San Francisco headquartered Atara Biotherapeutics is a pioneer in T-cell immunotherapy, leveraging its novel allogeneic Epstein-Barr virus (EBT) T cell platform to develop personalized, off-the-shelf therapies for patients with cancer and autoimmune disease. Multiple sclerosis could be one of the diseases the new therapies could treat.
Atara is currently enrolling for a Phase 2 trial to evaluate the efficacy and safety of ATA188 in patients with progressive multiple sclerosis (PMS).
Tracking the link between EBV and MS
For most people, EBV represents a virus that causes either a temporary illness or no illness at all. In the US, more than 90% of individuals will be infected with EBV by the age of 35.
However, EBV also appears to be involved in the development of certain cancers and autoimmune diseases, including MS. B cells - white blood cells that produces antibodies - infected with EBV are found in the brains of patients with MS.
"A growing body of evidence suggests these patients have an abnormal immune response to EBV, which may permit accumulation of EBV-infected B cells in the central nervous system driving aberrant inflammation that ultimately damages myelin, the insulating layer covering nerves," Dr. Jakob Dupont, MD Head of Global Research and Development at Atara, told this publication.
Around 2.3 million people worldwide suffer from multiple sclerosis (MS). Despite advances, treatment options are limited or non-existent for those living with PMS.
For patients with PMS, prognosis is poor with current treatment options that modestly delay progression but do not fundamentally alter disease course for MS patients.
“Many studies show that all patients, including pediatric patients, with MS have EBV infection, particularly in B cells, suggesting EBV is a potential underlying cause of MS.
“In addition, in separate studies, clear differences in location and frequency of EBV-infected B cells and plasma cells were evident between the brains of subjects without MS and the brains of MS patients, where EBV-infected B cells and plasma cells were in close proximity to areas of active demyelination.”
Using EBV T-cells from healthy donors
People with EBV fight the virus by developing EBV-specific T-cells, which circulate in their peripheral blood. Atara, therefore, hopes to harness these T-cells from healthy donors to develop its MS therapy.
“We know EBV T cells have the intrinsic ability to target and kill cells expressing surface EBV proteins," said Dupont.
"Importantly, these EBV-specific T cells traffic to the site of disease and have a central memory phenotype, which allows them to rapidly expand and persist in the body long enough to target the disease. These T cells can be collected and isolated from the peripheral blood of healthy donors.”
The result is ATA188: an investigational allogeneic T-cell immunotherapy which is entering a Phase II randomized controlled trial targeting EBV antigens specific for the potential treatment of progressive forms of multiple sclerosis (PMS).
“Current treatments have broad effects on the immune system but do not specifically target EBV, positioning ATA188 as a potentially transformative treatment,” said Dupont.
“Using a targeted antigen recognition technology designed to enable the T cells we administer to selectively identify cells expressing the EBV antigens that we believe may be important for the potential treatment of MS.
Long-term, two-year clinical data from the Phase 1 open-label extension (OLE) and translational data from the Phase 1 study of ATA188 in PMS will be presented at the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in October.
Atara is enrolling the ATA188 Phase 2 randomized, 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 and safety. Based on current target, Atara expects to complete enrollment in H1 2022.
"ATA188 is designed to cross the blood brain barrier and attack B cells and plasma cells that express EBV surface proteins, leaving other cells and the EBV-negative B-cell repertoire intact. We believe that eliminating only EBV-positive B cells and plasma cells has the potential to benefit some patients with MS.”
Significantly, Atara believes its therapy could not only slow decline but also help patients regain function.
“Current treatments, which largely target activated immune cells in peripheral tissues, delay disease progression but ultimately do not alter the inevitability of progression in disability for patients with PMS," noted Dupont.
“PMS is driven by abnormally activated immune cells and subsequent inflammation originating from within the central nervous system (CNS); patients with PMS experience continual progression of their disease.
"More effective therapies are still urgently needed: particularly for patients with PMS or inactive PMS who have limited options with which to treat this debilitating disease.
“There is growing evidence that EBV has a major role in the etiology of MS, where a prior EBV infection may be the only risk factor required to develop MS. MS may therefore be mediated by B cells that are infected with EBV, and defective elimination of EBV-infected autoreactive B cells by CD8+ T cells may result in accumulation in the CNS, leading to inflammation and ultimately demyelination and axon destruction.
“Additionally, recent research identified autoreactive CD4+ T cells that can cross-react with self-peptides, EBV peptides, and a protein in the brain called RASGRP2. This corroborates a long-standing hypothesis that certain infections, like EBV, are thought to lead to increased immune and CD4+ T-cell activation via molecular mimicry, leading to broad activation of auto-reactive CD4+ T cells that can attack proteins in the white matter of the brain. This is another possible mechanism of how EBV may trigger the pathological cascade of MS.
“There is other evidence that patients who are EBV negative have a low risk of developing MS but when they get an EBV infection the risk increases sharply in those same individuals following EBV infection to develop MS.
“The hypothesis is that specific targeting of EBV+ B cells, that may be driving the pathological immune response in MS, can potentially reduce inflammation and allow for some recovery of myelination and function.”
Advantages of an off-the-shelf therapy
While autologous T-cell immunotherapies that use a patient’s own T cells have been used successfully to treat blood cancers, Atara instead sees ATA188 as a therapy that could offer an effective off-the-shelf approach.
“There are limitations associated with modifying a patient’s own T cells including potentially poor cell quality, challenges with cell collection, manufacturing and logistics, and difficulty in treating other diseases such as solid tumors," said Dupont.
"Enhanced safety and efficacy are also needed. These issues may currently limit a patient’s ability to be treated with these promising T cell therapies.
“Allogeneic cell-based platforms hold the promise of personalized, “off-the-shelf” treatments manufactured at scale and quickly delivered to the patient, having the potential to overcome typical barriers that have limited the success of current autologous T cell technologies. However, most allogeneic immunotherapies under investigation use cells that require T-cell receptor (TCR) or HLA editing to confer sufficient safety, expansion and persistence characteristics. Although these processes attempt to address key challenges of autologous cell therapy, these products have currently only been studied in early phase 1 trials.
“In contrast, Epstein-Barr virus (EBV) specific T cells are one example of a T-cell platform that is in development for cancer and autoimmune diseases, including multiple sclerosis. 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 HLA gene editing.”
The advantages of an off-the-shelf approach are numerous, according to Dupont: ranging from improved cell quality to scalable manufacturing.
“Allogeneic T cells originating from healthy donors are generated from immune cells that have not been exposed to the effects of other underlying autoimmune diseases, which may result in less variability and improved cell quality. In the case of investigational ATA188 for MS, an inventory of donated EBV T cells can be manufactured and stored in advance of patient need with the goal of rapid delivery (off-the-shelf). EBV T cells are present in large quantities in donors’ blood enabling streamlined collection and scalable manufacturing.”
Atara has a dedicated manufacturing facility, based in Thousand Oaks, California, which is designed to be scalable, reliable and flexible to produce multiple T-cell and CAR T immunotherapies. The company’s logistics capability has been utilized in clinical trials conducted at more than 60 trial sites across three continents: North America, Australia, and Europe, and is nearing commercial scale readiness.