On June 25, 2019 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium") reported at SNMMI or the 2019 Society of Nuclear Medicine and Molecular Imaging Annual Meeting that effective lymphodepletion with the radioisotope Lu-177 or lutetium-177 was achieved with its ACT or Adoptive Cell Therapy program for achieving safe, effective and transient lymphodepletion prior to the administration of CAR-T and other adoptive cell therapies (Press release, Actinium Pharmaceuticals, JUN 25, 2019, View Source [SID1234537249]). The ARC’s or Antibody Radiation-Conjugates used in the ACT program combines a CD45 targeting antibody with the cell killing power of radioisotopes.
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Lymphodepletion is an important step prior to CAR-T and adoptive cell therapies that facilitates infused cells to engraft, expand and persist. Currently, chemotherapy such as Flu/Cy or Fludarabine and Cyclophosphamide are used in standard practice for lymphodepletion. Patients receiving CAR-T and other adoptive cell therapies are often heavily pre-treated and their cancer is refractory or resistant to chemotherapy. Actinium is developing its ACT program to be a potential replacement of non-specific, chemotherapy-based lymphodepletion.
In vivo animal studies demonstrated that a Lu-177 labeled CD45 ARC transiently depleted CD45 positive immune cells while sparing platelets, red blood cells and bone marrow cells. A dose response was observed with 40µCi Lu-177 having a greater lymphodepletion effect on immune cells — including B-cells, CD8 and CD4 T-cells, NK cells, myeloid derived suppressor cells and regulatory T-cells — than 20µCi Lu-177. In tumor bearing mice, the Lu-177 labeled CD45 ARC was given prior to adoptive cell therapy, which demonstrated enhanced tumor control when compared to mice that were untreated and those that only received adoptive cell therapy with no lymphodepletion (Click here for the SNMMI poster).
Dr. Dale Ludwig, Actinium’s Chief Scientific Officer, said, "I am truly excited by these additional results from our ACT program that we have presented at SNMMI evaluating lutetium-177 for targeted lymphodepletion. The data generated exceeded my expectations and support the continued development of a Lu-177 CD45 ARC as part of our ACT program. As we work to establish collaborations and partnerships while advancing the ACT program into clinical trials, the expansion to multiple warheads will give us flexibility and utility that I trust will be well received. I look forward to highlighting our continued efforts in this area at future medical conferences and industry meetings."
The antigen CD45 is uniquely expressed on leukemia, lymphoma and immune cells making it an ideal target for targeted condition prior to BMT or Bone Marrow Transplant, CAR-T and adoptive cell therapies. Actinium’s Iomab-B and ACT programs utilize the anti-CD45 antibody apamistamab. Apamistamab has been studied in over 300 patients in 13 clinical trials, including the ongoing pivotal Phase 3 SIERRA trial, across multiple hematologic indications including acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, lymphomas and multiple myeloma. The ACT program utilizes a lower dose of the radioisotope I-131 or Iodine-131 than Iomab-B and can now also utilize Lu-177.
Actinium presented initial feasibility data for its ACT program at the Transplantation and Cellular Therapies Meeting in February 2019. The data demonstrated that a CD45 targeting antibody labeled with I-131 effectively depleted greater than 90% of lymphocytes in preclinical animal models (Click here for poster).
Sandesh Seth, Actinium’s Chairman and CEO, said, "I am excited to add the lutetium-177 warhead to our targeted conditioning armamentarium and expand our ACT program beyond iodine-131. Our targeted conditioning ARC’s are demonstrating promising results across our portfolio, including in our pivotal Phase 3 Iomab-B program for BMT and the ACT program for lymphodepletion for CAR-T and adoptive cell therapies. These therapies have the potential to significantly benefit patients and, in some instances, lead to long lasting remissions or even cures. We are confident that our targeted conditioning ARC’s can increase the number of patients that can receive these important therapies and improve patient outcomes. Recognizing the growth potential of this field we are committed to continuing to drive innovation across our ARC portfolio and further strengthening our leadership position in targeted conditioning."