Translational Studies for Targeted Alpha-Particle Therapy for Rare Melanomas
Abstract
Overall Program Lay Abstract Patients with metastatic uveal melanoma have dismal prognoses and are in significant need of novel, effective targeted therapies, that have low systemic toxicity, for personalized patient care. This is a critical unmet need that is relevant to rare melanoma patient care. There is only one approved drug for the treatment of metastatic uveal melanoma, Tebentafusp, but it is only applicable to half of uveal melanoma patients, provides only a marginal improvement over other available drugs, and patients can become resistant to this treatment over time. Development of targeted alpha-particle therapy (TAT) for the treatment of disseminated disease is an area of significant interest because TATs are specifically targeted to cancer cells, are highly effective in eradicating cancer tumors and metastases, have minimal toxicity to surrounding normal tissues, and can evade many mechanisms of developing resistance. We have developed a new TAT for the treatment of metastatic uveal melanoma, Ac-225-MTI-201, which is currently being tested at Moffitt Cancer Center in a single-injection phase 1 dose escalation clinical trial to determine safety, pharmacokinetics, radiation dosimetry, and efficacy in patients with metastatic uveal melanoma. However, it is now known that TATs may require multiple injection cycles to achieve complete metastasis eradication without metastasis regrowth. Project 1 of this proposal develops a multiple-injection cycle regimen (four doses, one every 4 weeks) of Ac-225-MTI-201 and includes a phase 2 clinical trial to test the safety and efficacy of this multi-administration regimen. Other rare melanomas express the cell-surface protein target (MC1R) for our TAT and expression of this target will be determined in rare melanomas other than uveal, such as acral and mucosal melanomas, and in vivo preclinical efficacy testing of our TAT will be performed in mouse models of these other rare melanomas. Companion imaging-based three-dimensional radiation dosimetry (3D-RD) methods are needed for the clinical translation of novel TATs in development because alpha-particle emissions cannot be practically imaged in the clinical setting and the standard methods that use only blood clearance and excretions from patients are not adequate. Project 2 involves preclinical and phase 1 clinical testing of a Ga-67-MTI-201 companion imaging tracer in healthy volunteers and a novel 3D-RD method we developed that uses the imaging data to compute the whole-body radiation dosimetry of the TAT. We have observed that our TAT is not evenly distributed throughout the kidney and standard radiation dosimetry methods are lacking in that the dose inside an organ is calculated to be evenly distributed, leading to an overestimate of dose in some kidney tissues and underestimate in dose in other kidney tissues. TAT uptake is higher in the kidney cortex relative to the medulla. Hence, we will also use our 3D-RD method to measure the distribution of radiation dose regionally throughout the kidney (termed kidney microdosimetry). Project 1 will result in the development of a multiple-administration regimen for our Ac-225-MTI-201 TAT and completion of a phase 2 clinical trial metastatic uveal melanoma. Expression of the MC1R target in other rare melanomas will be determined and preclinical efficacy studies completed in mouse xenograft tumor models for these other rare melanomas. Since our partner, Modulation Therapeutics Inc. (MTI), has obtained a U.S. Food and Drug Administration (FDA) orphan drug designation for the treatment of uveal melanoma with our TAT, completion of a phase 2 trial may be all that is needed to secure FDA approval through the FDA breakthrough designation. Project 2 facilitates the clinical translation of the Ga-67-MTI-201 companion SPECT tracer and a 3D-RD method for personalized radiation dosimetry. In vivo microdosimetry of Ac-225-MTI-201 in the kidney will also be determined. Res
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310909
Entities
People
- David Morse
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army