Activated Natural Killer cells for cancer immunotherapy and stem cell transplantation.
Prevention of graft rejection and malignant transformation would greatly enhance the safety and applicability of human embryonic (hES) and induced pluripotent (iPS) stem cell derived therapies for a broad range of degenerative diseases including cancer. The first malignancy shown to be propagated by a primitive population of cancer stem cells (CSCs) was acute myeloid leukemia (AML). Despite wide-spread implementation of targeted therapies and allogeneic hematopoietic cell transplantation (HCT), relapse related mortality rates in AML remain high (Sakamaki et al). Thus, recent clinical trials have focused on harnessing the capacity of activated NK cells to eliminate residual CSCs in AML (Rubnitz et al; North et al). In an ongoing Phase l clinical trial, NK cells from haploidentical donors were activated ex vivo with a leukemia cell line (CTV-1) membrane lysate, and infused into patients. To date, 6 AML patients received tumor activated NK (TANK) cell therapy. All have achieved complete remission (CR) for up to a year or more. The most durable CRs were associated with myelosuppression. Durable anti-leukemic responses suggest that TANKs target CSCs and protracted myelosuppression in responders indicates that TANKs may also transiently suppress hematopoietic stem cells (HSCs) and/or mesenchymal stem cells (MSCs). Indeed, research performed by ourselves and others illustrates that human MSCs are highly sensitive to IL-2 activated NK cell cytolysis and are killed more readily than differentiated cells. Notably, MSCs can be protected from NK-mediated lysis by activation of survival signaling through NF-kB and STAT3.
To enhance both the efficiency and safety of hESC or iPSC derived cellular therapies for degenerative diseases including leukemia, we aim to determine if:
1) CNDO102-activated NK cells prevent undifferentiated hESC or iPS cell engraftment and teratoma formation
2) CNDO102-activated NK cells reduce LSC engraftment
3) CNDO102-activated NK cells induced transient host HSC and/or MSC inhibition may be used as a novel, less toxic conditioning regimen to prevent rejection of normal allogeneic HSC and may be modulated by NF-kB activation.
We anticipate that these studies will inform the development of therapeutic strategies that enhance graft tolerance while eliminating malignant stem cells – a facet unique to NK and stem cell biology.
Although much is known about the genetic and epigenetic events involved in CSC production in a Acute Myeloid Leukemia (AML), comparatively little is known about the molecular pathogenesis. An ongoing Phase 1 trial in the UK is testing tumor-activated NK cells (TANKs) immunotherapy in AML patients and Coronado Biosciences, a San Francisco company is planning Phase 2 trials with CNDO102-activated NK cell therapy in AML patients; however, a detailed molecular pathogenetic characterization has been hampered by the paucity of stem and progenitor cells in AML derived blood and marrow samples. Because hESC have robust self-renewal capacity and can provide a potentially limitless source of tissue specific stem and progenitor cells in vitro, they represent an ideal model system for generating human stem cells. Thus, California hESC research harbors tremendous potential for understanding the utilization of NK cell immunotherapy in eradicating cancer stem cells, for example, in AML events that promote self-renewal and leukemic transformation.
CNDO102 activated NK cell mediated elimination of primitive stem cells from hESC and iPSC derived cellular products may obviate malignant transformation driving teratoma formation. Notably, an ongoing Phase 1 AML clinical trial has shown sustained remissions following TANK therapy, suggesting that primitive stem cells may be TANK targets. We will determine if leukemias stem cells (LSC) are susceptible to CNDO102 activated NK cell lysis. Finally, transient aplasia seen in patients receiving TANK therapy suggests that host HSC and/or MSC may be susceptible to TANK-mediated clearance. This may provide an alternative method for opening up stem cell niches and prevent graft rejection. Prevention of graft rejection and malignant transformation would greatly enhance the safety and applicability of stem cell derived therapies for a broad range of degenerative diseases including cancer.
The translational research performed in the context of this grant will not only speed the delivery of innovative NK cell immunotherapy therapies targeting undifferentiated primitive stem cells from hESC and iPSC derived cellular products and cancer stem cells from patients with AML, it will also help to train California’s future R&D workforce in addition to developing leaders in translational medicine. This grant will provide the personnel working on the project with a clear view of the importance of their research to regenerative medicine and cancer therapy and a better perspective on future career opportunities in California. It will also directly generate revenue through development and implementation of innovative therapies aimed at eradicating malignant stem cells that enhance the safety and applicability of stem cell therapies and reduce relapse related mortality in patients with frequently refractory malignancies such as AML.