On September 8, 2022 Alpha Tau Medical Ltd. ("Alpha Tau"), the developer of the innovative alpha-radiation cancer therapy Alpha DaRT, reported the acceptance of two landmark pre-clinical studies in major peer-reviewed journals, both demonstrating the significant potential synergies between Alpha DaRT therapy and standard-of-care solid tumor therapies used today (Press release, Alpha Tau Medical, SEP 8, 2022, View Source [SID1234619304]).
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
"We are very excited to have these fantastic results recognized by two leading journals in our field," said Alpha Tau CEO Uzi Sofer. "The potential synergy between Alpha DaRT and immunotherapies continues to be a strong area of focus for Alpha Tau, both in our ongoing pre-clinical work as well as in our endeavors to run multiple human clinical trials examining such combinations, including the trial currently underway combining Alpha DaRT with pembrolizumab in recurrent unresectable or metastatic head & neck squamous cell carcinoma patients. Similarly, the promising results for GBM patients are a key priority for Alpha Tau, as we continue to focus on advancing our solution for this deadly disease as quickly as possible. Armed with our Breakthrough Device Designation from the FDA in recurrent GBM, we have been progressing swiftly in large animal studies using our specially designed radial applicator for use in the brain, with the intent to begin a human clinical study in the near future."
Ronen Segal, CTO at Alpha Tau added, "These two significant studies continue to build on the ever-growing body of evidence that the Alpha DaRT may offer not only a compelling local radiation therapy solution, but also provide a broader systemic benefit through interaction with the immune system, and our incorporation of more advanced immunological analyses has improved our understanding of these amazing mechanisms. We also are impressed by the synergies we see with other mechanisms such as anti-angiogenesis and continue to explore those in parallel as well."
The first study, published in the International Journal of Radiation Oncology, Biology, Physics (known as the Red Journal) examines the transcriptional profile activated by Alpha DaRT, and its potential to enhance responsiveness to immune checkpoint inhibition of the programmed cell death protein 1 (PD-1) blockade. These results demonstrate potential synergies with immune stimulation in mice and support the further exploration of the Alpha DaRT as a compelling local radiation therapy with the potential to induce antitumor immunity.
In this pre-clinical study, Squamous Cell Carcinoma ("SCC") tumor-bearing mice were treated with Alpha DaRT in combination with an anti-PD1 therapy ("aPD-1"). This group was compared to groups of mice treated with either Alpha DaRT or aPD-1 as a monotherapy, as well as to a control group. The efficacy of the treatment was evaluated over time, and the immune level of activation was analyzed through immunophenotyping and immunohistochemical staining sixteen days after Alpha DaRT source insertion.
The group treated with Alpha DaRT in combination with aPD-1 demonstrated delayed tumor development, higher T-effector cell infiltration with enhanced cytotoxic potential, and reduced systemic Myeloid-Derived Suppressor Cells ("MDSCs") than either monotherapy alone. Gene expression and gene set enrichment analysis of mRNA levels seven days after Alpha DaRT insertion indicated that Alpha DaRT upregulated indicators of cell death, interferon signaling and myeloid related transcription, while downregulating indicators of DNA repair and cell proliferation. Moreover, immunophenotyping analysis at this timepoint showed that Alpha DaRT induced dendritic cell activation and affected the distribution of MDSC populations. Altogether, those findings demonstrated that the Alpha DaRT may offer tumor cell destruction via additional pathways beyond the immediate local impact of generating double-strand DNA breaks in tumor cells.
This study’s authors conclude that Alpha DaRT can promote a "hot" tumor microenvironment and changes in immune suppression that lead to a potentiation of aPD-1 blockade-induced effector T-cell function and improved treatment efficacy. The authors observe that this study provides a rationale for investigating the combination of Alpha DaRT and aPD-1 clinically in SCC patients.
The second study, accepted for publication by Frontiers in Oncology in its Radiation Oncology section, examines the use of Alpha DaRT in treating human glioblastoma multiforme ("GBM") xenografts, together with Temozolomide ("TMZ"), a standard-of-care chemotherapy, or Bevacizumab, a standard-of-care antiangiogenic therapy, both commonly used in treating GBM.
The results demonstrated that the combination of alpha radiation with TMZ doubled the cytotoxic effect of each of the treatments alone, and the surviving fraction of cancer cells treated by TMZ in combination with alpha irradiation was lower than alpha- or x-ray irradiation as monotherapies, or than by x-ray combined with TMZ. In addition, the treatment of GBM-bearing mice with Alpha DaRT and TMZ delayed tumor development more efficiently than the monotherapies. The studies further confirmed that, unlike other radiation types, alpha radiation did not increase the secretion of VEGF, a potent angiogenic factor that promotes tumor growth.
With respect to the combination of Alpha DaRT with anti-angiogenic therapy, Bevacizumab treatment introduced several days after Alpha DaRT implantation improved tumor control, compared to Bevacizumab or Alpha DaRT as monotherapies. The combination was also shown to be superior when starting Bevacizumab administration prior to Alpha DaRT implantation in large tumors relative to the size of the Alpha DaRT source. Bevacizumab induced a decrease in the endothelial cell marker CD31 staining in conjunction with the Alpha DaRT treatment, and increased the diffusive spread of Radium-224 daughter atoms in the tumor tissue, while decreasing their clearance from the tumor through the blood.
About Alpha DaRT
Alpha DaRT (Diffusing Alpha-emitters Radiation Therapy) is designed to enable highly potent and conformal alpha-irradiation of solid tumors by intratumoral delivery of radium-224 impregnated sources. When the radium decays, its short-lived daughters are released from the sources and disperse while emitting high-energy alpha particles with the goal of destroying the tumor. Since the alpha-emitting atoms diffuse only a short distance, Alpha DaRT aims to mainly affect the tumor, and to spare the healthy tissue around it.