Leveraging the T-Cell Response to Epstein-Barr Virus To Treat Life-Threatening Diseases

Epstein-Barr Virus (EBV) is believed to be associated with several life-threatening diseases. In response to exposure to the virus, the immune system produces EBV T cells specifically designed to target EBV-infected cells. Atara Bio is channeling the power of the immune system to treat a wide range of diseases including solid tumors, hematologic cancers and autoimmune diseases by harnessing EBV T cells and modifying them to attack specific targets on diseased cells.

Technology Networks recently spoke with Jakob Dupont, head of global research & development at Atara Bio, to learn more about the company’s novel allogeneic EBV T-cell platform and discover how it’s enabling a differentiated approach to allogeneic cell therapy.

Zoe Braybrook (ZB): What are the benefits to using EBV T cells as a means to develop personalized therapies for patients in need? Can you tell us more about the platform you have developed based on this approach?

Jakob Dupont (JD): Atara Biotherapeutics is a leading allogeneic T-cell immunotherapy company seeking to harness the power of the immune system to develop transformative treatments for patients with cancer and autoimmune diseases.

T cells are a type of white blood cell in the immune system that help to protect the body from infection as well as complex diseases, including cancer. When a virus invades the body, it produces highly specific T cells that target and kill infected cells.

EBV is one of the most common human viruses with 90 percent of adults worldwide harboring dormant infections. Once infected, the body creates T cells to target and destroy EBV-infected cells. These T cells have unique characteristics that make them prime candidates for the development of an allogeneic T-cell immunotherapy platform. EBV T cells naturally traffic to the site of disease and have a low likelihood of harming normal, healthy cells. EBV T cells also possess key immunological features that are required for successful allogeneic T-cell immunotherapies. For example, they have the ability to target disease at its source, like EBV-driven diseases, with proven trafficking, expansion and persistence without T-cell receptor (TCR) or human leukocyte antigen (HLA) gene editing. EBV T cells can also be modified to add receptors on the surface of the cells that target cancer cells to fight blood cancer and solid tumors.

EBV has been linked to many cancers and autoimmune diseases. Atara’s novel allogeneic EBV T-cell investigational product candidates are manufactured from unrelated healthy, living donors and are stored in inventory in advance of patient need. By creating an inventory of EBV T-cell products from a large donor pool over time, Atara intends to select product based on appropriate patient HLA profiles to begin treatment within days.

The goal with these investigational therapies is to reinforce a patient’s immune system to help treat either:

• Diseases that are directly EBV-associated, such as EBV-positive post-transplant lymphoproliferative disease (EBV+ PTLD) or multiple sclerosis (MS)
• Blood cancers and solid tumors by modifying the cells with a chimeric antigen receptor (CAR). These CAR therapies are designed to attack specific cancer targets. We’re assembling a toolkit of next-generation technologies designed to enhance the benefits of T-cell immunotherapies and address some of the current limitations in the field.

Laura Lansdowne (LL): What is the difference between the terms autologous and allogeneic? Can you highlight the key benefits and any challenges related to allogeneic T-cell immunotherapies?

JB: CAR T-cell autologous therapies are derived from collecting, genetically engineering and growing a patient’s own T cells, which can be a time-consuming process and challenging to scale to treat large numbers of patients. The process of harvesting cells and the time it takes to process and manufacture the CAR T product can present limitations to some patients. Even with the most advanced manufacturing capabilities, it often takes 3–4 weeks from the time of leukapheresis for patients to receive treatment, but manufacturing failures can occur and patients sometimes can’t wait. Additional limitations may include poor cell quality from patients, safety and re-dosing challenges.

The next evolution in immunotherapy, which is currently under investigation, is allogeneic T-cell therapy, which has the potential to leverage a healthy donor’s immune system. Importantly, this approach is designed to allow for more efficient batch manufacturing, so therapies can be available off-the-shelf, and mass produced, rather than custom-created for each patient individually. These donor cells have not been exposed to chemotherapy or the immune effects of cancer, which may result in less variability and improved cell quality.

While promising, early allogeneic programs have encountered their own set of risks, including the potential for graft-versus-host disease (GVHD). In this case, the presence of endogenous TCRs on donor cells – in addition to the engineered CAR – may lead to alloreactivity as well as preferential signaling through TCR over CAR. Newer programs have engineered steps to remove or reduce the expression of native TCRs, although this can also cause safety, cell expansion and durability-of-response issues.

Scaled-up allogeneic therapies also can present manufacturing challenges. All T-cell therapies are living drugs in culture, therefore carefully controlled conditions and protocols are critical throughout the entire production process to ensure quality. Scale-up of each production step, from modification to proliferation to purification, introduces new levels of complexity that require major adaptation in equipment and methodology. Overall, allogeneic therapies are an important step beyond the existing capabilities of T-cell therapies, but they require a significant investment in infrastructure as well.

LL: Could you walk us through the allogeneic cell therapy manufacturing process?

JB: T cells from donors with healthy immune functions are collected through leukapheresis, which collects and isolates white blood cells. They are then carefully stimulated, expanded and activated through a proprietary manufacturing platform that yields T cells highly specific for EBV or – through the addition of a CAR or even a TCR – other therapeutically relevant targets. After undergoing full characterization, the cells are cryopreserved and stored. For each product, an inventory of different manufactured lots provides a breadth of HLA coverage, helping to ensure immune compatibility for nearly all patients.

ZB: Are there any current bottlenecks that could be addressed by incorporating innovative solutions or strategies to improve the process?

JB: Currently, both autologous and allogeneic therapies are manufactured at a relatively small scale since these processes are manual and laborious. Consequently, cell therapies are potentially prone to human error, resulting in an increased risk of contamination, batch loss and batch-to-batch variability. This is due in part to difficulties with cell recovery and expansion as well as the lack of suitable equipment and analytical assays to track the differentiation of cells during process development.

The ability to scale up and scale out will be essential to decrease variability while also increasing patient access to these therapies. Allogeneic cell therapies may be scaled up to meet demand but must also be expanded without compromising function and quality. T-cell exhaustion and culture-associated cell aging, or senescence, restrict the number of population doublings, overall culture times and quantities. Importantly, over-cultured cells may also lose therapeutic efficacy in patients. At Atara, we’re able to grow EBV T cells in suspension, allowing us to scale up product yields.

Scalability on a global level is not just about technology but also being able to hire enough qualified staff. Due to the exponential growth in cell therapy, there is a real talent constraint that risks becoming a bottleneck. It is vital for the future of the field that we have a pool of talent with expertise in cell therapies, genetic engineering, tumor biology and how to work effectively with academic centers and investigators. Looking ahead, we also need to attract collaborators with disease-specific expertise to help us apply T-cell therapies to additional indications, beyond cancer. 

JB: Atara has assembled a large network of healthy donors to minimize unpredictability and help maximize the potential of these products. Through this network, we’re able to plan production well in advance of need, building an inventory of cells with the goal of rapid delivery (off-the-shelf) for patient need. EBV T cells are present in large quantities in donors’ blood helping enable streamlined collection and scalable manufacturing.

We’ve developed stirred-tank bioreactor processes which may allow use of a single donor batch to treat thousands of patients. Thus far, we’ve been able to scale the process in several cases from static, gas-permeable vessels to bioreactor production with the goal of providing hundreds to thousands of doses from a single donor. By investing in scalable technologies, we aim to produce enough drug to help address unmet medical needs in many different patients.

We have worked hard to establish each element of our commercial supply chain. We've evaluated each element from operational, quality, and compliance perspectives to help ensure that expectations for a successful commercial product launch are met. We’ve analyzed how we can efficiently get our drug to patients and how we can simplify our administration requirements for physicians and nurses.  

LL: Could you highlight some of your T-cell immunotherapy product candidates and the indications that they have been designed to treat?

JB: Atara’s platform leverages the unique biology of EBV T cells and has the potential to address a wide range of EBV-associated diseases, or other serious diseases through incorporation of CARs or TCRs. We are applying this one platform to create a robust pipeline across cancer and autoimmune diseases.

ATA188 for Progressive MS:

For a long time, scientists hypothesized an EBV infection was an important component in the development of MS. This January, two landmark studies published in Science and Nature strongly suggest this finding. EBV is a necessary trigger for the disease and likely contributes to its progression. This is compelling news for the MS community, because it points to a new avenue for potential treatments: selectively targeting EBV-infected cells. Atara has been pursuing this science for years with ATA188. ATA188 is an investigational, off-the-shelf, allogeneic T-cell immunotherapy that specifically targets EBV-infected B cells and plasma cells that may drive MS.

Our randomized Phase 2, double-blind, placebo controlled EMBOLD study (NCT03283826), evaluating the efficacy and safety of ATA188 in patients with progressive MS, is actively enrolling across clinical sites in North American and Australia. An interim analysis in Q2 is planned to assess efficacy and safety and we expect to complete enrollment in the first half of 2022.

Tabelecleucel (tab-cel®) for Post-Transplant Lymphoproliferative Disease (PTLD)

Tab‐cel is an investigational allogeneic T-cell immunotherapy in development for EBV+ PTLD, a type of lymphoma (cancer) that can occur after a solid organ transplant (SOT) or allogeneic hematopoietic cell transplant (HCT).

Tab‐cel is in a Phase 3 registration-enabling study called ALLELE to assess efficacy and safety for the treatment of EBV+ PTLD in SOT and HCT after failure of initial treatment and is currently under review to support registration in Europe, the first off-the-shelf allogeneic T-cell immunotherapy to be reviewed by a regulatory agency. The EMA’s Committee for Medicinal Products for Human Use (CHMP) granted tab‐cel Accelerated Assessment and an EU approval decision is anticipated for the second half of 2022. Tab-cel has also been granted Breakthrough Therapy Designation for EBV+ PTLD following allogeneic HCT by the US Food and Drug Administration (FDA).

A multi-cohort Phase 2 study evaluating tab-cel in six additional patient populations for EBV+ immunodeficiency-associated lymphoproliferative diseases (IA-LPDs) and other EBV-driven diseases is currently enrolling. Presentation of the first data from the multi-cohort study is planned for 2023.

CAR T Programs

Atara is continuing to make progress on IND-enabling studies for ATA3271, an investigational, off-the-shelf, allogeneic CAR-T therapy targeting mesothelin, expressed at high levels in a variety of solid tumors, using next-generation PD-1 dominant negative receptor (DNR) and 1XX CAR co-stimulatory signaling domain technologies for patients with advanced mesothelioma, and expects a filing in Q4 2022.

ATA3219 is an investigational allogeneic CD19 CAR T-cell therapy that does not require TCR or HLA gene editing and leverages our next-generation 1XX CAR co-stimulatory signaling domain and allogeneic EBV T-cell platform. We expect to submit an IND for B-cell malignancies expressing CD19 in Q4 2022.

Jakob Dupont was speaking with Zoe Braybrook, Marketing Campaign Coordinator and Laura Elizabeth Lansdowne, Managing Editor at Technology Networks.