Targeted alpha therapy for cancer

Abstract

Targeted alpha therapy (TAT) offers the potential to inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The practicality and efficacy of TAT is tested by in vitro and in vivo studies in melanoma, leukaemia, colorectal, breast and prostate cancers, and by a phase 1 trial of intralesional TAT for melanoma. The alpha-emitting radioisotope used is Bi-213, which is eluted from the Ac-225 generator and chelated to a cancer specific monoclonal antibody (mab) or protein (e.g. plasminogen activator inhibitor-2 PAI2) to form the alpha-conjugate (AC). Stable alpha-ACs have been produced which have been tested for specificity and cytotoxicity in vitro against melanoma (9.2.27 mab), leukaemia (WM60), colorectal (C30.6), breast (PAI2, herceptin), ovarian (PAI2, herceptin, C595), prostate (PAI2, J591) and pancreatic (PAI2, C595) cancers. Subcutaneous inoculation of 1-1.5 million human cancer cells into the flanks of nude mice causes tumours to grow in all mice. Tumour growth is compared for untreated controls, nonspecific AC and specific AC, for local (subcutaneous) and systemic (tail vein or intraperitoneal) injection models. The 213Bi-9.2.27 AC is injected into secondary skin melanomas in stage 4 patients in a dose escalation study to determine the effective tolerance dose, and to measure kinematics to obtain the equivalent dose to organs. In vitro studies show that TAT is one to two orders of magnitude more cytotoxic to targeted cells than non-specific ACs, specific beta emitting conjugates or free isotopes. In vivo local TAT at 2 days post-inoculation completely prevents tumour formation for all cancers tested so far. Intra-lesional TAT can completely regress advanced sc melanoma but is less successful for breast and prostate cancers. Systemic TAT inhibits the growth of sc melanoma xenografts and gives almost complete control of breast and prostate cancer tumour growth. Intralesional doses up to 450 microCi in human patients are effective in regressing melanomas, with no concomitant complications. These results point to the application of local and systemic TAT in the management of secondary cancer. Results of the phase 1 clinical trial of TAT of subcutaneous, secondary melanoma indicate proof of the principle that TAT can make tumours in patients regress.

Targeted α-particle radiotherapy with 211At-labeled monoclonal antibodies

“…The average [range] radiation absorbed dose delivered to the tumor SCRC margin was 2764 [155-35,000] Gy, reflecting in large part the fact that cavity volumes for these patients varied from 0.2 cm 3 to 37.2 cm. 3 As shown in Figure 2, median survival for GBM patients (n=14) and all patients (n=18) was 52 and 56.5 weeks, respectively. Particularly encouraging is the fact that 2 of these recurrent GBM patients survived for 150 and 151 weeks after 211 At-labeled mAb treatment, which is considerably better than that obtained with conventional treatments (25-30 weeks).…”

“…Targeting α-particle emitting radionuclides to cancer cells has emerged as a particularly promising approach to molecular radiotherapy based on accumulating evidence from preclinical studies, as summarized in several recent reviews [1][2][3]. Because the range of α-particles in tissue is only about 50-80 μm, equivalent to only a few cell diameters, at least on a conceptual level, they are well matched to the cellular specificity of molecularly specific targeting vehicles, and minimize irradiation of tumor-adjacent normal tissues.…”

Targeted Alpha Therapy Trial in Bangladesh: Promise for Advanced MUC1 – Expressing Tumors

“…Microdosimetry technique can measure the microscopic distribution of energy from different types of radiation. Using the Monte Carlo models for biological dosimetry, the location and form of radionuclides within cells can be used to estimate radiation dose distributions and effects (47).…”

Development of radioimmunotherapeutic and diagnostic antibodies: an inside-out view

“…helium nuclei) are quite large, have high energies of several MeV, and are associated with high probability of inflicting irreparable and cytocidal DNA double-strand breaks. 29 Consequently, α-emitters are well suited for hematologic disease, micrometastatic disease, and tumor cells near the surface of cavities.…”