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  • Review Article
  • Published:

Radioimmunotherapy of human tumours

Nature Reviews Cancer volume 15, pages 347–360 (2015)Cite this article

Subjects

A Corrigendum to this article was published on 24 July 2015

This article has been updated

Key Points

  • Antibodies with practical healthcare applications are being introduced into modern medicine at a rapid pace by academic laboratories and industry. Therapeutic applications of these biologics are becoming increasingly important for cancer, either by promoting the body's own defence against the tumour or as a carrier for immunotoxins, drugs or radiation.

  • Radioimmunotherapy, which is the subject of this Review, exploits the immune protein as a carrier for radioactive isotopes, tracers or targeted therapeutics. The radioantibody is introduced into the blood or a body cavity such as the peritoneum, pleura or intrathecal space, and is carried to its natural target or antigen-binding site on the tumour cell by blood flow, diffusion or the bulk flow of fluid.

  • Cancer cells naturally produce cancer-associated biological molecules, which are adaptive features of malignant change that are suitable as antigenic binding sites owing to their relatively high abundance in cancer cells in comparison to normal tissues. These cancer-associated antigens may be located in the membrane, cytoplasm or organelles, including the nucleus. Typical concentrations of target antigens are in the nanomolar to low micromolar range.

  • Cancer-selective antibodies and related immunoproteins are particularly well suited for conjugation with radioisotopes, for the purpose of detection or targeted radiotherapy. As a rule of thumb, the concentration of antibody at the binding site should approximate but not exceed the concentration of antigen (that is, the nanomolar range), and this amount of carrier is enormous relative to the required concentrations of attached radioisotopes for detection or therapy. This is because radioisotopes are among the most energetic moieties known, and this energy can be used for imaging or radiotherapy when attached to antibodies, in the femto-molar to pico-molar range.

Abstract

The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has demonstrated potential involves the selective targeting of radionuclides to cancer-associated cell surface antigens using monoclonal antibodies. Such radioimmunotherapy (RIT) permits the delivery of a high dose of therapeutic radiation to cancer cells, while minimizing the exposure of normal cells. Although this approach has been investigated for several decades, the cumulative advances in cancer biology, antibody engineering and radiochemistry in the past decade have markedly enhanced the ability of RIT to produce durable remissions of multiple cancer types.

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Figure 1: Target antigens for RIT.
Figure 2: Intrathecal RIT imaged quantitatively with PET imaging using 124I–8H9 antibody.
Figure 3: Results of selected trials of RIT as part of front-line therapy for follicular lymphoma.
Figure 4: Schemas for conventional and pre-targeted RIT.

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Change history

  • 24 July 2015

    Nai-Kong V. Cheung and Steven M. Larson have now declared competing interests that were not stated in the version of this article that was originally published. The following competing interests statement has now been added to the online version: "S.M.L. has ownership interest (including patents) in nanoparticle constructs of C-DOTs, use of mAB A33, and small molecular radio label drugs in Dasatinib and the HSP 90 inhibitor PUH71 and kinetics of immunoPET localization to tumours. N.-K.V.C. has ownership interest (including patents) in scfv constructs of anti-GD2 antibodies, therapy-enhancing glucan, use of mAb 8H9, methods for preparing and using scFv, GD2 peptide mimics, methods for detecting MRD, anti-GD2 antibodies, generation and use of HLA-A2-restricted peptide-specific mAbs and CARs, high-affinity anti-GD2 antibodies, multimerization technologies, bispecific HER2 and CD3 binding molecules, affinity matured hu8H9, anti-chondroitin sulfate proteoglycan 4 antibodies and uses thereof, and ROR2 antibodies. J.A.C. and O.W.P. declare no competing interests.".

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Acknowledgements

This study was supported in part by the Center for Targeted Radioimmunotherapy and Theranostics, USA, and the Ludwig Center for Cancer Immunotherapy, USA. Additional financial support was provided by the Donna and Benjamin M. Rosen Chair and the Enid A. Haupt Chair (for S.M.L. and N.K.C., respectively). O.W.P. was supported in part by NCI PO1 CA044991, NCI R01 CA076287, NIH R01 CA109663, NCI R01 CA136639, NCI R01 CA154897 and NCI R01 CA138720. S.M.L. was also supported in part by NCI P50-CA86438 and Sloan Kettering Institute, USA. The authors wish to thank D. A. Scheinberg, J. D. Wolchok and W. A. Weber for their valuable contributions to this research.

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Author notes

  1. Nai-Kong V. Cheung and Oliver W. Press: These authors contributed equally to this work.

Authors and Affiliations

  1. Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10065, New York, USA

    Steven M. Larson, Jorge A. Carrasquillo & Nai-Kong V. Cheung

  2. Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, P.O. BOX 19024, Seattle, 98109, Washington, USA

    Oliver W. Press

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  1. Steven M. Larson
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  2. Jorge A. Carrasquillo
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  3. Nai-Kong V. Cheung
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Corresponding author

Correspondence to Steven M. Larson.

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Competing interests

Nai-Kong V. Cheung and Steven M. Larson have now declared competing interests that were not stated in the version of this article that was originally published. The following competing interests statement has now been added to the online version: "S.M.L. has ownership interest (including patents) in nanoparticle constructs of C-DOTs, use of mAB A33, and small molecular radio label drugs in Dasatinib and the HSP 90 inhibitor PUH71 and kinetics of immunoPET localization to tumours. N.-K.V.C. has ownership interest (including patents) in scfv constructs of anti-GD2 antibodies, therapy-enhancing glucan, use of mAb 8H9, methods for preparing and using scFv, GD2 peptide mimics, methods for detecting MRD, anti-GD2 antibodies, generation and use of HLA-A2-restricted peptide-specific mAbs and CARs, high-affinity anti-GD2 antibodies, multimerization technologies, bispecific HER2 and CD3 binding molecules, affinity matured hu8H9, anti-chondroitin sulfate proteoglycan 4 antibodies and uses thereof, and ROR2 antibodies. J.A.C. and O.W.P. declare no competing interests."

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Supplementary information

Glossary

Theranostics

A chemical moiety that can be used for both therapy and diagnostic purposes; for example, radioisotopes of iodine, 131I and 124I, can be used for both quantitative nuclear imaging and therapy.

Dosimetry

Assessment (by measurement or calculation) of radiation dose.

Therapeutic index

The ratio between the dosage of a drug that causes a major therapeutic effect and the dosage that causes a toxic effect; in radioimmunotherapy, this is the ratio of radiation-absorbed dose to the tumour divided by the dose to a radiosensitive tissue such as kidney or bone marrow.

Bystander effect

The phenomenon in which radiation affects neighbouring cells in addition to cells at the site of targeting.

Residualized

A radioactive form that is trapped in the tumour cell after catabolism of an internalized antigen–antibody complex; some non-residualizing radionuclides can be made residualizing through the use of specific chemical constructs that limit catabolism.

Path length

The actual distance that a nuclear particle travels in tissue as part of the process of radioactive decay.

β-particles

Electron-like negative particles emitted from the nuclei of β-emitting radionuclides.

α-particles

Particles the size of a helium nucleus made up of two protons and two neutrons, produced by α-emitting radionuclides (for example, 225Ac).

Bremsstrahlung

A type of electromagnetic radiation produced when a high-energy charged particle is decelerated or deflected by another charged particle.

Myelosuppression

A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells and platelets.

Cardiopulmonary toxicities

Adverse effects on the blood systems, heart or lungs, resulting from exposure to toxic chemicals, for example, cardiac ischaemia, pulmonary inflammation and an increased level of toxins in the blood.

Linear energy transfer

(LET). The action of radiation on matter that describes how much energy an ionizing particle transfers to the material transversed per unit distance.

Half-life

The characteristic period of decay during which half of the population of radioactive atoms will undergo spontaneous radioactive decay.

Leptomeninges

The two innermost layers of tissue (arachnoid mater and pia mater) that cover the brain and spinal cord.

Ommaya reservoir

A device surgically placed under the scalp and used to deliver anticancer drugs to the cerebrospinal fluid.

Human anti-mouse antibodies

(HAMAs). Antibodies found in humans that react to immunoglobins found in mice.

Convention-enhanced delivery

A therapy in which therapeutic compounds are forced directly into the region of interest through a needle or cannula by applying a low-pressure gradient.

Haptens

Small molecules that, when combined with larger carriers such as a protein, can elicit the production of antibodies that bind specifically to them (in the free or combined states).

Bispecific antibodies

Artificial proteins composed of fragments of two different monoclonal antibodies, which consequently bind to two different types of antigen.

Fragment antigen-binding fragments

(Fab fragments). Regions on an antibody that bind to antigens and that are composed of one constant and one variable domain of each of the heavy and the light chains.

DOTA

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. DOTA functions as a chelating agent for the radioisotope 90Y3+ or other radiometals. It can be conjugated to monoclonal antibodies by attachment of one of the four carboxyl groups as an amide.

Single-chain variable fragment

(scFv). A fusion protein of the variable regions of the heavy (VH) and light (VL) chains of immunoglobulins, connected with a short linker peptide of ∼10–25 amino acids.

Phosphorodiamidate morpholino oligomers

(MORFs). A family of synthetic oligomers that are water soluble and reported to be stable both in vitro and in vivo.

Area under the curve

(AUC). The overall amount of drug in the bloodstream or other tissue after a dose.

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Larson, S., Carrasquillo, J., Cheung, NK. et al. Radioimmunotherapy of human tumours. Nat Rev Cancer 15, 347–360 (2015). https://doi.org/10.1038/nrc3925

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