Celyad: CAR-T cells with natural killer skills fight cancer

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Celyad, based in Mont-Saint-Guibert (Belgium), was originally established in 2004 as a company active in regenerative cell therapy. However, two years ago, Celyad decided to move into immuno-oncology. The company has licensed technology from Dartmouth College in the US that is based on CAR T cells expressing an NK cell receptor. A phase I clinical trial to evaluate the safety of this treatment started in January 2017.

Celyad’s CAR T cells in a nutshell

T cells eliminate infected cells and cells under stress, but they also have a central role in targeting cancer. The difficulty for T cells when  fighting cancers is that tumor cells develop many systems to avoid the immune response. Celyad is now engineering these T cells by introducing a gene that encodes a cell surface receptor that enhances the capability of T cells to recognize tumor target proteins. More specifically, the first receptor Celyad is working with is the NK cell receptor NKG2D. NKG2D recognizes up to eight different ligands, of which at least one is expressed on 80% of tumors, including hematological as well as solid tumors.

The NKG2D receptor is expressed in fusion with a T cell receptor activating domain called CD3ζ. When NKG2D binds the target ligand, the T cell becomes operational because of the fusion with CD3ζ that drives activation. These cells are referred to as NKR-2 CAR T cells (in brief, NKR-2 T cells).

Overexpression of NKG2D is preferred in T cells rather than NK cells because NK cells possess a great deal of inhibitory receptors, making it more difficult to trigger them against individual targets. Additionally, the methods to isolate T cells from a patient’s blood and multiply them to large numbers before reinfusion are well described, while clinical manipulation of NK cells remains challenging.

THINK without chemotherapy

When Celyad licensed the NKR-2 technology, a small clinical trial was being carried out at the Dana-Farber Cancer Institute in Boston. David Gilham, Vice President of R&D at Celyad, says: “Twelve patients have been treated with a very low dose of cells, starting from 1 million and going up to 30 million NKR-2 T cells. There was no evidence of toxicity, no cytokine release syndrome or anything else adverse due to the NKR-2 T cells. The trial also gave us some indications about the potential clinical activity. Actually, one acute myeloid leukemia (AML) patient treated at the highest dose 7 months ago had his blood parameters normalized with no subsequent therapy.”

This pilot study led to a trial that Celyad is completely sponsoring and initiating, called Therapeutic Immunotherapy Using NKR-2 T cells (THINK). This is a multinational trial, involving three centers in Belgium and three centers in the US, and it is planned to treat around 100 patients across seven different cancer indications.

A major difference concerning this trial compared to most CAR T cell trials is that patients do not undergo preconditioning with toxic chemotherapy.

Gilham explains: “The reasons to use preconditioning chemotherapy prior to receiving cell therapy are numerous. It creates space for the T cells so that they can expand when they get into the patient and can generate as many T cells possible to target the tumors. However, in our trial, chemotherapy might reduce the activity of the NKR-2 T cells because they not only have a direct antitumor effect but also might induce other aspects of the immune system. Because our patients do not receive chemotherapy, they also don’t have to be hospitalized for an extensive period during the treatment, which is a great advantage for the patients.”

The trial is split into two arms, one treating hematological tumors (i.e., AML and multiple myeloma) and the other solid tumors (more specifically pancreatic, ovarian, bladder, colorectal, and triple- negative breast cancer). The patients will be treated in a dose escalation manner. A first cohort of patients receives 300 million cells per dose, with each dose administered three times, 2 weeks apart. Then, the same is done for 1 billion, and 3 billion cells per dose. When the maximum tolerated dose is established, it will be tested against the different types of tumors. “This phase I trial is so extensive because of the broad targeting capacity of NKG2D. The main readout is safety, but we’re hoping to see some suggestions and observations concerning the activity, giving us directions to go into a further clinical testing. Initial exploratory results are expected in Q4 2017,”adds Gilham.

Monopoly on NK receptors

When asked about the competitors in the field, Gilham is not worried: “Other companies that work in the CAR T cell field, such as Novartis and Kite Pharma, target CD19 or B cell specific malignancies. We are working in non–B cell hematologic and solid tumors, where there are a limited number of early competitive trials at the time being, using targets which are present in a more limited number of cancer types. But there is an increasing level of academic and early commercial activity in the area. However, there are no other companies that are directly exploiting NK receptors in a CAR T cell format as far as we are aware, so I think we can say with some certainty that we are the world leaders in this specific area.”

There is great excitement and enthusiasm in immuno-oncology, with new and established companies entering the field. Gilham replies: “For Celyad, we clearly hope to eventually show strong clinical responses with NKR-2. Ideally, of course, we hope this will be seen at a stage that will allow us to discuss with the regulatory authorities optimal routes toward a licensed product that we hope will offer a major benefit for patients with advanced cancer. In this field, CD19 CAR T cell therapy sets the benchmark with the possibility of getting an effective product to the market in 1 to 2 years, and we truly hope that NKR-2 will be the first such impactful product that is able to target hematological and solid cancers.”

This article appears in the BioVox White Paper on Immunotherapy, May 2017. Download the complete work here for free.