Cancer is the most devastating chronic disease affecting humankind. More than 1 out of 3 people in the United States will have cancer during their lifetimes, of which 30% of them will die 5 years from diagnosis [i]. As people live longer, the number of new cancer cases set to nearly double by the year 2050 [i]. For those who survive, existing treatments can lead to severe cancer side effects in many cases, resulting in significant negative impact on quality of life.
Consequently, there is a great need for effective treatments that maintain patient’s quality of life. Alpha Tau’s development of the first alpha-radiation-based cancer treatment for various types of solid tumors provides us with a promising new cancer treatment option.The treatment, Alpha DaRT, can either be used instead of surgery or in combination with surgery, chemotherapy and immunostimulatory agents. In addition, the treatment is very safe showing much less toxicity or morbidity compared to existing treatments.
So where did it all start?
From alpha radiation to cancer therapy
As Professor of the Human Microbiology Department at the School of Medicine in Tel Aviv University, I remember very well, when I first came across the idea which became the core of the Alpha Tau’s remarkable technology.
In the Spring of 2003, Professor Itzhak Kelson from the University Physics Department, walked in my door and introduced himself. He had invented seeds that enable the spread of alpha-emitters in tissue and he was looking to investigate the use of this unique technology for treating cancer. His invention overcame alpha particles’ short range in tissue, while harnessing its ability to create complex double-strand DNA breaks. He had realized the benefits of the alpha particle’s high potency for killing cancer cells intratumorally.
Realizing the clinical promise of alpha radiotherapy for cancer
Metastasis are considered to be the main cause of death in 85% of all patient cases [ii].The development of a highly powerful technology that not only enabled local tumor ablation, yet was also able to activate the body’s immune response, and as such, to effectively treat cancer metastasis and prolong patients’ survival, held huge treatment promise. Could alpha radiation be it – a cure for cancer?
As early as the 1950s, the Abscopal Effect had been known. Mole proposed the idea that localized radiation therapy of a single solid tumor did not only cause shrinkage of the treated tumor, but also a shrinkage of tumors outside the scope of the localized treatment. This term later came to encompass other localized treatments, such as electroporation and intra-tumoral injection of therapeutics, that also resulted in systemic effects. However, the mediators of the Abscopal Effect of radiotherapy were unknown for decades.
Alpha’s powerful radiation effect suggested it may effectively activate the body’s immune response to treat metastases.
I understood quickly the great potential of Prof. Kelson’s invention and decided to dedicate my team of PhD students to initiate immediate studies. No existing cancer solid tumor treatment had utilized alpha radiation treatment until that day.
It was an exciting prospect!
With strong research interest and experience in the role of the immune response to trigger anti-tumor activity, I was delighted to help advance the treatment potential.
Highly promising preclinical results
Initial studies on mice were highly promising, demonstrating significant tumor shrinkage[iii],[iv], [v], [vi], [vii], [viii], [ix], [x], [xi], [xii], [xiii], [xiv]. Thanks to the assistance of Ms. Margalit Efrati, my talented and loyal lab manager, I was able to quickly expand the research team to include more than 10 PhD students. The potential was there!
Successful proof of concept followed. The preclinical studies showed the technology was effective with no systemic side effects in various cancer types. In many cases a single DaRT seed was significant enough to destroy the entire tumor and to cure the animal.
In other tumors, the DaRT created a neoadjuvant effect: when inserted into the tumor, it caused immediate cancer cell death and tumor shrinkage without harming the surrounding healthy tissue. This enabled easier and minor surgery to remove the remaining of the tumor.
In addition, I was pleased to have found an effective method to activate systemic anti-tumor immune response [xv]. By then combining DaRT with various checkpoint inhibitors, we found that the alpha-radiation treatment with DaRT and immunostimulants significantly prolonged survival of the mice treated!
With such great results, it was not surprising that the technology garnering interest and an investment was made by a group of angels in the USA.
However, successful development of any new technology does not only depend on a great idea but also on great timing and a bit of luck! In 2008, the global financial crisis and various other business setbacks slowed down the progress of our project and our ability to raise funding.
Nonetheless, thanks to public grants, government funding opportunities and our determination to continue – the research was rewarded. We successfully published 12 papers in peer-reviewed scientific journals showing the feasibility and potential of the technology [xvi].
Alpha Tau is born!
Then one day in November 2015, Howard Sterling, strategic advisor for financing and partnering, who later became one of the co-founders of Alpha Tau, introduced me to Uzi Sofer.
Uzi, was famous in Israel as the Co-founder and the successful CEO of Brainsway (TLV:BRIN), that developed an advanced non-invasive treatment of brain disorders and launched it successfully in the USA. Hot off the back from retiring from Brainsway, he had no interest in entering a new role – but like I had been easily convinced by Prof. Kelson years before, Uzi likewise could not resist his curiosity and the great potential of the exciting alpha radiation technology for cancer treatment!
The technology was now back on its way to being commercialized, with Uzi at its helm, at first unofficially, and then officially.
In November 2015, Alpha Tau Medical was officially born.
“Alpha” for the radiation type and the fact that the DaRT was the first to enable its use for solid tumor.
“Tau” representing Tel Aviv University for its ancient times meaning for life and resurrection.
The clinical future is Alpha
Soon after Alpha Tau was founded, we started to test the DaRT in clinical trials. We got highly-encouraging preliminary clinical results showing that Alpha DaRT is safe and effective for treating squamous cell carcinoma tumors – all patients' tumor sizes reduced and more than 70% of patients' tumors completely disappeared within a few days after treatment.
And we are just getting started! As of today, we have multiple clinical trials planned with leading cancer centres throughout the world using different protocols across a variety of indications, including:
Head and neck cancer
As I have realized – my book will wait – I won’t be retiring any time soon! This is far more exciting!
About Professor Yona Keisari, Ph.D.
Prof. Keisari is the Co-founder and Chief Biomedical Officer of Alpha Tau Medical and a member of the Human Microbiology Department, Tel Aviv University. His studies focus on in-situ destruction of solid metastatic tumors in order to stimulate anti-tumor immune reactivity and eradicate metastases. Professor Keisari taught immunology and has held a variety of faculty management positions at the Faculty of Medicine of Tel Aviv University. He was a Postdoctoral Fellow at the Tumor Biology Department, National Cancer Institute of the NIH, Bethesda, USA.
[ii] Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1,559–64. https://www.ncbi.nlm.nih.gov/pubmed/21436443
[iii] Arazi, L., Cooks, T., Schmidt, M., Keisari, Y., Kelson, I.Treatment of solid tumors by interstitial release of recoiling short-lived alpha emitters. Phys. Med. Biol, 52: 5025-5042: 2007.
[iv] Cooks, T., Arazi, L., Schmidt, M., Marshak, G., Kelson, I., Keisari, Y. Growth retardation and destruction of experimental squamous cell carcinoma by interstitial radioactive wires releasing diffusing alpha-emitting atoms. Int. J. Cancer 122: 1657-1664; 2008.
[v] Cooks, T., Schmidt, M., Bittan, H., Lazarov, E., Arazi, L., Kelson, I., Keisari, Y. Local control of lung derived tumors by diffusing alpha-emitting atoms released from intratumoral wires loaded with Radium-224. Int. J. Rad. Oncol. Biol. & Phys. 74: 966-973; 2009.
[vi] Cooks, T., Arazi, L., Efrati, M., Schmidt, M., Marshak, G., Kelson, I., Keisari, Y. Interstitial wires releasing diffusing alpha-emitters combined with chemotherapy improved local tumor control and survival in squamous cell carcinoma bearing mice. Cancer 115: 1791-1801; 2009.
[vii] Arazi, L., Cooks, T., Schmidt, M., Keisari, Y., Kelson I. The treatment of solid tumors by alpha emitters released from 224Ra-loaded sources—internal dosimetry analysis. Phys. Med. Biol. 55: 1203-1218; 2010.
[viii] Horev-Drori, G., Cooks, T., Bittan, H., Lazarov, E., Schmidt, M., Arazi, L., Efrati, M., Kelson, I., Keisari, Y. Local control of experimental malignant pancreatic tumors by treatment with a combination of chemotherapy and intratumoral 224Radium-loaded wires releasing alpha-emitting atoms. Transl. Res. 159: 32-41; 2012.
[ix] Lazarov, E., Arazi, L., Efrati, M., Cooks, T., Schmidt, M., Keisari, Y., Kelson, I. Comparative in vitro microdosimetric study of murine and human-derived cancer cells exposed to alpha particles. Radiat Res. 177: 280–287; 2012. [2011 Nov 11, Epub ahead of print].
[x] Milrot, E., Jackman, A., Flescher, E., Gonen, P., Kelson, I., Keisari, Y., Sherman, L. Enhanced killing of cervical cancer cells by combinations of methyl jasmonate with cisplatin, X or alpha radiation. Invest. New Drugs. Epub 6 Sept. 2012.
[xi] Cooks, T., Tal, M., Raab, S., Efrati, M., Reitkopf, S., Lazarov, E., Etzyoni, R., Schmidt, M., Arazi, L., Kelson, I., Keisari, Y. Intratumoral Ra-224-loaded wires spread alpha emitting atoms inside solid human tumors in athymic mice and can achieve local tumor control. Anticancer Res. 32(12): 5315-21; 2012.
[xii] Confino, H., Hochman, I., Efrati, M., Schmidt, M., Umansky, V., Kelson, I., Keisari, Y. Tumor ablation by intratumoral Ra-224- loaded wires induces anti-tumor immunity against experimental metastatic tumors. Cancer Immunol Immunother. 2015; 64(2):191-9. doi: 10.1007/s00262-014-1626-8.
[xiii] Reitkopf, S., Cooks, T., Schmidt, M., Efrati, M., Arazi, L., Rath-Wolfson, L., Marshak, G., Kelson, I., Keisari, Y. doi: 10.3109/09553002.2015.959666. Ablation of experimental colon cancer by intratumoral 224 Radium-loaded wires is mediated by alpha particles released from atoms which spread in the tumor and can be augmented by chemotherapy. Int J Radiat Biol. Int J Radiat Biol. 91:179-186; 2015.
[xiv] Confino, H., Schmidt, M., Efrati, M., Hochman, I., Umansky, V., Kelson, I., Keisari, Y. Inhibition of mouse breast adenocarcinoma growth by ablation with intratumoral alpha-irradiation combined with inhibitors of immunosuppression and CpG. Cancer Immunol Immunother. e-press Aug 06 2016. DOI: 10.1007/s00262-016-1878-6.
[xv] Keisari, Y. Tumor abolition and antitumor immunostimulation by physico-chemical tumor ablation. Frontiers in Bioscience, Landmark, 22, 310-347, January 1, 2017.