Targeted alpha therapy (TAT) using alpha particle-emitting radionuclides is in the spotlight after the approval of 223RaCl2 for patients with metastatic castration-resistant prostate cancer and the development of several alpha emitter-based radiopharmaceuticals. It is acknowledged that alpha particles are highly cytotoxic because they produce complex DNA lesions.
Hence, the nucleus is considered their critical target, and many studies did not report any effect in other subcellular compartments. Moreover, their physical features, including their range in tissues (<100 μm) and their linear energy transfer (50–230 keV/μm), are well-characterized.
Theoretically, TAT is indicated for very small-volume, disseminated tumors (e.g., micrometastases, circulating tumor cells). Moreover, due to their high cytotoxicity, alpha particles should be preferred to beta particles and X-rays to overcome radiation resistance. However, clinical studies showed that TAT might be efficient also in quite large tumors, and biological effects have been observed also away from irradiated cells.
These distant effects are called bystander effects when occurring at short distance (<1 mm), and systemic effects when occurring at much longer distance. Systemic effects implicate the immune system. These findings showed that cells can die without receiving any radiation dose, and that a more complex and integrated view of radiobiology is required. This includes the notion that the direct, bystander and systemic responses cannot be dissociated because DNA damage is intimately linked to bystander effects and immune response.
Alpha Tau Medical has been running clinical trials of the treatment for patients with skin cancer, breast cancer, and oral cavity cancer, with promising results.
But this is the first time in the world that the revolutionary therapy – called Alpha DaRT (Diffusing Alpha-emitters Radiation Therapy) – has been used to treat a patient with prostate cancer, the company’s CEO Uzi Sofer tells NoCamels. It directly damages the cell DNA, creating double-strand breaks which kill the cancer cells.
The patient, a 60-year-old man with an aggressive form of prostate cancer, felt no pain after the two-hour outpatient procedure and went home the same day from the Rambam Health Care Center in the northern Israeli town of Haifa.
He will return 50 days later to have the prostate surgically removed. Alpha DaRT is designed to destroy the tumor without harming the healthy tissue around it.
“The historical event that we had last week is that this is the first time that we are treating an internal organ – the prostate – and that will give us a very, very good sign of [treating] internal organs,” Sofer explains, noting that Jerusalem-based Alpha Tau Medical aims to use its Alpha DaRT therapy for treatment of GBM glioblastoma brain tumors, pancreatic cancers, and tumors in the liver, in the future.
The goal of the procedure was to assess the feasibility and safety of the Alpha DaRT implantation, which went smoothly, says Dr. Tomer Charas, head of the GU Radiotherapy Unit in the Oncology Division at Rambam. The team at Rambam is also assessing radiological and pathological objective response rate of the tumor and changes in quality of life measures.
“In the first case, we planned something ahead of time. And when we actually did the implant, it was identical. So the results were good. The patient himself felt very well. He went home on the same day with no issues. So hopefully moving forward, that’s going to be replicated to all our patients,” Dr. Charas tells NoCamels.
The company’s technology potentially treats solid cancer tumors by injecting them with radioactive substances that decay and release high-precision alpha radiation that destroy the cancer cells. The procedure takes up to two hours of outpatient treatment for superficial tumors, according to the company.
During the treatment a needle containing radium-224, a radioactive isotope, is inserted into the tumor, releasing the alpha radiation that gets rid of cancer cells through breaks in the DNA of these cells.
The treatment of the first prostate patient was part of a feasibility study evaluating the Alpha DaRT as what is called a neoadjuvant therapy, that’s a treatment given as a first step to shrink a tumor before the main treatment (usually surgery). Dr. Charas says doctors inserted five long, thin needles or “darts” into the patient.
They contained seeds that release the therapy in a minimally invasive brachytherapy procedure (internal radiation) that involved inserting radiation into the tissue of the tumor. It was an outpatient procedure under general anesthesia, that took “about two hours or so,” Dr. Charas explains. The patient was not hospitalized.
“We did it under ultrasound guidance while the patient was asleep [under general anesthesia], we used the ultrasound to guide us,” Dr. Charas explains. “If it’s outside of the skin, you basically see what you do, but when it’s an internal organ, you have to have some sort of mechanism to be able to know exactly what you’re doing.”
Dr. Charas tells NoCamels that when the patient woke up, there were no pains, no cuts, no incisions, and no tubes or drains.
“We want to see that technically and clinically patients are okay, and the implant can be done safely. And in the future, we hope that either this will be evaluated for a treatment that will be sort of adjunct or connected to the surgery. So you do that before you remove the prostate, if that will improve the outcome.
That’s going to be one thing that we want and hope to achieve. And the other thing we hope that this will achieve is that we will maybe use this technology in patients who already failed previous radiation treatments,” Dr. Charas explains.
The study involves two separate procedures, with surgical removal (resection) of the prostate 50 days following Alpha DaRT source insertion, a statement from the company said. The surgical resection will be performed at the Carmel Medical Center in Haifa, Israel using a da Vinci surgical robot, and will be led by Dr. Yuval Freifeld and his senior team.
Alpha Tau Medical’s product is based on technology developed in 2003 by Prof. Yona Keisari and Prof. Itzhak Kelson at Tel Aviv University. Sofer founded the company in 2016 after he left a previous company, Brainsway, a firm that focuses on the treatment of brain disorders.
Between 2017 to 2019, Alpha DaRT was used for its first in-human clinical study for squamous cell carcinoma of the skin and head and neck. The study was launched at the Rabin Medical Center in Israel and the Romagna’s Scientific Institute for the Study and Cure of Cancers (IRST) in Italy.
Last year, clinical trials used Alpha DaRT for treatment of skin, oral cavity, and breast cancer began in Israel, Japan Russia, the United States, and Canada. The startup already has production facilities in Israel, Massachusetts (USA), and Japan, with more to come, says Sofer.
The company raised $26 million in a Series B round in 2020 and completed a merger in 2021, when it entered an agreement with special purpose acquisition company (SPAC) Healthcare Capital Corp (HCC) to go public on the Nasdaq, at an approximate valuation of $1 billion.
reference link: https://www.frontiersin.org/articles/10.3389/fmed.2021.692436/full