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Alpha DaRT: Turning alpha radiation into a high-precision cancer therapy

Prof. Itzhak Kelson, Chief Physics Officer

Radiation therapy, the use of high-energy particles or waves, such as x-rays, gamma rays, electrons, or protons, has long been used to treat cancer. From as early as the 20th Century, physicians have given regular doses of radiation to greatly improve the patient’s chance for a cure.

Yet, though the medical community has known for some time that alpha particles are highly lethal to cancerous cells, their short range in tissue has made them unsuitable for cancer treatment.

Until now…

From physics research to a cancer treatment idea

Going back now nearly 15 years, it all started in the physics laboratory of Tel Aviv University, where I am now an Emeritus Professor of the Raymond and Beverly Sackler Faculty of Exact Sciences.

Working with my PhD student, Lior Arazi (today a Senior Lecturer at Ben Gurion University of the Negev) we were researching ways to measure the thickness of thin layers grown on a given substrate. We had developed a technology that by using the energy lost by alpha particles in passing through matter, one could measure in real time the growth progression and thickness of thin layers.

Though the technology had clear industrial applications, the use of radiation proved a regulatory barrier to bring potential business partners on board. We then started seeking different applications.

So how did our technology turn into a cancer treatment?

Quite by chance, we had a researcher who was also a Medical Doctor working next to our lab. He suggested to Lior to use the technology in the medical field.

It did not take us long to realize the huge potential our technology had for the treatment of cancer!

After a few preliminary, but promising trials on our own, we joined forces with Prof. Yona Keisari at the Human Microbiology Department at Tel Aviv University. Prof. Keisari’s clinical expertise would help us prove whether the technology might work and the rest is history. It is very well described in Professor Keisari’s story, is his blog – The Birth of Alpha Tau Medical.

But why was our technology so promising for cancer treatment?

The benefits of alpha radiation over gamma and beta radiation

1 - The Alpha Particle

To understand better alpha radiation’s benefits over beta and gamma, let me quickly outline the major characteristics of alpha, beta and gamma radiation.

Alpha radiation is released when an atom undergoes radioactive decay, giving off a particle (called an alpha particle) consisting of two protons and two neutrons (essentially the nucleus of a helium atom).

Due to their positive electric charge and heavy mass, alpha particles interact strongly with matter, and have a very short range. They only travel a few centimeters in air, and in cell tissue, their range is limited to only a few 50-90 μm (equivalent to a few cell diameters).

2- Alpha Decay and Recoil

Beta radiation takes the form of either an electron or a positron (a particle with the size and mass of an electron, but with a positive charge) being emitted from an atom. Beta particles are about 7,000 times lighter than alpha particles. This allows them to travel further in tissue, penetrating clothing and skin. Because of their comparatively long range in tissue (0.8-5 mm), beta particles create a prominent cytotoxic effect. This compromises the cell integrity, leading not only to the destruction of targeted cancerous cells, but also to the killing of normal healthy cells potentially producing a higher risk of toxicity.

3- Comparison: Effect of Alpha Particle on Cell vs. Beta Particle

Gamma radiation, unlike alpha or beta, does not consist of any particles; instead, it is a photon of energy being emitted from an unstable nucleus. Having no mass or charge, gamma radiation can travel through most forms of matter and further than alpha or beta radiation. Because of its long-range and high penetration effect, gamma radiation is less targeted; increasing the risk that radiation will not only be deposited inside the tumor but will also harm surrounding healthy tissue. In addition, because photons interact weakly with matter, there is a large amount of activity required to generate damage to the tumor.

4 - Gamma decay, X-ray

However, its long-range actually makes it very beneficial for the treatment of tumors using External Beam Radiotherapy (EBRT) – the most common form of radiation therapy.

Alpha particles are stopped by a simple piece of paper. By comparison, massive shielding (like lead) is required to stop energetic gamma rays.

5 - Materials used to stop or reduce radiation types

When we compare the use of alpha radiation to gamma and beta radiation in radiotherapy, we can see there are some clear advantages:

1. Short-range irradiation

The alpha particles’ primary benefit is their ability to deliver radiation in a highly localized manner.

Their short-range in tissue compared to gamma and beta radiation, means that if delivery to cancerous cells is achieved; there is a very low risk of healthy cells being caught in the radiation crossfire.

2. High potency to destroy cancer cells

As a high linear energy transfer (LET) radiation type (a good measurement of radiation effectiveness to efficiently kill tumor cells), alpha radiation provides a greater potential for biologic damage compared to gamma and beta radiation.

Alpha radiation causes double strand breaks in the cancer cells DNA. This damage has proven to be highly complex, more likely to be irreparable and more concentrated along the particle track, meaning it is more destructive than double strand breaks caused by other modalities [1][2]. As a result, the relative biological effectiveness of alpha particles is higher than other forms.

3. No oxygen needed

6 - Alpha particles destroying the cancer cell DNA causing double-strand breaks

Alpha particles do not require the presence of oxygen for therapeutic effect as they directly damage the cell's DNA.

For gamma radiation, the presence of oxygen is required to create significant damage to the DNA - the so called Oxygen Enhancement Ratio (OER) effect.

Solid tumors, which are not homogeneously oxygenated, can survive gamma radiotherapy treatment. This is because the dose that is needed to destroy hypoxic areas is up to three times higher than the dose that is needed to achieve the same therapeutic effect in well oxygenated areas. As you can imagine, the use of increased dose brings with it increased risks of side effects from the long range of activity from gamma radiation.

Overcoming the alpha particles’ short range in tissue

As I have explained, alpha particles major benefit is their ability to destroy cancer cells in a highly localized manner. Yet, until the Alpha DaRT, this same short path length of alpha particles in tissue, had made them unsuitable for the treatment of larger bodies such as solid tumors.

The Alpha DaRT treatment overcomes this range limitation through the use of diffusing alpha-emitter atoms. Instead of using a radiation source which directly shoots out alpha particles, we used a source that releases alpha emitters, atoms that emit alpha particles during radioactive decay.

7- Decay Chain of Radium-224

The Alpha DaRT treatment is delivered by intratumoral insertion of seeds that are impregnated with alpha-emitting atoms, Radium-224. The Radium-224 stays on the seed, while its alpha-emitting daughter atoms diffuse and disperse inside the tumor tissue to a therapeutically significant range of several millimeters. During the atoms’ decay they "shoot out" an high-energy alpha particle into the tumor tissue.

Thanks to the alpha particle's short range, the treatment delivers a high dose of alpha radiation in a targeted, localized area, without harming the healthy tissue!

From theory to saving lives

I vividly recall being on a flight to Geneva, Switzerland – I was going to CERN, the European Organization for Nuclear Research. At that time, we had been using very weak sources of Radium-224 with minimal efficacy. During my flight, we had just amended the trial and I was waiting to hear the results. I remember arriving in Geneva and getting the sensational results; even with the seeds being charged with a relatively low activity, the mouse’s tumor had been completely cured.

I was so pleased; I took my partner, Hannah, out for dinner to one of the top restaurants in Geneva. The owner of the restaurant, a well-built 2 m tall Swiss man asked how our meal was and where we were from. I couldn’t help sharing my story and to this day I remember his reaction.

His father had died 3 weeks previously from cancer. He was very moved to hear there was a new treatment out there that could help save so many lives! For me, seeing a big man get very emotional, put everything into perspective and motivated me like never before to continue our efforts.

Now several years later, our clinical results show that we are succeeding. Our recent trial to treat squamous cell carcinomas, showed all patients' tumor sizes reduced and more than 70% of patients' tumors completely disappeared within a few days after treatment!

Of course, there is more work to do but I am proud of our accomplishments so far.

About Professor Itzhak Kelson, Ph.D.

Prof. Kelson is the Co-founder and Chief Physics Officer of Alpha Tau Medical and the retired Chairman of the Tel Aviv University Physics Department. He has previously held research and teaching positions at the Weizmann Institute, Yale University, Lawrence Livermore National Laboratory, University of Wisconsin, Brookhaven National Laboratory, and other institutions.




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