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 Table of Contents  
EDITORIAL
Year : 2018  |  Volume : 2  |  Issue : 4  |  Page : 67-68

Radioimmunotherapy: Is it future?


Department of Radiotherapy, HCG Panda Cancer Hospital, Cuttack, Odisha, India

Date of Web Publication26-Dec-2018

Correspondence Address:
Dr. Tapan Kumar Sahoo
Department of Radiotherapy, HCG Panda Cancer Hospital, Cuttack, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/oji.oji_41_18

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How to cite this article:
Sahoo TK. Radioimmunotherapy: Is it future?. Oncol J India 2018;2:67-8

How to cite this URL:
Sahoo TK. Radioimmunotherapy: Is it future?. Oncol J India [serial online] 2018 [cited 2019 Mar 25];2:67-8. Available from: http://www.ojionline.org/text.asp?2018/2/4/67/248537



Cancer is the major contributor toward morbidity and mortality worldwide. Most of the cases have been presented in advanced stage. Instead of advance in management, the outcome is poor in metastatic disease. Due to the development of resistance to conventional therapies, hope for the outcome is questionable.

Antibodies are glycoproteins secreted from plasma B-cell. It identifies foreign pathogens by the use of immune system and removes it. Because of the presence of cytotoxic potency of antibodies against some cancer cells, the therapeutic efficacy in malignancy has been examined. However, there was no dramatically improvement in survival rate by intact antibodies. With this background, the concept of radioimmunotherapy (RIT) comes forward to enhance therapeutic response in oncological practice.

RIT is a selective internal radiation therapy, in which radionuclides are conjugated to tumor-directed monoclonal antibodies or peptides to deliver cytotoxic radiation to a target cell.[1] It is based on radiobiologic and immunologic processes without cross-resistance with other anticancer cytotoxic drugs.[2] Selective accumulation of cytotoxic radioisotopes at affected areas requires high-binding affinity to the intended target, high specificity, high tumor-to-background ratio, high metabolic stability, and low immunogenicity.[3] Therapeutic principle of RIT is the selective targeting of tumors relative to normal tissues to deliver a lethal dose of radiation to the tumor cells while decreasing the dose to normal tissues. The ideal therapeutic index is never achieved as continuous low-dose irradiation causes lethal effects on nearby normal cells. Safe deliver of high-radiation dose to a tumor can be achieved if the tumor is confined in an accessible body cavity or space. The development of quantitative methods for estimating the radiation-absorbed dose both for tumor tissue and normal tissue is important for individualizing patient treatment and avoiding toxicity due to excessive radiation exposure.[4]

Cytotoxic radioisotopes (α- or β-particle emitters) are conjugated to antibodies or the fragments through immunological techniques. Once injected, the radioantibody binds to receptors/tumor antigens expressed on the surface of cancerous tissue. Radionuclide emits therapeutic quantities of particulate radiation and delivers the tumoricidal dose to the tumor mass during radioactive decay. The antibody–antigen complex may either enhance anticancer effects by retaining the radionuclide within lysosomes or storage proteins or reduce effects by expelling the radioactivity from the cell.[4]

β-particle-emitting isotopes 131I and 90Y have been used in >95% of clinical RIT trials because of their favorable emission characteristics, availability, and tractable radiochemistry, which permits reliable and stable attachment to antibodies.[4] In comparison to β-emitters, α-particle emits its energy to the surrounding molecules within a narrow range and leads to high-linear energy transfer within the target and less bystander effect to nontarget tissues. Furthermore, it leads to the high relative biological effectiveness, and its cytotoxic efficacy is independent of the local oxygen concentration and cell cycle state.[3]

IT can be administered in several routes such as intravenous and direct injection into a body compartment where tumor is confined such as peritoneum, pleural, intrathecal, and intraventricular space. For solid tumors, several clinical trials resulted modest clinical results on intravenous administrations whereas direct injection may have long-term impact on survival. Intrathecal and intraventricular administration of 131I-81C6 for leptomeningeal carcinomatosis and intratumoral therapy of malignant brain tumors have prolonged patient survival.[4]

RIT is mostly used for radiosensitive tumors such as leukemias and lymphomas. RIT has a safety and proven efficacy for non-Hodgkin lymphoma patients resistant to both chemotherapy and rituximab.[2] Furthermore, it has therapeutic potential for some other cancers such as prostate cancer, metastatic melanoma, ovarian cancer, neoplastic meningitis, leukemia, and high-grade glioma of the brain.[5],[6],[7]

Myelosuppression, fatigue, and thyroid dysfunction (with 131I) are the side effects of RIT. However, the incidence of RIT-induced myelosuppression and secondary malignancies is not more than patients treated with chemotherapy. 131I tositumomab or 90Y ibritumomab tiuxetan is not recommended in patients with significant bone marrow involvement (>25%) or limited bone marrow reserve.[4]

Delivery of RIT is simple and more convenient than conventional chemotherapy and is administered over a matter of minutes, delivering the radiation payload over days during which no need of a patient to return for additional injections. The advantage of RIT over external beam radiation therapy is the ability to attack lesions systemically metastasizing along with the primary tumor. Furthermore, targeted radiotherapy can be used for residual micrometastatic lesions, residual tumor margins after surgical resection, tumors in the circulating blood including hematologic malignancy, and malignancies that present as free-floating cells.[3]

RIT treatment has not been widely adopted by the medical community due to a combination of factors such as secondary myelodysplasia/acute leukemia risk, the lack of large randomized studies, the availability of many novel competing targeted agents such as ibrutinib or idelalisib, and the inability of oncohematologists to administer the therapy in their own departments.[2] Intravenous administration of RIT causes slow clearance of unbound form from the circulation resulting high levels of background radioactivity and limits the tumor-to-normal organ ratios of absorbed radiation. Smaller antibody moieties can employ to decrease the circulating half-life of the RIT and to reduce the toxicity. However, lower intratumoral concentrations and undesirable renal accumulation are the important issues for the smaller moiety.[4]

Low therapeutic index remains as a key problem for solid tumors and needs improvement of antibody uptake and enhancement of radiosensitization of cancer cells.[3] Dose fractionation increases therapeutic efficacy allowing bone marrow recovery in between doses, leading to higher administered doses.

RIT is expensive and severe side effects may occur for a minority of patients. There is a need for a preselection of patients likely to respond, the estimation of target antigenic molecule expression, post-RIT tumor uptake assessment by immunoscintigraphy, pre-RIT biomarker doubling time, and impact of RIT on biomarker doubling time. Combination therapy in the form of fractionated RIT with radio-sensitizing agents or chemotherapy is an attractive option for poor prognostic metastatic solid tumors. RIT and immune checkpoint inhibitors could act synergistically in metastatic tumors.[2]

The current concept of RIT is single-injection therapy agent but is not realistic for metastatic cancers. It needs to develop fractionation schedule to reduce hematologic toxicity and improve efficacy. Development of better real-time dosimetry methods and understanding of the radiobiology of targeted therapy, especially emission properties of radionuclides, will refine and optimize RIT. Finally, field of RIT is still challenging. Development in RIT methods and novel radioimmunoconjugates is the era of personalized medicine, especially for treatment of poor-prognosis cancer resistant to conventional therapies. However, randomized clinical trials have to be designed for response to RIT.



 
  References Top

1.
Milenic DE, Brady ED, Brechbiel MW. Antibody-targeted radiation cancer therapy. Nat Rev Drug Discov 2004;3:488-99.  Back to cited text no. 1
    
2.
Kraeber-Bodéré F, Barbet J, Chatal JF. Radioimmunotherapy: From current clinical success to future industrial breakthrough? J Nucl Med 2016;57:329-31.  Back to cited text no. 2
    
3.
Kawashima H. Radioimmunotherapy: A specific treatment protocol for cancer by cytotoxic radioisotopes conjugated to antibodies. ScientificWorldJournal 2014;2014:492061.  Back to cited text no. 3
    
4.
Larson SM, Carrasquillo JA, Cheung NK, Press OW. Radioimmunotherapy of human tumours. Nat Rev Cancer 2015;15:347-60.  Back to cited text no. 4
    
5.
Smith-Jones PM. Radioimmunotherapy of prostate cancer. Q J Nucl Med Mol Imaging 2004;48:297-304.  Back to cited text no. 5
    
6.
Dadachova E, Nosanchuk JD, Shi L, Schweitzer AD, Frenkel A, Nosanchuk JS, et al. Dead cells in melanoma tumors provide abundant antigen for targeted delivery of ionizing radiation by a mAb to melanin. Proc Natl Acad Sci U S A 2004;101:14865-70.  Back to cited text no. 6
    
7.
Quang TS, Brady LW. Radioimmunotherapy as a novel treatment regimen: 125I-labeled monoclonal antibody 425 in the treatment of high-grade brain gliomas. Int J Radiat Oncol Biol Phys 2004;58:972-5.  Back to cited text no. 7
    




 

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