"Challenges in cancer management can be divided into treatment of local and disseminated disease," Bezak explained. "We have to ask how we can improve outcomes in both of these branches." Treatments for localized cancers are reasonably successful, she said, though with highly site-dependent outcomes. But there are few effective options available to successfully manage advanced metastatic cancer. "So can we come up with new strategies that can deliver more benefit for a limited increase in cost?"

Bezak proposed that short-range, targeted, high-LET (linear energy transfer) radiation may provide a means to destroy disseminated micrometastases. She introduced the concept of targeted alpha therapy (TAT) – a type of radio-immunotherapy. TAT works by labelling a tumour-specific antibody with an alpha-emitting radioisotope. This radio-immunoconjugate then attaches to antigens on the cancer cells, delivering a highly targeted radiation dose to the tumour while minimizing irradiation of surrounding healthy tissue.

Alpha particles are particularly suited for this approach as they have a short range (20–80 μm, which encompasses 2–4 surrounding cells), and a high LET of around 100 keV/μm. Potential alpha-emitting isotopes include: bismuth-213, with a half-life of 46 minutes; astatine-211, with a half-life of 7.2 hours; radium-223 with a half-life of 11.4 days; and thorium-227, which has a half-life of 18.7 days.

The antibodies used for tumour targeting, meanwhile, must be chosen for each particular cancer type. Example monoclonal antibodies include 9.2.27 for treating melanoma or glioblastoma, WM-53 for leukaemia, C595 for pancreatic and prostate cancers, C30.6 for colorectal cancer, and Herceptin for breast and ovarian tumours. "It's a major task to find a tumour-specific antigen and create the radio-immunoconjugates," said Bezak, noting that alpha-emitting drugs are already being developed for several solid cancers and leukaemia.

There are also phase 1 clinical trials of TAT in place, mostly for treating leukaemia and lymphomas, with a couple of studies looking at melanomas and glioblastomas. "Radium-223 chloride has been approved in the US for palliative therapy of advanced prostate cancer," Bezak told the delegates. "Recent clinical trials have been positive."

Addressing hypoxia

Next, Bezak introduced a new concept: "necrotic TAT", which uses a radio-immunoconjugate that specifically targets necrotic cells. The aim here is to deliver alpha emitters directly to radioresistant hypoxic tumour cells, by exploiting the observed spatial correlation (co-location) between necrotic tumour regions and regions of hypoxia. Using the emitted alpha particles to kill hypoxic tumour cells should help reduce the likelihood of recurrence and metastasis.

Bezak described an investigation performed by her research team at the University of Adelaide and the Royal Adelaide Hospital. In this study, mice with Lewis lung tumours were treated with the murine monoclonal antibody DAB4 (which targets an antigen that is overexpressed in necrotic tissue) radiolabelled with thorium-227. Each mouse received about 18 kBq of Th-227-DAB4 and some were also given cisplatin beforehand.

After therapy, the researchers performed autoradiography using a Timepix detector to monitor Th-227-DAB4 uptake and distribution in excised tumour sections. The results showed that the radio-immunoconjugate accumulated in the tumour, and that the density of detected alpha particles increased four-fold after chemotherapy, due to an increase in necrotic tissue volume following chemotherapy.

"TAT will play an important role in the treatment of disseminated, chemoresistant and radioresistant metastatic disease," Bezak concluded. "When combined with other therapies, TAT is likely to improve survival." The next step in the evolution of this approach, from a physics point of view, will be to develop appropriate techniques to monitor and quantify radio-immunoconjugate uptake and local dose deposition using novel microdosimetry detectors.

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About the author

Tami Freeman is Editor of medicalphysicsweb.