Celyad's High Hopes for a Path Forward in Cancer Immunotherapy with CYAD-211

Cancer immunotherapy

Celyad Oncology is at the forefront of cutting-edge immunotherapy and is hopeful of providing a new way forward for patients with relapsed/refractory multiple myeloma. After receiving FDA approval on July 14th to begin Phase I trials, they plan to be in the clinic with their first patient the end of 2020.

The Belgian clinical-stage biotechnology company is focused on the discovery and development of chimeric antigen receptor T cell (CAR-T) therapies for cancer. Celyad Oncology is also developing CYAD-101, an investigational non-gene edited, allogeneic NKG2D-based CAR-T therapy for metastatic colorectal cancer.  

The two primary types of cell therapy are autologous and allogeneic.  Autologous CAR-T therapy uses the transplantation and genetic editing of a patient’s own immune cells in a single batch, while an allogeneic transplant uses immune cells from a donor manufactured in large batches. Celyad Oncology is only the fourth company to proceed to Phase I with an allogeneic CAR-T working against a target known as B-cell maturation antigen (BCMA), which is highly expressed in multiple myeloma patients.

The Phase I objectives for CYAD-211 are to establish the viability, effectiveness and further possibilities opened up by the shRNA-based technology. Along with analyzing the merits of targeting BCMA with a CAR-T, Celyad Oncology Chief Executive Officer Filippo Petti shared that the company’s first priority is to prove the premise that ShRNA bears out for allogeneic CAR-T.

The first level is to get into the clinic and evaluate the question, is shRNA a novel, non-gene edited allogeneic approach to CAR-T? Where the majority of our peers in the space work on genome using the gene editing technology, if we can show that another non-gene editing technology like ShRNA works, it would just open up the whole field in terms of allogeneic CAR-T. It would demonstrate that we have an unencumbered asset and technology platform for us to create next-generation CAR-T candidates with,” Petti said. “We’ll know very quickly, within the first few patients, if we are seeing an absence of graft-versus-host disease, and if ShRNA carries its weight in terms of being an allogeneic technology.”

He expects to have a sense of how competitive the data is in terms of both safety and clinical efficacy by end of year 2021.

Dr. Laurence Cooper, Chief Executive Officer (CEO) of Ziopharm Oncology, who is also a veteran innovator in pairing genetic engineering with immunotherapies, explained that Graft-versus-Host Disease (GvHD) is one of biggest challenges facing companies who take the allogeneic approach.

“When you put in third party cells, those cells get really confused right off the bat because now they’re somewhere new, and all of a sudden they perceive the patient as the threat. This can result in Graft-versus-Host Disease, an autoimmune disease triggered by the native biology in the T cell through its T cell receptor,” Cooper said. “The engineering that you’re talking about is to eliminate that threat. Some cut out the genetic material coding for the endogenous T cell receptor so that now a T cell can go into another person, and it can’t perceive the threat anymore because its lost its antennae.  Another way is to prevent expression of the T cell receptor.  Now the T cell can do something useful if you put in a CAR, it can go off and target…BCMA.”

Frédéric F. Lehmann, Head of the Oncology Franchise at Celyad Oncology, explained how the shRNA-based therapy is engineered to reign in the cell’s new rampant disregard for threat, and lessen the chances of an autoimmune response.

“One of the innovations for CYAD-211 is incorporating in the vector a short hairpin RNA (shRNA) targeting the CD3ζ subunit of the T cell Receptor (TCR). This effectively downregulates the surface expression of the TCR thereby inhibiting the signaling that would lead to Graft-versus-Host Disease,” Lehmann said.

A notable drawback with the autologous approach to CAR-T therapy is that it is costly and time-consuming. Petti explained how CYAD-211 not only has the potential to improve efficacy, but also make the treatment process more scalable and therefore economically expedient.

“When it comes to commercialization, because we use an all-in-one-vector approach, we benefit from less manipulations during manufacturing, allowing us to enrich for the engineered cells we want, which eventually could help during potential commercialization of a product that’s streamlined,” Petti said.

He added that the all-in-one vector approach increases efficiency because, as opposed to the case with the gene editing process, they are able to accomplish everything in a single step. 

Long term, Cooper is excited about the possibility that, whether autologous or allogeneic, immunotherapy may one day replace bone marrow transplants, or even chemotherapy, but emphasized that it must be made accessible.

“If these immunotherapies can be advanced really to replace chemotherapy, not to replace transplantation for liquid tumors, but to replace chemotherapy, which is a huge goal – if you can get it to do that, you have to bring the costs down to make it available for the masses, inside first world economies as well as less privileged societies,” Cooper said.

In 2013, the overall five-year survival rate for multiple myeloma stood at 49.6%. Relapsed/refractory patients for whom currently available treatments have failed, are the intended beneficiaries of much of the biotechnology work being done in this area.  And impressive steps have recently been made.

GlaxoSmithKline’s BLENREP (Belantamab Mafodotin) is the first in its class to work against BCMA, while Janssen Biotech’s (Johnson & Johnson) DARZALEX (Daratumumab) is the first human Anti-CD38 monoclonal antibody in the space.  After their 2019 acquisition of Celgene Corp., Bristol-Myers Squibb gained Revlimid (Lenalidomide), a hematology drug approved for multiple myeloma, and Amgen and Takeda have popular proteasome inhibitors on the market.

With Celyad Oncology moving the needle forward once again, the future looks a little brighter for multiple myeloma patients.

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