope therapy to other tumours. Radionuclide therapy uses radioactive isotopes labelled with specific targeting agents that aim to deliver the irradiation of the isotope to the tumour, while sparing normal tissues. Its unique modality allows to systemically target radiosensitive tumours throughout the body. Another important principle is its so-called ‘cross-fire’ action, whereby, owing to the larger reach of the radiation in relation to the cell diameter, a tumour cell receives lethal hits also from isotopes in the neighbourhood that are not directly associated with this cell. The treatment is therefore less hampered by inhomogeneous distribution and metabolism than for example chemo- or immunotherapy. The European Association of Nuclear Medicine has issued guidelines on so-called ‘established’ therapies ( www.eanm.org), i.e. hyperthyroidism, thyroid carcinoma, refractory synovitis, bone metastases, mIBG therapy, 32P therapy and Lipiodol therapy. Newer therapies include radio-peptide therapy, radio-immunotherapy of lymphoma and microsphere therapy for liver cancer. The aim of a recently held workshop at the ECCO13 conference 2005 and this review is to inform the oncology community about these new developing therapies.

A21 The microscopic tumour biodistribution of 131I-labelled mAb is critical in predicting successful radioimmunotherapy of lymphoma

A21 The microscopic tumour biodistribution of 131I-labelled mAb is critical in predicting successful radioimmunotherapy of lymphoma

New strategies in radioimmunotherapy for lymphoma.

Treatment options for patients with indolent non-Hodgkin's lymphoma historically involved radiation or chemotherapy. Although initial response rates are excellent, treatment is increasingly less effective with each successive relapse. The advent of immunotherapy heralds a new era for the treatment of these patients. Radioimmunotherapy adds the benefits of cytotoxic radiation to immunotherapy and represents a significant addition to the treatment armamentarium. Various antigens for lymphoma have been targeted, of which anti-CD20 antibodies are the furthest in development. Ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San Diego, CA), a (90)yttrium-labeled agent, and (131)iodine-labeled tositumomab (Bexxar; Corixa, Seattle, WA) are approved by the US Food and Drug Administration. Both agents have shown utility in therapy for relapsed and refractory low-grade and transformed lymphomas. This review highlights features of radioimmunotherapy that are relevant to non-Hodgkin's lymphoma, focusing on the two anti-CD20 antibodies.

Radioimmunotherapy for lymphoma.

After more than a decade of unfulfilled promises, radioimmunotherapy for the treatment of non-Hodgkin's lymphoma has been demonstrated to be efficacious in the treatment of refractory disease. It is likely that in the near future, the Food and Drug Administration will approve one or more radioimmunoconjugates for clinical use. However, the optimal use of the agents in the treatment of non-Hodgkin's lymphoma remains to be defined. The role for these drugs is influenced by the target antigen as well as the radionuclide. In this review, the biologic principles, seminal clinical results, and avenues for future development of RIT are discussed.

Efficient recombination of Lym-1 scFv gene using multiple doubly-restricted DNA fragments.

In order to improve radioimmunotherapy of lymphoma, a Lym-1 single-chain antigen-binding (scFv) protein molecule was produced. Because the commonly used polymerase chain reaction (PCR) method frequently causes unexpected mutations, we developed a non-PCR method for scFv gene assembly. The method involved a stepwise linkage of doubly-restricted DNA fragments and re-digestion of the resultant concatamers. Using this strategy, the Lym-1 scFv expression gene was readily constructed without mutations. The recombinant gene was cloned into an expression vector and scFv protein was expressed. The method can be used for other genes or DNA recombination.