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Review
. 2019 Nov 8;20(22):5579.
doi: 10.3390/ijms20225579.

Combination Radioimmunotherapy Strategies for Solid Tumors

Javeria Zaheer  1   2 , Hyeongi Kim  1 , Yong-Jin Lee  1 , Jin Su Kim  1   2 , Sang Moo Lim  1
Affiliations
Review

Combination Radioimmunotherapy Strategies for Solid Tumors

Javeria Zaheer et al. Int J Mol Sci. .

Abstract

Combination radioimmunotherapy is an emerging approach for the treatment of solid tumors where radio immunotherapy alone has proven to be reasonably ineffective. Radioimmunotherapy (RIT) using monoclonal antibodies (mAbs) labeled with radionuclides is an attractive approach for cancer treatment because tumor-associated mAbs with cytotoxic radionuclides can selectively bind to tumor antigens. However, due to various limitations, mAbs cannot reach solid tumors, consequently reducing RIT efficacy. Combination RIT is a pragmatic approach through which the addition of drugs or other agents not only help mAbs to reach the targeted site but also improves its efficacy. Thus, the combination of drugs or moieties with RIT can be applied to overcome the barriers that RIT faces for solid tumors. This review covers the RIT approach, along with the mechanism of action of mAb used in RIT, limitations of solid tumors, and strategies that can be used in combination RIT to enhance the treatment regimen for solid tumors.

Keywords: cell-to-cell junctions; extracellular matrix; immune suppressive environment; interstitial pressure; monoclonal antibody; radioimmunotherapy; solid tumors.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Schematic of radioimmunotherapy (RIT). RIT delivers radiation directly to the tumor-specific antigen of a specific cancer type. The downward blue arrow shows downregulated oncogene signals
Figure 2
Figure 2
Mechanism of action of an mAb. The mAb binds to its targeted antigen and provokes antibody-dependent cellular cytotoxicity (ADCC) and a complement-dependent cytotoxicity (CDC) response. ADCC includes (natural killer) NK cells, which release granzymes and cytotoxic agents that are responsible for cell lysis. The Fc region of mAb may also bind to soluble protein C1q to promote a cascade reaction that eventually forms a membrane attack complex, as in the CDC-mediated response. Membrane attack complex (MAC) is responsible for disrupting cell membrane and inducing cell lysis.
Figure 3
Figure 3
Limitations of RIT in terms of drug delivery. The extracellular matrix (ECM) is composed of collagen, hyaluronic acid (HA), and fibroblasts that hinder drug delivery. Tight junctions and high interstitial pressure are some of the restrictions to RIT delivery in solid tumors.
Figure 4
Figure 4
Strategies for combination RIT. The ECM was found to present a considerable barrier to mAb penetration; therefore, ECM-degrading elements are crucial when designing a combinational RIT strategy. Another approach involves liberating tight cell–cell junctions by using drugs that target junctional proteins. Chemotherapeutic agents are cytotoxic agents that are commonly applied in combination RIT. Cell damage reduces the solid stress, which eventually reduces the interstitial pressure and improves RIT efficacy. The combination of RIT with other agents enhances drug transport by vessel normalization or by agents increasing antitumor immunity. The downward blue arrow shows decreased collagen and downregulated oncogene signaling. The upward red arrow shows improve transport and upregulated oncogene signaling.
See this image and copyright information in PMC

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