Existing CAR-T therapies for blood cancers require painstaking preparation. Exuma Biotech believes its rapidly manufactured cell therapy can save patients precious time and obviate the need for preconditioning.
Exuma’s rapid point-of-care technology leverages a specially designed lentiviral vector to generate a unique type of T- and NK-like cells, which the company calls CAR-TaNKs.
When given under the skin in a mouse study, such a cell therapy showed enhanced ability to expand and persist in the blood compared with conventional CAR-T cells. The novel therapy also showed it could clear target cells in mice at a low starting number of cells, Exuma said in a presentation at the American Association for Cancer Research annual meeting.
Cell therapies made with Exuma’s platform can shorten manufacturing time—from a blood draw to product release—to within the same day, compared with what typically would be a two-week process. And patients don’t need to undergo days of lymphodepleting chemotherapy before receiving the treatment, Exuma CEO Gregory Frost, Ph.D., told Fierce Biotech.
During the production of a traditional CAR-T therapy, T cells isolated from a patient’s blood need to be activated with CD3/28 stimulators and transduced with viral vectors to express the cancer-targeting CAR. The cells also are stimulated to increase in number before they’re infused back into the patient.
“We really wanted to say, can we make the vector itself do the heavy lifting,” Frost said in an interview.
Taking a page from many bispecific antibodies, Exuma designed a viral vector that not only expresses the CAR but carries an envelope that binds to CD3+ T cells, thereby providing the signaling to activate the cell therapy inside the body.
The second and “scientifically the biggest” challenge was, “can we do this without lymphodepleting chemotherapy?” Frost said. “If you want to do this very quickly, there’s no time to lymphodeplete a patient.”
Before taking a conventional cell therapy, patients must receive low-dose chemotherapy to suppress the immune system to make room for the new, engineered immune cells. For Gilead Sciences’ Yescarta, patients start the chemo regimen five days before getting the CD19-targeted CAR-T therapy.
After a long process of searching through deep sequencing, Exuma zeroed in on a cell therapy that could expand in the body without additional support but at the same time wouldn’t proliferate uncontrollably. And these cells possess properties of both T and NK cells. So Exuma designed its product to give rise to CAR-TaNK cells.
To make the product, immune cells from the patient’s blood are loaded with lentiviral vectors for four hours, and then, after unwanted residuals are washed away, the product—with a set of instructions—is injected under the skin. Once inside the body, the cells form little structures that resemble lymph nodes, where immune instructions are generated and assigned in a natural process, Frost explained.
The lasting cells are just CD8+ T- and NK-like cells. The cells gradually expand and persist with strong anti-tumor activity, but because the CD4+ component is gone, they don’t appear to produce too many troublesome cytokines, Frost said. Currently marketed CAR-T therapies all come with the dangerous side effect of cytokine release syndrome, in which a sudden release of a large number of cytokines triggers an immune system overreaction against normal tissues
At the same starting dose, a Exuma product spawned far more CD19-CAR-TaNK cells at peak in a humanized mouse model compared with a traditional CAR-T construct, the company reported at AACR. The CAR-TaNK cells showed strong anti-cancer activity against large lymphoma tumors. The results suggest the product could be effective at a very low starting dose.
After being rechallenged with cancer cells in lab dishes, the CAR-TaNK cells still appeared active with stable expression of PD-1, TIM-3 and LAG-3, while the traditional CAR-T cells exhibited spikes of those exhaustion markers.
Exuma recently wrapped a pre-IND meeting with the FDA and hopes to start a first-in-human clinical trial in early 2023, Frost said. If everything goes to plan, Exuma would be the first to enter the clinic with a subcutaneous CAR cell therapy.
The chief executive envisions an umbrella trial of a CD19/CD22 product. The company designed the lead candidate that way because many patients will likely join the trial after having already failed on a CD19-targeted CAR-T therapy, he said.
The short preparation time without the need for lymphodepletion could give Exuma’s products an advantage even against potential allogenic cell therapies, Frost argued. Even though allogenic therapies would be available immediately off the shelf they do require lymphodepletion. Besides, he suggested the CAR-TaNK cells’ profile could potentially allow for redosing, which might come in handy one day in solid tumors.
The Florida-based biotech, with a manufacturing footprint in China, is also exploring taking the entire cell processing into the body. Also at AACR, the company reported proof-of-concept data from two humanized mouse models, showing that CD3-directed lentiviral vectors—without preloading of immune cells—could directly generate CD19 CAR-T cells inside the body.