Patient-derived CAR-T immunotherapies have dominated the cancer immunotherapy space over the last decade. The EU approval of Atara Biotherapeutics’ Ebvallo marks the first immunotherapy based on T cells sourced from healthy donors.
Since the approvals of Kymriah and Yescarta in 2017, CAR-T immunotherapies have changed the way we treat rare forms of blood cancer. In this type of cell therapy, the patient’s immune T cells are extracted, genetically engineered in the lab to hunt cancer, and then reinfused. In many patients, CAR-T therapies provide a powerful, long-lasting response to cancer, and an increasing number of CAR-T therapies are being approved for more indications.
One big issue with these types of immunotherapy is that they require weeks of preparation from when the patient’s T cells are extracted. This can cost vital time for patients with life-threatening blood cancer.
Atara Biotherapeutics approval takes T-cell immunotherapies off the shelf
This week, the EU approved Ebvallo, a new type of T-cell immunotherapy that is sourced from healthy donors instead of from the patient — known as an off-the-shelf or “allogeneic” cell therapy. Unlike existing cancer cell immunotherapies, which are sourced from the patient, off-the-shelf cell therapies can be harvested ahead of time and given to a patient quickly.
Ebvallo was developed by the U.S. firm Atara Biotherapeutics and will be commercialized by French partner Piere Fabre. It was greenlit 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-derived, T-cell immunotherapy to receive approval from any regulatory agency in the world, this marks a historic moment for Atara, our European partner, Pierre Fabre, and for the broader cell therapy field,” stated Pascal Touchon, president and CEO of Atara Biotherapeutics in a public statement.
EBV+ PTLD can occur in patients that have been given 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 off infections.
In immunosuppressed patients that were previously infected with the Epstein‑Barr virus (EBV), the lack of immune protection can let the virus cause blood cancer. If chemotherapy fails and the patient relapses, there are very few other treatment options.
How Atara’s Ebvallo works
Unlike CAR-T cells, the T cells used in Ebvallo are not genetically modified. To prepare the therapy, Atara harvests T cells from a donor and then trains them to hunt down EBV-infected cells by mixing them with another type of immune cell from the donor that has been infected by EBV. The company then grows and expands the T cells.
The resulting T-cell immunotherapy specifically hunts down EBV-infected cells, taking the fight to EBV+ PTLD and other conditions caused by the virus such as forms of multiple sclerosis.
Before approval, Atara was only able to offer its lead cell therapy in clinical trials or via expanded access programs for patients with no other treatment options. The EU approval could improve the access for this select group of patients to a lifesaving therapy.
“I’ve been working on virus-specific T cells for 15 years,” tweeted Patrick Hanley, associate professor at the Children’s National Hospital, George Washington University, who wasn’t involved in the development of Ebvallo. “It’s great to see this work from [Atara] finally becoming widely accessible to patients, not just available to those close to a few boutique centers.”
The EU approval of Ebvallo itself has been met with caution; the partners can only market it to a small patient population, which could be tricky to commercialize. Atara will likely focus on applying for approval from the U.S. Food and Drug Administration in the coming months.
“We could anticipate that this performs more similar to gene therapies (e.g. Zolgensma) which are typically expensive and have very manual, high-cost manufacturing processes,” noted Jason Foster, CEO of the cell therapy manufacturing firm Ori Biotech. “The potential value for allogenic cell and gene therapies is centered around providing economies of scale—for smaller patient populations we may not be able to realize these benefits yet.”
Allogeneic CAR-T therapies on the march
Despite the small number of patients that can benefit from the EU approval of Ebvallo, the event sets a precedent for the marketing of allogeneic T-cell therapies in other indications.
Some of the most advanced CAR-T developers that aim to source T cells from donors are ImmunityBio, TC Biopharm and Allogene. Allogene, for example, launched a phase 2 trial of an off-the-shelf CAR-T therapy for a form of blood cancer in October 2022. Atara itself is developing CAR-T therapies based on its EBV T cells.
Allogene had been slapped with a clinical hold by the U.S. FDA on trials of its candidate therapies in October 2021. This move was in response to the discovery of chromosomal abnormalities in the CAR-T cells, and the hold was lifted when the company found no link to the company’s manufacturing process nor any clinical impact.
However, the safety of these emerging off-the-shelf CAR-T therapies remains to be established. Challenges to address in the field include the risk of chromosomal aberrations in the modified cells, maintaining quality control procedures, and preventing the T cells from becoming exhausted and losing their cancer-busting quality.
Nonetheless, explained Foster, approved CAR-T therapies have themselves been overcoming significant safety and manufacturing challenges over the last decade.
“Allogeneic, off-the-shelf CAR-T therapies have the potential to have great impact in our industry, and it’s reasonable to anticipate that it will take at least 5 years for that patient impact to start to expand,” said Foster.
Getting advanced therapies to European patients
In addition to safety and technical hurdles, companies developing allogeneic CAR-T therapies face other challenges in pricing their therapies and getting them reimbursed. These include the need for Europe’s regulatory process to catch up to advanced therapies, and the fragmentation of the market in the EU member states.
“Ebvallo delivers a compelling value proposition for patients, payers and European healthcare systems, with significant pricing potential in such an ultra-rare disease. However, at this stage it is too early to make further comments on pricing,” said a representative from Atara Biotherapeutics. Pierre Fabre is expected to release their pricing strategy once Ebvallo is launched in 2023.
The typically high asking prices of advanced therapies can create problems when rolling out in Europe. For example, the gene therapy developer bluebird bio withdrew from the EU market in 2021 after failing to negotiate a price for its approved gene therapy Zynteglo, which was set at over €1.5 million.
“These processes take significant time and investment to navigate,” said Foster. “Gene therapies like Zolgensma have taken years of challenging negotiations and the development of innovative reimbursement structures to provide access.”