by Manasi Vaidya in New York.

Fate TherapeuticsandCelyadsnatural killer (NK) cell biology-focused cell therapies could overcome cell persistence challenges and consequent efficacy concerns with redosing strategies, experts said.

One of Fate Therapeutics lead products, FT596, is an allogeneic, multitargeted, chimeric antigen receptor (CAR) NK cell product. Celyads 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 meeting 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 leukaemia (AML) and myelodysplastic syndrome (MDS) are expected by YE20, as per the companys August corporate presentation. Celyads 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.

FT596s sales are expected to reach $136m in 2026, according to a GlobalData Consensus forecast. Celyad did not respond to a request for comment.

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 Therapeutics platforms remains largely unknown, they added.

Because the immune system can recognise 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 are 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 maximise 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 therapy could also potentially lead to complete remission, said Sallman. In Fate Therapeutics 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 Therapeutics CEO Scott Wolchko. Redosing has the potential to offer multiple infusions as 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 ClinicalTrials.gov.

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 patients 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 an IL-15 fusion protein.

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, the activity can be mediated, Davila said. Eleven r/r patients with CD19-positive cancers, such as non-Hodgkins 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. 545553). 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). 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 patients 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. Celyads 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.

The economic advantage to developing off-the-shelf therapies has driven interest in NK-cell based platforms, said Miller and Davila. If 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.

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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 advancement in expansion protocols, which can provide multiple doses, Miller added. Fate Therapeutics 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.

Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalDatas investigative journalism team. A version of this article originally appeared on the Insights module of GlobalDatas Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.

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