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| Fig. 1: Micrograph of mantle cell lymphoma, a type of non-Hodgkin lymphoma. Terminal ileum. H&E stain. (Source: Wikimedia Commons) |
Radioimmunotherapy (RIT) represents a selective internal radiation therapy, that is, the use of radionuclides conjugated to tumor-directed monoclonal antibodies (including those fragments) or peptides. Antibodies (Abs) are glycoproteins secreted from plasma B cell and are used by immune system to identify and remove foreign pathogens such as bacteria and viruses. Because it is considered that Abs also have cytotoxic potency against some malignant tumor cells, the therapeutic efficacy in cancer has been examined. However, intact Abs are insufficient to improve patient survival rate dramatically. As a one approach to enhance the therapeutic response by using immunological technique, cytotoxic radioisotopes (alpha or beta particle emitters) are conjugated to Abs or the fragments. This strategy is employed to deliver radioisotopes to the targeting tissue by appropriate vehicle. After the radiolabeled Abs bind to receptors/tumor antigens expressed on the surface of cancerous tissue, cells within an anatomic region of the alpha or beta range will be killed. [1]
Malignant lymphoma is a primary malignant neoplasm of lymphoid tissue arising from the expansion of malignantly transformed lymphocytes, which may contain one or more genetic abnormalities. It is divided into two broad categories; Hodgkin's lymphoma and Non-Hodgkin's lymphomas (NHLs). [2] Non-Hodgkin lymphoma (NHL) is a collection of malignancies of lymphocyte origin (Fig. 1). In Western countries, 85% of NHLs have a B-cell origin. NHL subtypes vary in prognosis, treatment options and outcome. Diffuse large B-cell lymphoma (DLBCL) patients with different molecular or genetic abnormalities can have diverse presentation and outcomes. Risk of developing NHL can be influenced by both environmental and genetic factors that affect the survival of lymphocytes. [3]
Lymphocyte development is a complex process, with checkpoints in place to ensure that the cells whose function is to quickly and effectively protect the host from a variety of offences, will also withhold such an assault on host cells. Cell growth and cell death need to be regulated so that the number of lymphocytes is controlled in such a way that they are sufficient to fight infections, but not so numerous that they are a burden to maintain. Three important aspects of this control are:
Immunity and inflammation to respond to stimuli that cause their activation and rapid cell cycle division
DNA repair to counteract errors from cell division or lymphocyte receptor gene rearrangement
Cell death to remove lymphocytes that are not able to meet cell cycle checkpoints and/or reduce autoimmunity
Previous work by several research groups has identified genetic variants associated with NHL in genes related to B-cell survival, DNA repair and immunity and inflammation. Collectively, genetic variants in these types of genes are likely to play a role in susceptibility to NHL. [3]
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| Fig. 2: Monoclonal Antibody. (Source: Wikimedia Commons) |
RIT has become an important treatment for NHL with Ibritumomab tiuxetan (Zevalin) and Iodine (I-131) tositumomab (Bexxar) being prominent FDA approved drugs used for NHL's treatment. Recently, another form of RIT in the shape of Iodine-131 Rituximab Radioimmunotherapy has shown immense promise after long term successful clinical trials. Rituximab (Fig. 2) is a chimeric mouse-human anti-CD20 monoclonal antibody that is effective in non-Hodgkin's lymphoma (NHL). [4] It binds against the protein CD20 which is found on surface of B cells. Due to this reason, Rituximab can be used to kill both normal and malignant B cells that have CD20 on their surfaces. So, Rituximab is proposed as an effective therapy to treat diseases which consist of having too many B cells or overactive B cells. This means that Rituximab can be used in treatment of many lymphomas (characterized by high B-cell growth), leukemias and auto-immune disorders.
Within NHL, Follicular lymphoma (FL) is the most common form of indolent B cell non-Hodgkin lymphoma and accounts for approximately 20% of lymphomas in adults. In 2014, a study evaluated the response and toxicity, after long-term follow up of Iodine-131 rituximab radioimmunotherapy in patients with follicular lymphoma under the routine clinical care of a single hematologist over a period of 12 years and found that I-131 Rituximab radioimmunotherapy is an effective treatment which does not compromise future therapy options upon relapse. [5] Similarly promising results were observed for I-131 Rituximab treatment for other forms of NHL and its repeat treatment has been found to be relatively safe. Because 131-Iodine has high radio- activity, it is rarely used for diagnostic purposes but because it can be used for killing targeted tissues, it is extensively used for 'therapeutic use'.[1]
Because Ab-based targeted radiation is considered to mediate direct cytotoxic effects, RIT could provide us with opportunities for safer and more efficient cancer treatment. Indeed, these techniques have been extensively used as conventional anticancer strategies. [1] Within RIT, I-131 Rituximab is a promising treatment and is achievable without significant toxicity in non-selected patients, including those pretreated with chemotherapy. [5]
© Mitesh Agrawal. The author grants permission to copy, distribute and display this work in unaltered form, with attribution to the author, for noncommercial purposes only. All other rights, including commercial rights, are reserved to the author.
[1] H. Kawashima, "Radioimmunotherapy: A Specific Treatment Protocol for Cancer by Cytotoxic Radioisotopes Conjugated to Antibodies," Scientific World Journal, 2014, 492061 (2014).
[2] K. H. Hamid et al., "Immunophenotyping of Non-Hodgkin's Lymphomas in Sudan," Pan African Medical Journal 18, 82 (2014).
[3] J. M. Schuetz et al., "Non-Hodgkin Lymphoma Risk and Variants in Genes Controlling Lymphocyte Development," PLoS ONE 8, e75170 (2013).
[4] P. Ataca et al., "Successful Desensitization of a Patient with Rituximab Hypersensitivity," Case Reports in Immunology 2015, 524507 (2015).
[5] P. C. Kruger, D. J. L. Joske, and J. H. Turner, "Iodine-131 Rituximab Radioimmunotherapy: Durable Control of Follicular Lymphoma," J. Nucl. Med. Radiat. Ther. 5, 4 (2014).
