Over the last decade, groundbreaking chimeric antigen receptor (CAR) T-cell immunotherapies have become a well-established cancer treatment modality. Clinical research continues to demonstrate the encouraging potential this approach holds for treating a wide array of conditions while increasing safety, tolerability, and efficiency in manufacturing. Atara Biotherapeutics, a California-based biotechnology company, seeks to harness the immune system’s innate power to fight a common human virus in order to create targeted treatments for a variety of conditions. With their pipeline of investigational therapies, Atara aims to tackle the unmet treatment needs of serious diseases such as multiple sclerosis using an innovative approach to T-cell therapeutics. Here, Jakob Dupont discusses the foundation of Atara’s unique T-cell platform, the development of ATA188 as a potential therapy for progressive multiple sclerosis, and what it may mean for the future of T-cell therapeutics.
A Novel Therapeutic Target for Progressive Multiple Sclerosis
Multiple sclerosis (MS) is a devastating neurological illness affecting 2.8 million people worldwide, with up to 1.2 million living with the progressive form of the disease. With progressive MS (PMS), some clinical decline and worsening disability over time are expected, ultimately leading to disability and a loss of independence for many patients. MS is driven by abnormally activated immune cells and subsequent inflammation which damages and ultimately destroys the protective myelin sheath surrounding cells in the central nervous system (CNS).
Despite advances, treatment options are limited or non-existent for those living with PMS and prognosis is poor; current treatment options delay progression but do not fundamentally alter disease course for MS patients.
In the US, more than 90% of individuals will be infected with Epstein-Barr virus (EBV) by the age of 35. Most of these individuals will experience either a temporary illness or no illness at all; as part of their immune response, they develop EBV T cells, which circulate in their peripheral blood. Growing evidence implicates EBV in the etiology of several cancers and autoimmune disorders, including MS.
Numerous studies show that up to 100% of MS patients are EBV-positive, and several have indicated clear differences in the location and frequency of EBV-positive B cells and plasma cells within the brains of patients with and without MS. Additionally, in the brains of MS patients, EBV-positive B cells and plasma cells tended to be in close proximity to areas of active demyelination. Scientists have hypothesised that an abnormal immune response to EBV causes defective elimination and accumulation of EBV-infected autoreactive B cells in the CNS, potentially leading to the aberrant inflammatory response that damages myelin.
By targeting the EBV-positive B cells and plasma cells that may be responsible for this inflammation, and ultimately demyelination and axon destruction, a therapy could potentially halt MS pathology. Atara placed this concept within the expanding landscape of investigational T-cell therapies to develop ATA188.
Leveraging EBV Infection as a Novel Approach to T-Cell Immunotherapy
Atara is using EBV T cells from healthy donors to develop a pipeline of investigational therapies for cancers and autoimmune diseases including MS. ATA188 is an investigational allogeneic off-the-shelf T-cell immunotherapy in a Phase II randomised controlled clinical trial (called EMBOLD) targeting EBV antigens for the potential treatment of PMS. This approach may permit specific targeting and clearing of accumulated EBV-positive B cells and plasma cells potentially halting the harmful inflammatory siege on myelinated axons.
EBV T cells naturally traffic to the site of disease and have a low likelihood of harming normal, healthy cells. The cells’ central memory phenotype makes them highly sensitive for EBV, and they are typically circulating constantly to detect latent virus. EBV T cells naturally possess key immunological features that are required for successful allogeneic T cell immunotherapies: The ability to target disease at its source, like EBV-driven diseases, with proven trafficking, expansion, and persistence without TCR or human leukocyte antigen (HLA) gene editing.
One feature makes EBV T cells particularly appealing for the development of allogeneic immunotherapies: their near-ubiquitous presence, even in healthy individuals. Despite the previous success of autologous CAR T-cell therapies, 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 three to four weeks from the time of leukapheresis for patients to receive treatment, but manufacturing failures can occur, and patients sometimes can’t wait.
EBV T cells can be stimulated for proliferation using EBV peptides, which may offer unique advantages within the cellular expansion step of manufacturing for both allogeneic and autologous therapies. In contrast to the anti-CD3/28 beads commonly used in autologous CAR-T manufacturing, this process of stimulation is less aggressive and may result in consistently healthier, high-quality T cells.
Additionally, because EBV infection is so common in humans, a large pool of healthy EBV T cell donors is available. EBV T cells can be collected from healthy individuals using leukapheresis, processed and expanded, and then stored as inventory to provide off-the-shelf therapies at the time of patients’ need.
By creating an inventory of EBV T cell products from a large donor pool over time, Atara intends to select products based on appropriate patient HLA profiles to begin treatment within days. The EBV T-cell platform shows promise for numerous EBV-driven disease applications thus far, and the company continues to explore further therapeutic opportunities through the incorporation of engineered CARs.
ATA188: An Investigational Allogeneic EBV T-Cell Therapy for Progressive MS
Atara Biotherapeutics’ ATA188 is an investigational allogeneic T-cell immunotherapy for progressive MS that leverages this EBV T-cell platform. Currently in a Phase II randomised clinical trial, ATA188 is designed to address the urgent unmet need for MS therapies that can meaningfully impact disease course or potentially reverse disability progression. The therapy is designed to cross the blood-brain barrier to attack B cells and plasma cells in the CNS expressing EBV surface proteins while leaving EBV-negative cells intact. The hypothesis is that by destroying these EBV-positive cells, the inflammatory milieu responsible for MS pathogenesis will be eliminated, halting further progression, and potentially allowing for some recovery of myelination and function.
Towards the end of 2017, we initiated an open-label, single-arm, multi-center, multi-national Phase I study with allogeneic ATA188 for patients with PMS. Initial published data from Atara’s Phase I dose-escalation study, presented at the European Academy of Neurology (EAN) in June 2020, demonstrated that ATA188 was well tolerated across all four dose cohorts, with no dose-limiting toxicities and no fatal adverse events.
An open-label extension (OLE) of the Cohort 3 dose from this trial has continued, with further results presented at the European Charcot Foundation 28th Annual Meeting in November 2020 including data on 24 patients from the 12-month dose escalation portion of the trial, 16 of whom entered the OLE and had ≥15-month data available as of October 2020. Data have demonstrated encouraging clinical signals, with an increased proportion of patients achieving sustained disability improvement (SDI) at higher doses (in cohorts 3 and 4). SDI is defined as clinically significant improvement in Expanded Disability Status Scale (EDSS) or Timed 25-foot Walk (T25FW) observed at two consecutive time points.
Long-term, two-year clinical data from the Phase I open-label extension (OLE) and translational data from the Phase I study of ATA188 in PMS was presented at the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in October 2021. The presentation, titled “Updated open-label extension clinical data and new magnetisation transfer ratio imaging data from a Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive multiple sclerosis” featured updated Phase I OLE data in patients with progressive MS treated with ATA188 for up to 39 months, and new magnetisation transfer ratio (MTR) data, an imaging biomarker considered to reflect the state of myelination in the central nervous system. Findings continue to demonstrate that patients may achieve SDI at a higher rate and longer duration than would be expected based on the natural history of progressive MS; the majority of SDI is driven by improvement in EDSS. Patients who achieved EDSS improvement at any time showed a significant increase in MTR from baseline at 12 months, suggestive of remyelination, and providing a potential biological basis for the clinical improvements observed.
Based on these results, we initiated a randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ATA188 in patients with PMS using the cohort 4 dose and enrolled the first patient in June 2020. Atara is making progress on enrolling the ATA188 Phase II randomised, double-blind, placebo-controlled trial (EMBOLD study) evaluating the efficacy and safety of ATA188 in patients with PMS. An interim analysis in H1 2022 is planned to assess efficacy, safety, and biomarkers like MTR.
Atara’s Path Forward
By harnessing the innate power of the human immune system, Atara aims to deliver treatments to patients with serious conditions such as progressive MS through an innovative EBV T cell platform. ATA188, the company’s novel allogeneic T-cell candidate for the treatment of PMS, targets EBV-positive B cells and plasma cells in the CNS thought to drive disease pathogenesis. As an allogeneic product, the therapy may offer some distinct manufacturing advantages due to the large pool of potential healthy, EBV-positive donors. More importantly, the development of ATA188 represents a meaningful step towards tackling the unmet treatment need for PMS patients who have few options in fighting this debilitating illness.
In advancing the EBV T-cell platform, Atara aims to develop treatments not only for EBV-associated conditions but also other illnesses through the integration of CARs. The unique and inherent biological advantages of EBV T cells present a promising path forward for the development of innovative therapies and the field’s growing understanding of allogeneic T cells.
About the author
Dr. Jakob Dupont serves as Global Head of Research & Development and EVP at Atara Biotherapeutics. Previously, he was the Chief Medical Officer at Gossamer Bio, overseeing global development, regulatory, and quality activities, and advancing therapeutics in immunology, inflammation, and oncology. Dr. Dupont is committed to bringing transformative therapies to patients.