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Caring Cross to Pilot Low-Cost, Point-of-Care CAR T-Cell Manufacturing Approach in Brazil


Marco Krieger's comments have been translated from Portuguese by the author.

NEW YORK – Nonprofit Caring Cross has partnered with Fundação Oswaldo Cruz (Fiocruz), a biological research and development foundation associated with Brazil's Ministry of Health, to provide low-cost CAR T-cell therapies under that country's national health plan.

Caring Cross will provide Fiocruz with the technology, expertise, and training to develop local, point-of-care CAR T-manufacturing capabilities. The collaboration will focus initially on therapies for leukemia and lymphoma as well as an HIV cell therapy that is currently in clinical trials in the US. The project will first center on the Rio de Janeiro area, with plans to expand throughout the country in stages.

"The collaboration is really to enable Fiocruz to work with local hospitals in order to produce their own CAR T [cells]," said Boro Dropulic, executive director and cofounder of Caring Cross.

More than simply being able to produce CAR T therapies locally, Marco Krieger, VP of production and health innovation at Fiocruz, said that it is critical to be able to do so at a price point that makes these therapies accessible to the general public.

"These advanced therapies," he said, "reach countries like Brazil at prices that are so high, they're impossible to use in society at large."

Instead, Caring Cross has developed a workflow capable of producing patient-specific CAR T cells for approximately $20,000 in materials — including the vector — and $10,000 in labor and facilities costs. Various studies have estimated average per-patient costs using traditional approaches ranging from approximately $350,000 to $1 million, which would be unsustainable for Brazil's public healthcare system.

Caring Cross has been developing point-of-care CAR T-manufacturing processes for some time, and the collaboration with Fiocruz marks a significant step forward in implementing what the US-based nonprofit has learned. Two years ago, for instance, the organization demonstrated the feasibility of its methodology in two proof-of-concept Phase I clinical trials in Cleveland and in Moscow.

Caring Cross has simplified its process using several off-the-shelf devices that help ensure efficiency and replicability.

The process, Dropulic explained, can begin with either apheresis, in which T cells are harvested from patients, as CAR T cells are typically made, or with just whole blood, which is a much more economical option for healthcare systems with constrained resources. These samples are then fed into Cytiva's Sepax C-Pro cell processing instrument, which purifies peripheral blood mononuclear cells, and the T cells are further purified using proprietary antibodies developed by Caring Cross. Purified T cells are then expanded in ScaleReady's G-Rex bioreactors.

Then, said Dropulic, "just add your vector, some medium, some activation reagent, stick it in an incubator in a clean room, [and] seven days later, formulate it back into the same device, and it's ready for infusion."

In addition to licensing this methodology to Fiocruz, Caring Cross is also licensing the vector manufacturing process, so that Fiocruz can perform all relevant steps in-house, which contributes to reaching an affordable price point for Brazil's public health system.

Caring Cross will work with Ormond Beach, Florida-based laboratory equipment supplier Germfree to set up lightweight manufacturing units that can be delivered by truck to the sites participating in the pilot phase of this initiative.

"They're clean room units that will be placed near hospitals in Brazil to actually manufacture the final autologous CAR T-cell product," said Rimas Orentas, scientific director and cofounder of Caring Cross.

The units are made to each have identical footprints and workflows to enable identical product manufacturing quality to create an approvable process.

"That's why we need the same footprint [and] same workflow," Orentas said, "because the regulators want to be able to approve the process." In point-of-care manufacturing, he explained, "we have to demonstrate through our assays and release criteria that we have the same [results] and quality of systems in all the different places."

Identical mobile manufacturing units with identical processes, he said, can then all report to a central reference facility.

"That makes it regulatable [and] approvable just like any other, centrally manufactured cell and gene therapy product," Orentas said.

Fiocruz's Krieger added that Brazil already has the infrastructure in place to begin manufacture immediately.

"Our industrial capacity in this respect," he said, "was put in place for the manufacture of COVID vaccines through a collaboration with AstraZeneca. We have the [relevant] assets ready to go and certified in good manufacturing processes by our health authority."

Krieger estimated that the total cost of implementing the program, including the cost of hardware and planned clinical studies, amounts to roughly $50 million.

"This is a significant investment," he said, but one that he expects will save far more money in the long run.

"Just to give you an idea," Krieger said, "we estimate that the number of third-line treatments for hematological cancers in Brazil currently costs us in the range of … $70 million per year."

Dropulic said that the CAR T-cell field in general is moving toward point-of-care manufacturing. But while other cell therapy companies are exploring decentralized CAR T-manufacturing strategies, few appear to be focusing on lower- to middle-income countries.

Belgium-based Galápagos, for example, has entered the point-of-care CAR T-manufacturing space with a platform consisting of its xCellit workflow management and monitoring software system; a decentralized, functionally closed, automated manufacturing platform for cell therapies using Lonza's Cocoon; and a proprietary quality control testing-and-release strategy. Galápagos recently partnered with Thermo Fisher Scientific to bring this platform to the San Francisco Bay area, and last year, it partnered with Landmark Bio to do the same in the Boston area.

While Caring Cross is currently focusing its efforts in the engineered T-cell space, it also plans to explore low-cost manufacturing processes for stem cell therapies in the future. In Caring Cross' view, the stem cell therapy field is moving in the wrong direction with respect to accessibility.

"We're trying to make these curative therapies as broadly available as possible," Orentas said, "[whereas] they seem to be becoming more and more expensive."

As a case in point, Orentas referenced the US Food and Drug Administration's recent approval of Orchard Therapeutics' Lenmeldy (atidarsagene autotemcel), a stem cell therapy for children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy.

That therapy, the first FDA-approved gene therapy for that indication, earned the title of the world's most expensive drug, with a list price of approximately $4.25 million.

Similarly, Vertex Pharmaceuticals' Casgevy (exagamglogene autotemcel) and Bluebird Bio's Lyfgenia (lovotibeglogene autotemcel), both gene therapies for sickle cell disease, have price tags of approximately $2.2 million and $3.1 million, respectively. That sort of price, Orentas said, "doesn't even really apply to most of the world that's suffering from sickle cell disease."

Following the initial phase of the Caring Cross-Fiocruz collaboration in Rio de Janeiro, Fiocruz plans to expand the program throughout the country.

"We're already in early discussions with possible strategic partners in São Paulo state," Krieger said, "as well as with states in the southern, northern, northeastern, and central-western regions."

In the end, he said, "we want to have at least one or two of these centers in all the main regions of Brazil."