Natural Killer Cell Therapy Well Tolerated in Solid Tumors
Thorsten Graef, MD, PhD, chief medical officer, Acepodia, discussed data on ACE1702 presented at ESMO 2021.
Thorsten Graef, MD, PhD, chief medical officer, Acepodia
Acepodia presented positive data on their lead program, ACE1702, an allogeneic, amplified natural killer (NK) cell therapy for HER2-positive solid tumors, at the European Society of Medical Oncology (ESMO) 2021 Virtual Congress, September 16-21, 2021.
The investigative therapy is being evaluated in a phase 1 study (NCT04319757). Initial data from the study have shown efficacy and safety in 8 patients dosed so far, with no signs of dose limiting toxicities (DLTs), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (IECNS) or graft versus host disease (GvHD).
GeneTherapyLive spoke with Thorsten Graef, MD, PhD, chief medical officer, Acepodia, to learn more about the initial data on ACE1702. He discussed next steps for the therapy and compared it to other NK cell therapies.
GeneTherapyLive: How does ACE1702 compare to other investigational NK cell therapies?
Thorsten Graef, MD, PhD: ACE1702 is an off-the-shelf NK cell product which combines Acepodia’s proprietary NK cells with a clinically validated anti-HER2 antibody employed in multiple approved therapies. ACE1702 is currently in a Phase 1 dose-escalation study evaluating the safety and tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with advanced or metastatic HER2-expressing solid tumors. The study aims to dose up to 15 billion cells per cycle and once a recommended dose has been established, we plan to treat additional patients to further characterize the compound.
The interim results at ESMO show that repeat dosing of ACE1702 was safe and well-tolerated across the first four dose levels, comprising 9 billion cells per cycle at dose level four. No clinical signs of dose limiting toxicity (DLT), such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (IECNS) or graft versus host disease (GvHD) have been reported so far. These initial data were presented based on eight subjects who received escalating doses of ACE1702 in the range of 0.3 to 9 billion cells per cycle (DL1 and DL4, respectively) over the course of 14 days following a standard low dose lymphodepletion regimen. Enrolled patients have HER2-expressing tumors with an immunohistochemistry score of 2+ or higher and may or may not have received prior treatment with a HER2-specific targeted therapy.
The key differentiator between ACE1702 and other NK-based cell therapies is that our Antibody-Cell Conjugation (ACC) technology allows us to armor NK, or other cell types which have been optimized to express a pattern of activating receptors, directly with tumor targeting mABs. The combination of immune cells optimized for attacking the tumor, which are also armored with a specific tumor targeting antibody, allow the cells to easily identify their targets. This means that we are not introducing any genetic modifications, so there is no risk of genotoxicity and does not require the company to follow patients for over 10 years. We also increasing 10-fold the number of tumor-targeting antibodies per cell compared to technologies using genetic modification to insert chimeric antigen receptors (CAR). This enables Acepodia to develop antibody cell effector (ACE) therapies that can also help activate the entire immune system to fight a tumor, which provides for an enhanced immune response compared to current NK cell therapies. Theoretically, this could make therapeutics utilizing ACC safer, easier to manufacture and more accessible.
What advantages does ACE1702 offer in this space in terms of manufacturing and accessibility?
Acepodia is working to develop and manufacture first-in-class cell therapies that address the significant limitations of today’s cell therapies and is leading the way to advance and realize the full potential of this promising treatment area. Acepodia utilizes a simple and scalable manufacturing process to develop its therapies such as ACE1702, in contrast to traditional cell therapies, which can be difficult and complicated to make. Because ACC does not employ genetic engineering, Acepodia’s therapeutic candidates have reduced risk of the genotoxicity associated with other cell therapies and do not have to navigate the manufacturing complexities associated with genetic engineering. Furthermore, the viability and potency of Acepodia’s investigational therapies can be maintained through cryopreservation, allowing for an ‘on the shelf’ product that waits for the patient to arrive at the treatment site.
What are the next steps for ACE1702?
Following the interim Phase 1 results presented at ESMO, the trial will continue to enroll patients with advanced HER2-expressing tumors. Dose escalation is continuing up to 15 billion cells per cycle with updated clinical data to be provided in the first half of 2022.
What other indications are being explored with NK cell therapies?
Acepodia’s unique ACC technology allows us to armor different immune cell types, including but not limited to NK cells, necessary to fight solid and liquid malignancies. In our next clinical program, we will explore the safety and efficacy of gamma delta T cells conjugated to a CD20 mAB for NHL disease, which we are very excited about. In our ongoing preclinical efforts, we are currently evaluating additional targets for solid and liquid tumors, and we are testing different cell types to identify the perfect pair of tumor target and cell type for specific clinical indications. Technologies using gene modifications often take months of preparation; however, our established DNA linker library allows us to develop different candidates quickly using a variety of different mAB and cell types, such as NK cells or other immune effector cells, to identify potential clinical candidates to be optimized for further evaluation.
Transcript edited for clarity.
