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Fate and Celyad's CAR Therapies Offer Potential to Amplify Efficacy With Multiple Doses

Fate Therapeutics’ (NASDAQ:FATE) and Celyad’s (NASDAQ:CYAD) natural killer (NK) cell biology-focused cell therapies could overcome cell persistence challenges and consequent efficacy concerns with redosing strategies, experts said.

One of Fate’s lead products, FT596, is an allogeneic, multitargeted, chimeric antigen receptor (CAR) NK cell product. Celyad’s autologous CYAD-01 and CYAD-02 and allogeneic CYAD-101 are CAR T cell products using NK cell specificity to target T-cells. One analyst considered the potential to redose allogeneic products as a key item to consider while assessing clinical potential. While clinical data establishing the additive efficacy advantages of giving multiple doses is still preliminary, redosing allogeneic products could increase their expansion and persistence, experts said. Autologous therapies carry source constraints, so the ability to manufacture and administer allogeneic therapies is an advantage, they said.

While past NK cell therapy data has been mixed, experts saw potential in CAR NKs like FT596 or CAR T-cell products engineered to express NKG2D like CYAD-101, given the advancements in cell production.

Phase I FT596 results in B-cell lymphomas/ CLL are expected at either the American Society of Hematology (ASH) meeting in December or an investor meet in early 2021, as per a second analyst report. Phase I data for CYAD-01 and CYAD-02 in relapsed/refractory (r/r) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are expected by YE20, as per the company’s August corporate presentation. Celyad’s allogeneic CYAD-101 is being tested in a Phase I alloSHRINK trial (NCT03692429) in metastatic colorectal cancer (CRC), which has a primary completion date of November 2020.

FT596’s sales are expected to reach USD 136m in 2026, according to a GlobalData Consensus forecast. Celyad did not respond to a request for comment.

Redosing carries potential efficacy advantages

Increasing the persistence of cell therapies once they are infused into a patient has been a challenge, especially with NK cell-based therapies, experts said. The issue of persistence and consequent efficacy is significant because the potential efficacy with Celyad and Fate’s platforms remains largely unknown, they added.

Because the immune system can recognize foreign cells, cell products would not last for more than a few weeks, said Dr Marco Davila, medical oncologist, in the Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, Florida. With CAR T-cell therapies, the expansion and persistence of CAR cells is said to correlate with the durability of response, said Dr David Sallman, assistant member, Department of Malignant Hematology, Moffitt Cancer Center.

Strategies involving multiple doses of cell therapies could maximize the total dose, improve duration, and increase efficacy magnitude with both autologous and allogeneic cell therapies, said Dr Tara Lin, associate professor of medicine, University of Kansas Medical Center, Kansas City. Multiple infusions of a therapy could also potentially lead to a complete remission, said Sallman. In Fate’s Phase I FT500 (NCT03841110) study, patients had been given up to six doses of the therapy, which was not found to be toxic, according to Fate CEO Scott Wolchko. Redosing has the potential to offer multiple infusions as a maintenance therapy, said Dr Jeffrey Miller, professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis.

The persistence of allogeneic therapies is not well understood, and it is unknown how long cells need to persist to be effective or whether persisting cells confer durability of response, said Wolchko. Giving multiple doses is one way to overcome the lack of persistence, if it is an important factor for efficacy, he said. In a 4Q19 call, the FDA said it was allowing the dose to be repeated on a patient-by-patient basis, Wolchko said. In the alloSHRINK study, CYAD-101 is administered three times with a two-week interval between each administration in metastatic CRC, as per

However, even if the engineered cells do not persist in the body, the response rate and ability to eradicate the disease should not be limited, said Davila. With a limited lifespan, allogeneic cell therapies would dissipate as the patient’s immune system recovers, said Dan Kaufman. With the incorporation of interleukin (IL)-12 or IL-15 into the cell product, the cell therapy could persist without exogenous cytokines, said Kaufman. The FT596 construct contains a IL-15 fusion protein.

Strategies involving multiple doses of cell therapies could maximize the total dose, improve duration, and increase efficacy magnitude with both autologous and allogeneic cell therapies

Experts cited the data from a Phase I/II (NCT03056339) investigator-led effort at MD Anderson Cancer Center using cord blood-derived anti-CD19 CAR NK cells as an example of an effective CAR NK therapy. The study by Rezvani and colleagues showed a persistence challenge did not seem to hamper the response, because once a critical threshold for cell expansion is crossed, activity can be mediated, Davila said. Eleven r/r patients with CD19-positive cancers, such as non-Hodgkin’s lymphoma or CLL, were treated with a single infusion; eight had a response, including seven with a complete remission (Rezvani et al. [2020] N Engl J Med, 382, pp. 545–553). Even if the cells do not persist, they expand to sufficient levels to eradicate the disease before they are lost, Davila added.

In the Phase I THINK (NCT03018405) CYAD-01 data, decreased bone marrow blasts were observed in eight patients, including five objective responses and one stable disease for three or more months, as per the company presentation. Responding patients did have blast clearances, but some of the remissions were short-lived and the cells did not persist in the system, said Sallman. However, the short hairpin (sh) ribonucleic acid (RNA) technology employed CYAD-02, which could increase persistence and expansion, said Sallman (Fontaine et al., [2019] Blood, 134[Suppl 1], p. 3931). The shRNA technology allows T cell engineering without the need for gene editing to inhibit alloreactivity and increase persistence, according to Celyad.

Ongoing research on improving preconditioning regimens by combining additional drugs could also help with the persistence of allogeneic products, said Davila. It is not known whether every dose needs a conditioning regimen, but since conditioning regimens can suppress a patient’s immune system for several months, it may not be necessary before every therapy infusion, he added.

Patients will not have to receive a preconditioning regimen before every cell infusion, said Wolchko, adding redosing FT500 was found to be safe. Celyad’s protocol does not specify the preconditioning strategy for redosing. No predictive biomarkers are available to explain why some patients respond well and others do not, said Sallman, adding it is critical to identify potential responders. Nonetheless, there is no way to predict clinical efficacy based only on preclinical data, so data is still needed, said Miller.

Potential advantages over existing autologous CAR T-cell products

The economic advantage to developing off-the-shelf therapies has driven interest in NK-cell based platforms, said Miller and Davila. If a quick treatment is needed, then an allogeneic NK cell therapy would be better than an autologous therapy, which may take up to six weeks to manufacture, said Sallman. While the results with autologous CAR T-cell therapies have been significant, their scale up and costs are challenging, said Kaufman.

The ability to use induced pluripotent stem cell (iPSCs) or cord blood cells as a source would help scale up the cell manufacture and allow effective results, said Kaufman. iPSCs provide an advancement in expansion protocols, which can provide multiple doses, Miller added. Fate has an iPSC-derived NK cell franchise. Also, since T cell therapies require donor apheresis to collect cells in a process lasting four to five hours, it is not feasible to keep going back to the same donor, said Miller.

Moreover, newer platforms are expected to improve on past NK cell therapy trials, specifically those showing mixed efficacy. Past studies had feasibility limitations in getting the required number of cells, said Miller. Those small studies were conducted at a time when cell isolation and production systems were not as advanced as they are now, said Davila.

November 2, 2020

Manasi Vaidya

Reporter, New York

Manasi Vaidya has a Masters degree in biotechnology. After a stint in a research lab, she spent two years as correspondent in India for BioSpectrum, a publication focused on the Asian biotechnology industry. She then moved to the United States to pursue a Masters degree in Science, Health and Environmental Reporting at New York University. Manasi has reported primarily on topics that combine health and policy, and her work has appeared in Nature Medicine, Nautilus and Scienceline. Her coverage at BioPharm Insight focuses on cancer.


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