While Natural Killer or NK cell infusions may induce complete remissions in about 30?50% of patients with refractory acute myeloid leukemia or AML when combined with lymphodepleting chemotherapy and interleukin-2 (IL-2),? NK cell therapy is limited by lack of antigen specificity and by IL-2 mediated induction of Tregs, regulatory T cells, formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease.
To overcome the problem, scientists at the?Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, have generated a bispecific killer engager (BiKE) containing single-chain scFv against CD16 and CD33. The purpose was to create a so called immunologic synapse between NK cells and CD33(+) myeloid targets.
In advancing the treatment options, these scientists have now developed a second-generation anti-CD16-IL-15-anti-CD33 TriKE, a? single-chain, tri-specific NK cell engager (TriKE), which incorporated a novel modified human IL15 crosslinker, producing a novel trispecific killer engager or TriKE to induce expansion, priming, and survival. The scientists believe that this approach will enhance clinical efficacy.
The TriKE platform technology, developed by Jeffrey Miller, Deputy Director of the Masonic Cancer Center, University of Minnesota, and his colleagues at the University of Minnesota, is designed to enhance the activity of Natural Killer (NK) cells. NK cells are a type of white blood cell which are an important component of the innate immune system and play a major role in the rejection of tumor and virally infected cells.
The original anti-CD16-IL-15-anti-CD33 TriKE (OXS-3550; GT Biopharma) utilizes the inclusion of a modified Interleukin-15 (IL-15), a peptide that activates NK cells, while the “engager” further increases NK cancer-cell killing capabilities and improves their function in the tumor microenvironment (Vallera et al, 2016). OXS-3550 is expected to enter human clinical trials in 2018.
In contrast, OXS-C3550, the second-generation anti-CD16-IL-15-anti-CD33 TriKE, utilizes a modified anti-CD16 component while incorporating the wild-type IL-15.
Mode of Action
NK cell cancer-killing activity is expected to be increased by bringing the NK cells in close proximity to the cancer cells. This may be achieved by ‘engagers’ that bind to CD16 on the surface of NK cells and bind specific proteins (such as CD33) on the surface of cancer cells, thus forming an immune synapse between the NK cell and the cancer cell.
The anti-CD16-IL-15-anti-CD33 (OXS-3550) ‘TriKE construct’, which is expected to be in the clinic in the second half of 2018, utilize the inclusion of interleukin-15 (IL-15), a peptide that leads to proliferation and activation of the NK cells. This further increases NK cancer-cell killing capabilities and improves their function in the tumor microenvironment.
The OXS-C3550 TriKE was developed following continued research with the TriKE platform at the University of Minnesota Masonic Cancer Center. As demonstrated in non-clinical models, this targeted immunotherapy directs immune cells to kill cancer cells while diminishing drug-related toxicity.
The TriKE platform technology can be viewed as a protein version of CAR-T. However, unlike traditional CAR-T platforms, it is anticipated that TriKEs could service a much larger part of the cancer population at a fraction of the cost. TriKEs are an antibody platform that could be tailored to treat any form of cancer, liquid or solid tumors.
Unlike traditional CAR-T platforms, TriKEs are potentially a cost effective cell therapy and not relegated to treating liquid tumors only.
Unmet medical needs
OXS-C3550 will focus on acute myeloid leukemia (AML), the most common form of adult leukemia with 43,000 new cases each year. These patients will require frontline therapy, usually chemotherapy including cytarabine,?also known as cytosine arabinoside or ara-C and an anthracycline, a therapy that has not changed in over 40 years. Also, about half of these patients are likely to have relapses and require alternative therapies.
In addition, OXS-C3550 could be used to treat myelodysplastic syndrome (MDS), which has about 20,000 new cases diagnosed each year with minimal current treatment options (Siegel et al, 2014). At a minimum, OXS-3550 is expected to serve as a relatively safe, inexpensive, and easy to use therapy for resistant or relapsing AML. From a biologic standpoint, it could also be combined with chemotherapy as frontline therapy.
“The data on our second-generation TriKE, was presented at annual meeting of the American Society of Hematology (ASH), held in December 2017 in Atlanta, Georgia. I expect that our research will be noticed by [other] investigators in the field and will set the tone for all future discussions on the use of NK cells in the treatment of cancer. We believe the distinctions and potential benefits relative to other immunotherapies, including CAR-T, will become apparent.” explained Raymond Urbanski, Ph.D, Chief Medical Officer at GT Biopharma, a clinical?stage biotechnology, company developing next?generation, targeted immuno?oncology therapies for hematological malignancies, sarcomas and solid tumors.
“In collaboration with the experts from the University of Minnesota Masonic Cancer Center, GT Biopharma continues to advance the search for next generation anti-cancer treatments, especially on novel ways to enhance the cancer-killing capabilities of NK cells,” said Kathleen Clarence-Smith Chief Executive Officer at GT Biopharma.
“In my view, the potential for the success of this immunotherapy approach is substantial and the possibility of extending it to solid tumors gives us even added hope,” she added.
The development team at GT Biopharma believes that TriKEs are an antibody platform that can be tailored to treat any form of cancer, liquid or solid tumors.
Last Editorial Review: March 16, 2018
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