Combination Radioimmunotherapy Approaches and Quantification of Immuno-PET

Abstract

Monoclonal antibodies (mAbs), which play a prominent role in cancer therapy, can interact with specific antigens on cancer cells, thereby enhancing the patient’s immune response via various mechanisms, or mAbs can act against cell growth factors and, thereby, arrest the proliferation of tumor cells. Radionuclide-labeled mAbs, which are used in radioimmunotherapy (RIT), are effective for cancer treatment because tumor associated-mAbs linked to cytotoxic radionuclides can selectively bind to tumor antigens and release targeted cytotoxic radiation. Immunological positron emission tomography (immuno-PET), which is the combination of PET with mAb, is an attractive option for improving tumor detection and mAb quantification. However, RIT remains a challenge because of the limited delivery of mAb into tumors. The transport and uptake of mAb into tumors is slow and heterogeneous. The tumor microenvironment contributed to the limited delivery of the mAb. During the delivery process of mAb to tumor, mechanical drug resistance such as collagen distribution or physiological drug resistance such as high intestinal pressure or absence of lymphatic vessel would be the limited factor of mAb delivery to the tumor at a potentially lethal mAb concentration. When α-emitter-labeled mAbs were used, deeper penetration of α-emitter-labeled mAb inside tumors was more important because of the short range of the α emitter. Therefore, combination therapy strategies aimed at improving mAb tumor penetration and accumulation would be beneficial for maximizing their therapeutic efficacy against solid tumors.

Improving theranostics in pancreatic cancer

“…Others are developing similar approaches for other targets, often with the goal of radioimmunotherapy . Beyond the issue of tumor penetration, a major challenge with using mAbs to image disease is the discrepancy between amount of time it take for an antibody to accumulate at the disease site (signal) and clear the blood stream (noise) as well as the half life of the radionuclide. Moreover, a circulating radiolabeled antibody will deposit significant amounts of radiation to healthy tissues.…”

FDG-Pet Scan: A New Paradigm for Follicular Lymphoma Management.

“…The steps associated with tumour targeting by MoAbs are blood flow to the tumour extravasation across the capillary wall, diffusion en the extracellular fluid and binding to the tumour. Extravasation across the endothelium is the rate-limiting step; the estimated permeability of extravasation is 1 μm/s for FDG and 0.003 μm/s for MoAbs 54. Finally, tumours are surrounded by a layer of extracellular matrix (ECM) proteins, such as collagen, elastin, fibronectin, which inhibit the penetration and dispersion of cancer therapeutic agents.…”

Improved Quantification of 18F-FDG PET during 131I-Rituximab Therapy on Mouse Lymphoma Models after 131I Prompt Emission Correction

“…Radioimmunotherapy (RIT), such as 131 I labelled tositumomab (Bexxar) and 131 I labelled rituximab [1,2], is used for targeted treatment of cancer and involves selective delivery of radionuclidelabelled monoclonal antibodies (mAbs) [1,3]. Imaging mAb using Positron Emission Tomography (PET) or Single-photon emission computed tomography (SPECT) was applied to quantitatively estimate expression of accessible antigens in the target tissue [4][5][6].…”

“…However, in a preclinical mouse model, tumor size increases faster than in humans, while their maximum life span is much shorter than humans. The tumor in lymphoma mouse model grew from 200 mm 3 to 100 mm 3 within 10 days. In preclinical study, therefore, there was a necessity of a 18 F-FDG PET follow-up scan immediately after 131 I therapy.…”