A new chimeric antigen receptor (CAR) T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has been approved for a phase 1 clinical trial in relapsed/refractory multiple myeloma. The allogeneic therapy, CYAD-211 from Celyad Oncology, is unique insofar that it uses short-hairpin RNA (shRNA) editing to knock down the CD3 zeta component of the T-cell receptor (TCR). It is a first-in-class CAR-T candidate, meaning it would represent the first CAR-T therapy that uses this gene-editing approach.

“We are the fourth allogeneic CAR T-cell therapy targeting BCMA. It is a very competitive landscape, which includes autologous T cells, Bispecific T-cell engagers and antibody-drug conjugates,” said Filippo Petti, chief executive officer of Celyad Oncology.

Celyad worked with Dharmacon, a Horizon Discovery Group company, to design their shRNA vectors, an approach that they hope will provide several advantages in creating an allogeneic, off-the-shelf approach.

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“We wanted to do the trial with a clinically validated target for the first half-dozen patients to check safety — we want to achieve well-established technology we can build on and we need to figure out how our technology translates into the clinic,” said Mr Petti.

“The shRNA is in the same vector as the CAR and the positive selection marker. We are then able to enrich the population for the positive selection marker – it means the CAR and the shRNA are both there, it’s a one step process, it’s a modular approach to how we think about CAR T-cells,” said Petti.

Petti claims that this approach can provide benefits for quicker manufacturing, production, efficiency, and potentially, persistence of the therapy.

“Every time you have to deplete the cells that are TCR positive, you don’t want them kicking around — the less manipulation and depletion steps you have, you maintain a larger population of these cells, resulting in cost reduction and more efficiency,” said Petti.

There are several barriers to autologous T-cell therapies including cost, long manufacturing time, and the additional consideration that many patients with relapsed disease tend to have — being that they have likely been treated previously with several lines of immunosuppressive therapies, which can affect their T cells.

“This is an allogeneic approach, which means that the CAR T cells will be generated from donor-derived T cells,” said Djordje Atanackovic, MD, medical oncologist and scientific director of the Multiple Myeloma Program and codirector of cancer immunotherapy at Huntsman Cancer Institute/University of Utah. “This potentially carries the advantage that they can use T cells that are ‘fitter’ than the ones collected from patients after multiple rounds of chemotherapy,” he added.

“Most of the CAR T-cell therapies for myeloma right now are autologous,” said said Deepu Madduri, MD, medical oncologist and assistant professor of medicine for The Tisch Cancer Institute at Mount Sinai Hospital in New York. “We don’t really have that many processes; we do need some more allogeneic CAR T cells off the shelf, as it takes 5-6 weeks manufacturing for autologous,” she added.

For CYAD-211, the company is depleting the CD3 zeta component of the native TCR, but the shRNA approach means that this may be a significant reduction in expression, rather than complete ablation of the gene using CRISPR-Cas9, or other similar editing techniques.