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ASH 2019: Novel off-the-shelf CAR NK product overcomes CD19 antigen escape in preclinical studies

Preclinical studies provide the first evidence that cellular immunotherapy for B cell cancers could ultimately become an off-the-shelf product, capable of being uniformly manufactured in large quantities as prescription drugs are.

“We have taken the concept of traditional pharmaceutical drug development and applied it to cellular therapy,” said senior author Bob Valamehr, PhD, of Fate Therapeutics, a San Diego biopharmaceutical company.

The product, dubbed FT596, is among the first cellular immunotherapies to be based on off-the-shelf NK cells – the “first line of defence” of the immune system – and is the first cellular immunotherapy to be genetically engineered to contain three active anti-tumour components, according to Dr. Valamehr.

FT596 demonstrated comparable ability to kill cancerous white blood cells as standard CAR T cells and, when combined with the drug rituximab, killed cancerous white blood cells that were no longer responding to standard CAR T-cell therapy due to loss of the CD19 antigen target.

The U.S. Food and Drug Administration (FDA) approved investigational new drug application for FT596 in September and there are plans to begin a first-in-human phase I clinical trial for the treatment of B-cell lymphoma and chronic lymphocytic leukaemia in the first quarter of 2020.

The primary purpose of this trial will be to assess the safety and activity of FT596 in patients.

The process of creating FT596 begins with human induced pluripotent stem cells (iPSCs) that are uniquely capable of unlimited self-renewal and can differentiate into more than 200 types of human cells.

The iPSCs are genetically engineered, after which a single clone (genetically engineered cell) is selected and multiplied in the laboratory to create a master engineered cell line that can be repeatedly used to generate cancer-fighting immune-system cells such as NK and T cells.

NK cells are part of the innate immune system, the body’s first line of defence against infection and disease.

Unlike T cells, which have to be trained to recognise their target and can kill only cells that display that target on their surface, NK cells do not need special preparation before going on the attack and can kill many different types of transformed or infected cells. 

“NK cells are multifaceted and can be viewed as a ‘jack-of-all-trades’ when it comes to protecting the host, whereas T cells can act in only one way,” explained Dr. Valamehr.

But NK cells are unlike T cells in a couple of other ways: They are inherently limited in their capacity to multiply and expand when infused into patients, and they have a shorter lifespan. 

Dr. Valamehr and his colleagues used genetic engineering to address these shortcomings.

In addition to engineering FT596 to carry a CAR targeting the CD19 protein – which is produced by nearly all B-cell lymphomas and leukemias – they inserted two other novel proteins: CD16, which boosts and broadens the NK cells’ ability to kill cancer cells, and IL15, which stimulates FT596 to proliferate and persist. 

FT596 has been designed to address two other limitations of CAR T-cell therapy, said Dr. Valamehr.

  • As an off-the-shelf product, it significantly improves the current patient-by-patient CAR-T treatment paradigm by eliminating the time-consuming and costly process that is currently required to treat a patient with CAR T cells (harvesting the patient’s own T cells, sending those cells to a manufacturing site to be genetically engineered, processing the manufactured product for shipment back to the treating hospital, and finally infusing the CAR T cells into the patient).
  • The addition of the CD16 protein gives FT596 broader therapeutic activity and versatility.

In combination with a drug such as rituximab, FT596 has the potential to lead to deeper and more durable responses and overcome resistance that hampers the long-term efficacy of CAR T-cell therapy.

“Eliminating the high production cost, weeks of manufacturing time, and complex manufacturing process required for CAR T-cell therapy and replacing it with a mass-produced, off-the-shelf product promises to expand access to effective cell-based cancer immunotherapy to many more patients who may benefit from it,” said Dr. Valamehr.

Source: American Society of Hematology

Watch the press conference here.

Watch our interview with Dr Valamehr here



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