Experimental radioimmunotherapy

doi:10.1016/S1053-4296(00)80052-1

Seminars in Radiation Oncology

Volume 10, Issue 2, April 2000, Pages 156-167

https://doi.org/10.1016/S1053-4296(00)80052-1 Get rights and content

Experimental radioimmunotherapy (RIT) studies in animal models have contributed significantly to the design of clinical RIT protocols, although the results have not always been directly translated. Reviewed in this article are current areas of active research in experimental RIT to increase the therapeutic ratio that are likely to have a significant impact on the design of future clinical studies. Approaches for increasing the therapeutic efficacy of RIT include the development of new targeting molecules (genetically engineered monoclonal antibodies, antibody fragments, single-chain antibodies, diabodies and minibodies, fusion toxins, or peptides); improved labeling chemistry; novel radionuclide use and fractionation; locoregional administration; pretargeting; use of biological response modifiers or gene transfer techniques to increase target receptor expression; bone marrow transplantation; and combined modality therapy with external-beam radiation therapy, chemotherapy, or gene therapy. Further research with these new experimental approaches in preclinical animal models is necessary to contribute to advances in the treatment of cancer patients using radiolabeled antibodies and peptides.

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Citation Excerpt :
Although combinations of RIT with PBSC permits delivery of several times more radionuclide/radiation dose, it diminishes the simplicity of RIT and increases the adverse events (15). The potential for CMRIT has been shown (59–65). Both agent type and timing of delivery are important determinants of the outcomes (66).
Although radioimmunotherapy (RIT) has been effective in non-Hodgkin’s lymphoma (NHL) as a single agent, solid tumors have shown less clinically significant therapeutic response to RIT alone. The clinical impact of RIT or other forms of targeted radionuclide therapy for solid tumors depends on the development of a high therapeutic index (TI) for the tumor vs. normal tissue effect, and the implementation of RIT as part of synergistic combined modality therapy (CMRIT). Preclinical and clinical studies have provided a wealth of information, and new prototypes or paradigms have shed light on future possibilities in many instances. Evidence suggests that combination and sequencing of RIT in CMRIT appropriately can provide effective treatment for many solid tumors. Vascular targets provide RIT enhancement opportunities and nanoparticles may prove to be effective carriers for RIT combined with intracellular drug delivery or alternating magnetic frequency (AMF) induced thermal tumor necrosis. The sequence and timing of combined modality treatments will be of critical importance to achieve synergy for therapy while minimizing toxicity. Fortunately, the radionuclide used for RIT also provides a signal useful for nondestructive quantitation of the influence of sequence and timing of CMRIT on events in animals and patients. This can be readily accomplished clinically using quantitative high-resolution imaging (e.g., positron emission tomography [PET]).
Tumour therapy with radionuclides: Assessment of progress and problems
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Radionuclide therapy is a promising modality for treatment of tumours of haematopoietic origin while the success for treatment of solid tumours so far has been limited. The authors consider radionuclide therapy mainly as a method to eradicate disseminated tumour cells and small metastases while bulky tumours and large metastases have to be treated surgically or by external radiation therapy. The promising therapeutic results for haematological tumours give hope that radionuclide therapy will have a breakthrough also for treatment of disseminated cells from solid tumours. New knowledge related to this is continuously emerging since new molecular target structures are being characterised and the knowledge on pharmacokinetics and cellular processing of different types of targeting agents increases. There is also improved understanding of the factors of importance for the choice of appropriate radionuclides with respect to their decay properties and the therapeutic applications. Furthermore, new methods to modify the uptake of radionuclides in tumour cells and normal tissues are emerging. However, we still need improvements regarding dosimetry and treatment planning as well as an increased knowledge about the tolerance doses for normal tissues and the radiobiological effects on tumour cells. This is especially important in targeted radionuclide therapy where the dose rates often are lower than 1 Gy/h.
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Current cancer therapies are highly toxic and often nonspecific. A potentially less toxic approach to treating this prevalent disease employs agents that modify cancer cell differentiation, termed ‘differentiation therapy.’ This approach is based on the tacit assumption that many neoplastic cell types exhibit reversible defects in differentiation, which upon appropriate treatment, results in tumor reprogramming and a concomitant loss in proliferative capacity and induction of terminal differentiation or apoptosis (programmed cell death). Laboratory studies that focus on elucidating mechanisms of action are demonstrating the effectiveness of ‘differentiation therapy,’ which is now beginning to show translational promise in the clinical setting.

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¹: Supported by NIH grants R01 CA62550, CA73636, and CA78505, and DOE grants DE-FG02-93ER6154 and DE-FG02-96ER62181.

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Experimental radioimmunotherapy1

Blood

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Blood

Ann Oncol

Experimental radioimmunotherapy

Med Phys

Experimental radioimmunotherapy: A brief overview

Cancer

Overview of studies on experimental radioimmunotherapy

Cancer Res

Experimental radioimmunotherapy and methods to increase therapeutic efficacy

Modeling analysis of the global and microscopic distribution of immunoglobulin G, F(ab')2, and Fab in tumors

Cancer Res

Vascular and interstitial barriers to delivery of therapeutic agents in tumors

Cancer Metastasis Rev

An analysis of monoclonal antibody distribution in microscopic tumor nodules: Consequences of a “binding site barrier”

Cancer Res

Pharmacokinetic analysis of the perivascular distribution of bifunctional antibodies and haptens: Comparison with experimental data

Cancer Res

Reconciliation of tumor dose response to external beam radiotherapy versus radioimmunotherapy with 131iodine-labeled antibody for a colon cancer model

Cancer Res

Implications of nonuniform tumor doses for radioimmunotherapy

J Nucl Med

Radioimmunotherapy of micrometastases in lung with vascular targeted 213Bi

Br J Cancer

Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer

Up-regulation of endoglin on vascular endothelial cells in human solid tumors: Implications for diagnosis and therapy

Clin Cancer Res

A murine model for antibody-directed targeting of vascular endothelial cells in solid tumors

Cancer Res

Increased binding affinity and valence of recombinant antibody fragments lead to improved targeting of tumoral angiogenesis

Cancer Res

Human monoclonal antibodies and engineered antibodies in the management of cancer

Semin Cancer Biol

Generation of tumor cell-reactive human monoclonal antibodies using peripheral blood lymphocytes from actively immunized colorectal carcinoma patients

Cancer Res

Reshaping human antibodies for therapy

Nature

Improving monoclonal antibody pharmacokinetics via chemical modification

Q J Nucl Med

Chemical modification to reduce renal uptake of disulfide-bonded variable region fragment of anti-Tac monoclonal antibody labeled with 99mTC

Bioconj Chem

Cytotoxic effects of anti-CD5 radioimmunotoxins on human tumors in vitro and in a nude mouse model

Cancer Res

Preclinical assessments of 90Y-labeled C110 anti-carcinoembryonic antigen immunotoxin: A therapeutic immunoconjugate for human colon cancer

Cancer Res

Radiolabeled fusion toxin binding, cytotoxicity and localization to colon cancer cells induced to express IL-4 receptor

Iodine-131-labeled MAb F(ab')2 fragments are more efficient and less toxic than intact anti-CEA antibodies in radioimmunotherapy of large human colon carcinoma grafted in nude mice

J Nucl Med

Successful radioimmunotherapy for lung, metastasis of human colonic cancer in nude mice

J Natl Cancer Inst

Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms

Cancer Res

Experimental studies on the role of antibody fragments in cancer radioimmunotherapy: Influence of radiation dose and dose rate on toxicity and anti-tumor efficacy

Int J Cancer

Characterization of scFv-Ig constructs generated from the anti-CD20 mAb 1F5 using linker peptides of varying lengths

J Immunol

Pretargeting: General principles; October 10–12, 1996

Cancer

Clinical application of the avidin-biotin system for tumor targeting

Delivery of therapeutic doses of radioiodine using bispecific antibody-targeted bivalent haptens

J Nucl Med

Pretargeting with the affinity enhancement system for radioimmunotherapy

Cancer Biother Radiopharm

Three-step radioimmunotherapy with yttrium-90 biotin: Dosimetry and pharmacokinetics in cancer patients

Eur J Nucl Med

Phage libraryderived human anti-TETA and anti-DOTA ScFv for pretargeting RIT

Hybridoma

Improving the tumor retention of radioiodinated antibody: Aryl carbohydrate adducts

Cancer Res

Improved therapeutic efficacy of a monoclonal antibody radioiodinated using N-succinimidyl-3-(tri-n-butylstannyl)benzoate

Cancer Res

Enhanced tumor specificity of 741F8-1 (sFv')2, an, anti-c-erbB-2 single-chain Fv dimer, mediated by stable radioiodine conjugation

J Nucl Med

Radiochemistry of therapeutic radionuclides

Modeling analysis of the global and microscopic distribution of immunoglobulin G, F(ab')₂, and Fab in tumors

Reconciliation of tumor dose response to external beam radiotherapy versus radioimmunotherapy with ¹³¹iodine-labeled antibody for a colon cancer model

Radioimmunotherapy of micrometastases in lung with vascular targeted ²¹³Bi

Chemical modification to reduce renal uptake of disulfide-bonded variable region fragment of anti-Tac monoclonal antibody labeled with ^99mTC

Preclinical assessments of ⁹⁰Y-labeled C110 anti-carcinoembryonic antigen immunotoxin: A therapeutic immunoconjugate for human colon cancer

Iodine-131-labeled MAb F(ab')₂ fragments are more efficient and less toxic than intact anti-CEA antibodies in radioimmunotherapy of large human colon carcinoma grafted in nude mice

Enhanced tumor specificity of 741F8-1 (sFv')₂, an, anti-c-erbB-2 single-chain Fv dimer, mediated by stable radioiodine conjugation