Chimeric antigen receptor T-cell therapy developer Celyad says it expects to make some go-or-no-go decisions about its lead CAR-T candidates now in Phase I/II trials, based on data readouts expected by year’s end.
The strength of that data will determine whether Celyad can advance its trials into Phase II studies—as well as whether the Belgian biotech expands to a second outpost on the other side of the Atlantic, the company’s recently-appointed CEO Filippo Petti told GEN.
Celyad plans to release proof-of-concept clinical data by year’s end on its lead clinical candidates—the autologous NKG2D-based CAR-T therapy CYAD-01, indicated for acute myeloid leukemia (AML) and metastatic colorectal cancer (mCRC); and the non-gene edited allogeneic NKG2D-based CAR-T therapy CYAD-101, an “off-the-shelf” candidate indicated for mCRC.
“We do think there’s a broad applicability to NKG2D, really a pipeline in a program. It’s really for us to spend the foreseeable future near-term to identify what the blueprint is for both of those, and allow us to push further into additional indications,” Petti said in an interview during the recent 2019 Biotechnology Innovation Organization (BIO) International Convention, held in Philadelphia at the Pennsylvania Convention Center.
“I don’t think we stop with AML or colorectal cancer with NKG2D. I think it’s just the tip of the iceberg, but we do want to make sure we understand exactly what we have in our hands, and how do we best optimize that,” Petti said.
Celyad isn’t the only drug developer focused on NKG2D, but its programs are in clinical phases, a competitive edge the company hopes to maintain. One competitor, Nkarta Therapeutics, reported positive preclinical results in November 2018 showing dramatic tumor shrinkage and complete suppression of the tumor for over two months following a single injection of Nkarta’s NK cells in a xenograft osteosarcoma model.
Recognizing, targeting ligands
Celyad’s CAR-T approach is designed to use the full human NKG2D receptor to recognize the tumor—a receptor that plays a key role in protecting the host from infections and cancer.
CYAD-01 consists of autologous T cells transduced with a CAR based on the NKG2D receptor, designed to recognize and target ligands expressed in up to 80% of all cancers including both hematologic and solid tumors. The receptor consists of the full-length native human NKG2D gene fused with the cytoplasmic signaling domain of native human CD3ζ, intended to allow NKG2D to function as a primary receptor in T cells.
CYAD-101 is designed to overcome a limitation of allogeneic T-cell therapies, the potential to induce life-threatening graft versus host disease (GvHD), triggered by the recognition of foreign human leukocyte antigen (HLA) molecules expressed on the patient’s cells by the T-cell Receptor (TCR) of the lymphocytes of the donor.
To avoid GvHD, Celyad inhibits TCR signaling using a non-gene-editing technology, and co-expresses a NKG2D-based CAR with a TCR inhibitory molecule (TIM), consisting of a truncated form of CD3ζ. According to Celyad, the CAR composed of the Immunoreceptor Tyrosine-based Activation Motif (ITAM)-bearing signaling cytoplasmic domain of human CD3ζ, fused with the full-length NKG2D, allows signaling upon binding to NKG2D ligands expressed on tumor cells, triggering cancer cell killing—while the TIM-incorporated TCR complex lacks the majority of ITAMs, thus lowering the TCR complex’s ability to signal and potentially avoid alloreactivity.
CYAD-101 uses one of two tech platforms Celyad is applying for its allogeneic CAR-T treatments. The other is the small hairpin RNA (shRNA) technology developed by Horizon Discovery Group, which Celyad is using under an exclusive license agreement announced in October 2018. Celyad is using Horizon Discovery’s SMARTvector technology to express shRNA optimized by Celyad, as an alternate method to knockdown the TCR complex in allogeneic CAR-T therapies.
Using shRNA, Celyad has developed a next-generation autologous, NKG2D-based CAR-T candidate, CYAD-02, and a novel, non-gene edited allogeneic CYAD-200 series of CAR-T candidates.
By using shRNA, the 200 series aims to fight cancer through a more efficient single-vector approach, with early preclinical tests showing potential best-in-class persistence of the immune cells and reduced GvHD, according to Celyad—even when compared with CRISPR-Cas9 gene-editing approaches.
IND planned for 1H 2020
Celyad plans to generate additional preclinical proof-of-concept data for CYAD-02 this year, with plans to submit an Investigational New Drug (IND) application for CYAD-02 in the first half of 2020.
“We take a modular plug-and-play approach to designing our CAR-Ts,” Petti said. “This is the plug-and-play dynamic: What receptor do you want to use in the CAR? What additional allo technology do you want to use in the CAR? And then maybe, what additional technology? There’s additional bells and whistles that we’re looking at, that we can help to enrich the T cell, arm the T cell, allow it to tumor infiltrate, allow it to engage a bit more, to drive additional clinical activity.”
Petti became Celyad’s CEO effective April 1, succeeding Christian Homsy, MD, MBA, who was the company’s founding chief executive since the company’s inception in 2007. Homsy continues as a member of Celyad’s Board of Directors and as chair of the Board’s Strategy Committee. A onetime research scientist at OSI Pharmaceuticals, acquired by Astellas Pharma in 2010, Petti joined Celyad in 2018 as CFO, after holding healthcare investment banking positions at Wells Fargo Securities, and before that at William Blair & Company.
Petti told GEN that Celyad will continue focusing its efforts on R&D primarily in Belgium, where the company is headquartered in Mont-Saint-Guibert, about 30 minutes south of Brussels—where all but a handful of Celyad’s 105 employees are based.
“We’ll look to certainly take the opportunity, with me having come in as CEO, to maybe expand our footprint in the United States,” said Petti, who is based in New York. “We will look to maybe leverage that, to see if we can build a presence in, maybe on the East Coast where we can bring some additional leadership team members there, and think about our next steps.”
Among operations that could be in the U.S., Petti said, are some additional manufacturing: “For us to really be successful, we continue to think that we need to be on both sides of the Atlantic.”