Atara Biotherapeutics’ approval heralds a ready T-cell therapy

Patient-engineered CAR-T immunotherapy has dominated the field of cancer immunotherapy for the past decade. The EU approval of Atara Biotherapeutics’ Ebvallo marks the first immunotherapy based on T cells derived from healthy donors.

Following the approval of Kymriah and Yescarta in 2017 CAR-T immunotherapy have changed the way rare forms of blood cancer are treated. In this type of cell therapy, a patient’s immune T cells are harvested, genetically engineered in the lab to hunt down cancer, and then reinfused. In many patients, CAR-T therapy produces strong and long-lasting responses to cancer, and more and more CAR-T therapies are being approved for more indications.

One big problem with these types of immunotherapies is that they require weeks of preparation from the moment a patient’s T cells are extracted. This can cost patients with life-threatening blood cancers vital time.

Atara Biotherapeutics’ approval takes T-cell immunotherapy off the shelf

This week, the EU approved Ebvallo, a new type of T-cell immunotherapy that is derived from healthy donors rather than patients – known as standard or “allogeneic” cell therapy. Unlike existing cancer cell immunotherapies, which are derived from the patient, standard cell therapies can be assembled in advance and quickly given to the patient.

Ebvalla was developed by US firm Atara Biotherapeutics and will be commercialized by French partner Pierre Fabre. It was recognized as the first and only treatment for a rare blood cancer called Epstein-Barr virus-positive post-transplant lymphoproliferative disease (EBV+ PTLD).

“As the first allogeneic or donor T-cell immunotherapy to receive approval from any regulatory body in the world, this marks a historic moment for Atara, our European partner, Pierre Fabre, and for the broader field of cell therapy,” said Pascal Tuchon, President and CEO of Atara Biotherapeutics in a public statement.

EBV+ PTLD can occur in patients who have received an organ transplant in addition to immunosuppressive drugs to stop the immune system from rejecting the organ. Immunosuppressive drugs also impair the patient’s ability to fight infections.

In immunocompromised patients who have previously been infected with the Epstein-Barr virus (EBV), the lack of immune protection can cause blood cancer. If chemotherapy fails and the patient relapses, there are very few other treatment options.

How Ebvallo by Atara works

Unlike CAR-T cells, the T cells used in Ebvallo are not genetically modified. To prepare the therapy, Atara collects T cells from a donor and then trains them to detect cells infected with EBV by mixing them with another type of immune cell from a donor who has been infected with EBV. The company then grows and expands the T cells.

The resulting T-cell immunotherapy specifically targets EBV-infected cells, fighting EBV+ PTLD and other diseases caused by the virus, such as forms of multiple sclerosis.

Before the approval, Atara could only offer its lead cell therapy in clinical trials or through expanded access programs to patients who had no other treatment options. EU approval could improve access to lifesaving therapy for this select group of patients.

“I’ve been working on virus-specific T cells for 15 years” tweeted Patrick Hanley, an assistant professor at George Washington University’s Children’s National Hospital, who was not involved in the development of Ebvallo. “It’s nice to see this work [Atara] is finally becoming widely available to patients, not just those close to a few boutique centers.”

The approval of Ebwal himself in the EU was met with caution; partners can only sell it to a small group of patients, which can be difficult to commercialize. In the coming months, Atara is likely to focus on submitting an application for approval to the US Food and Drug Administration.

“We could foresee it being more like gene therapy (like Zolgensma), which is typically expensive and has very manual and expensive manufacturing processes,” said Jason Foster, CEO of cell therapy firm Ori Biotech. “The potential value of allogeneic cell and gene therapy centers on providing economies of scale—for a smaller subset of patients, we may not yet be able to realize these benefits.”

Allogeneic CAR-T therapies on the march

Despite the small number of patients who may benefit from Ebvallo’s approval in the EU, this event sets a precedent for the marketing of allogeneic T-cell therapy in other indications.

ImmunityBio, TC Biopharm and Allogene are among the most advanced CAR-T developers looking to obtain T cells from donors. For example, in October 2022, Allogene launched a phase 2 trial of its standard CAR-T therapy to treat a form of blood cancer. Atara itself is developing a CAR-T therapy based on its EBV T cells.

The US Food and Drug Administration has granted Allogene clinical approval in a candidate therapy trial in October 2021. The move was made in response to the discovery of chromosomal abnormalities in CAR-T cells, and the suspension was lifted when the company found no link to the company’s manufacturing process or any clinical consequences.

However, the safety of these new off-the-shelf CAR-T treatments will still need to be installed. Challenges to be addressed in this field include the risk of chromosomal aberrations in modified cells, adherence to quality control procedures, and prevention of T cell exhaustion and loss of anticancer quality.

Still, Foster explained, the approved CAR-T therapy itself has overcome significant safety and manufacturing challenges over the past decade.

“Allogeneic standard CAR-T therapies have the potential to have a major impact on our industry, and it is reasonable to expect that it will take at least 5 years before this impact on patients begins to expand,” Foster said.

Access to modern treatments for European patients

In addition to safety and technical hurdles, companies developing allogeneic CAR-T therapies face other problems in determining treatment prices and reimbursements. These include the need for a regulatory process in Europe to catch up with modern treatments and market fragmentation in EU member states.

“Ebvallo provides a compelling value proposition for patients, payers and European healthcare systems with significant value potential in this very rare disease. However, at this stage, it is too early to comment further on pricing,” said a representative of Atara Biotherapeutics. Pierre Fabre is expected to announce its pricing strategy after the launch of Ebvallo in 2023.

In general, the high prices of advanced treatments can create problems for deployment in Europe. For example, gene therapy developer bluebird bio left the EU market in 2021 after failing to agree on a price for the approved gene therapy Zynteglo, which was set at more than €1.5 million.

“These processes require significant time and investment to navigate,” Foster said. “Gene therapies like Zolgensma have taken years of complex negotiations and the development of innovative reimbursement structures to ensure access.”