Bob Valamehr, PhD, discusses the process by which a targeted CAR natural-killer cell product is engineered as well as how it will be examined in future research efforts.
Bob Valamehr, PhD
FT596, a first-of-its-kind targeted CAR natural-killer (NK) cell product that has been engineered for the treatment of patients with B-cell malignancies, utilizes the intrinsic versatility of NK cells to enable an effective combination therapy in a single, standardized, scalable, off-the-shelf platform, according to Bob Valamehr, PhD, and it has been shown to be safe and well tolerated.
"NK cells are multifaceted. They have the unique ability to do many things," said Valameher. "They can sense healthy cells and leave them alone and, in the body, they are the frontline of immune defense. As such, when a cell becomes infected or transformed, NK cells are the first soldiers that come in and attack those changed cells in the body. We wanted to take advantage of that, but they do not have the persistence that T cells have."
FT596 is a NK cell product that has 3 modalities: CD19-targeting CAR to target B-cell malignancies, an enhanced functioning high-affinity, non-cleavable CD16 (hnCD16) to allow for it to be combined with monoclonal antibodies that target B-cell malignancies, and a recombinant fusion of IL-15 and IL-15 receptor alpha (IL-15RF), which helps it to overcome the lack of persistence of NK cells, said Valamehr.
To design the CD19-targeted CAR, investigators had to exploit the intrinsic multifunctionality of NK cells. Chimerization of an anti-CD19 single-chain variable fragment onto a NKG2D-2B4-CD3ζ signaling platform led to in vitro recognition of CD19-positive B-cell lymphoma cells in both short- and long-term NK cytotoxicity assays (>80% and <40% clearance of tumor cells at 60H, P <.001 respectively).1
Investigators further enhanced the functionality of the CD19-targeted CAR by pairing it with autonomous IL-15 signaling. The introduction of IL-15RF allowed for the expansion of induced pluripotent stem cell—derived NK (iNK) cells; this also improved the persistence of these cells in vitro and in animal models. iNK cells modified with CD19-targeted CAR and IL-15RF led to enhanced CAR functionality in vitro. Furthermore, when used in mouse models of B-cell malignancy, the iNK cells modified with both CD19-targeted CAR and IL-15RF were shown to have a curative effect against B-cell lymphoma (P <.002) compared with iNK cells alone or those modified with CD19-targeted CAR alone.
When iNK cells modified with CD19-targeted CAR and IL-15RF were also combined with hnCD16, the cells were found to have dual-specificity when paired with monoclonal antibodies. When targeting CD19-negative and CD20-positive B lymphoblast target cells and used in combination with rituximab (Rituxan), only FT596 eliminated the CD19 antigen escaped target cell (64% vs 30% clearance of tumor cells at 36H vs rituximab alone).
Investigators concluded that these studies of FT596 support the rationale for a first-of-kind phase 1 study, which will examine the product as both a monotherapy and in combination with CD20-targeted monoclonal antibodies, including rituximab, in patients with relapsed/refractory B-cell lymphoma and leukemia.
In an interview with OncLive, Valameher, chief development officer at Fate Therapeutics, discussed the process by which these NK cells are engineered as well as how they will be examined in future research efforts.
OncLive: What was the rationale for utilizing FT596?
Valamehr: CAR T-cell therapy has revolutionized the way we think about cancer treatment. However, to make a pharmaceutical drug product or adoptive cell therapy is very challenging. [With regard to] patient procurement, the cells are sometimes compromised and there is a complex logistical operation around [them]. We tried to overcome all that at Fate Therapeutics by creating a master cell bank, which can be accessed at a time of need for inventory purposes. We wanted to create a large bank of drug products that can be delivered just like aspirin is today—off-the-shelf—so that it is available at a time of need.
The other component is that when you engineer a population of cells, you can get heterogeneity. Some cells are engineered and some are not; those that are engineered are not always the same or pristine, so you need to ensure you characterize all of that, as well. By starting a massive cell bank that was derived from a single cell, you have full characterization ability to do precise engineering and then you’re able to access that every time you need to rebuild your inventory. This overcomes many of the challenges that are faced today in the current manufacturing and development process of adoptive cell therapies.
How is the FT596 NK cell engineered and used?
We wanted to engineer many things into the NK cells to arm them so that they are specialized. We added components that made them more persistent, more attractive to be combined with monoclonal antibody therapy, and a chimeric antigen receptor to go at the heart of the targeting of the cancer cells. To this end, we created 1 [NK] cell with many components.
NK cells naturally do not like to be genetically edited; they have an evolutionary way of killing themselves if they get foreign transgenes [integrated] into them. In being a part of the first line of defense, they do not want to be manipulated. As such, this clever way allows us to put a lot of things into the NK cells to make them the best cells for cancer immunotherapy and then be able to deliver those cells to the patient.
What data did you present at the 2019 ASH Annual Meeting?
We have many programs; some [products] are in clinical trials and some are in preclinical development. What I mentioned previously was the NK cell that has 3 modalities: CAR19 to target B-cell malignancies, a CD16 to be combined with monoclonal antibodies that target B-cell malignancies, and recombinant fusion of IL-15 and IL-15RF, which overcomes the lack of persistence of NK cells. That, combined with the off-the-shelf perspective of being able to deliver a homogeneous product at a time of patient need in a cost-effective manner, was the global overview of what the presentation was about.
What are the implications of this research?
What this suggests is that you can take adoptive cell therapy and convert it into a pharmaceutical drug product, and that's very exciting to see. It also suggests that you can engineer NK cells to be better. Finally, you can now have multiple antitumor modalities on 1 cell to overcome the heterogeneity or the evolution that the cancer cell goes through. You are not just attacking the cancer cell with CAR-19; you also have the antibodies that you can combine to overcome antigen escape or the heterogeneity in cancer that we see often.
What are the next steps?
We have developed the product; hundreds of doses have been created. It is the third product in our pipeline of IND-cleared products. Our first 2 products are in patients; they have shown to be safe and well-tolerated because we multidose. Just like how you would take aspirin every 4 hours to get rid of your headache, we are approaching that concept where you take this product every single period, every single cycle, to overcome the cancer. As such, this is the third of a pipeline of activities that we hope to bring to patients over the next few years.
Goodridge JP, Mahmood S, Zhu H, et al. FT596: Translation of first-of-kind multi-antigen targeted off-the-shelf CAR-NK cell with engineered persistence for the treatment of B cell malignancies. Blood. 2019;134(suppl 1):301. doi:10.1182/blood-2019-12319