CD70 & Autoimmune Diseases
By Erin Harris, Editor-In-Chief, Cell & Gene
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Back in August, Dr. Zachary Roberts, EVP of Research and Development and Chief Medical Officer at Allogene Therapeutics was my guest on Cell & Gene: The Podcast. On that episode, he and I discussed the scalability of allogeneic cell therapies. As we head into 2025, the cell and gene therapy space will continue to see impactful progression for advanced therapies for autoimmune diseases. As such, I caught back up with Dr. Roberts to discuss the rationale behind selecting CD70 as a target for activated T cells in autoimmune diseases as well as the potential benefits of targeting both CD19+ B cells and CD70+ T cells compared to targeting B cells alone. Here’s what he had to say.
Tell us about Allogene.
Allogene Therapeutics is a clinical-stage biotechnology company with a single-minded focus on pioneering the development of investigational allogeneic chimeric antigen receptor (CAR) T cell (AlloCAR T™) products for cancer and autoimmune disease.
Allogene is led by world-class management with significant experience in cell therapy with a fully integrated, in-house team of researchers dedicated to discovery and translational research, development, and product manufacturing. We are developing a pipeline of “off-the-shelf” CAR T cell candidates with the goal of delivering readily available cell therapy faster, more reliably, and at greater scale to more patients.
ALLO-329 extends Allogene’s expertise in CAR T to autoimmune diseases where there is growing interest for what may be possible with this modality. The recent preclinical data for ALLO-329 presented at the American College of Rheumatology (ACR) Convergence 2024 underscored the potential of an allogeneic CAR T to reset the immune system while reducing the need for lymphodepletion to meet the unique needs of these patients.
How does targeting both CD19+ B cells and CD70+ T-cells potentially enhance therapeutic benefit compared to targeting B cells alone?
ALLO-329 is designed to address immune dysfunction in autoimmune disease. By targeting two key drivers of autoimmunity: CD19+ B cells and activated, CD70+ T-cells, which comprise a subset of all T cells, ALLO-329 has the potential to enhance therapeutic benefit compared to treatments targeting B cells alone. With this dual targeting approach, both elements of the dysfunctional immune response against self-antigens - the pathophysiology at the core of autoimmunity - can be eradicated. B cells, which give rise to autoantibodies, and T cells, which both contribute to B-cell mediated autoimmunity as well as can cause direct tissue damage, are targeted by ALLO-329.
Our preclinical findings showed robust dual CAR expression and specific cytotoxic activity against both CD19+ B cells and CD70+ T cells, demonstrating its potential to target both sides of the immune response involved in autoimmunity, a first in this field.
What is the rationale behind choosing CD70 as a target for activated T cells in autoimmune diseases?
The rationale behind choosing CD70 as a target for activated T cells in autoimmune diseases is due to its expression pattern. CD70 is primarily expressed on activated T cells and plays a critical role in their function. By targeting CD70, we aim to regulate the overactive immune response that characterizes many autoimmune diseases.
How does ALLO-329 differentiate from other CAR T approaches being developed for autoimmune diseases?
This is a highly competitive field with many approaches focusing only on isolated aspects of autoimmune pathogenesis. ALLO-329 differentiates from other CAR T approaches being developed for autoimmune diseases through its unique dual-targeting ability. Unlike most CAR T therapies currently in development for autoimmune disorders that target only one antigen found on B cells, ALLO-329 simultaneously targets both CD19+ B cells and CD70+ activated T cells. This comprehensive approach allows us to address a broader spectrum of immune disorders, potentially improving patient outcomes.
Targeting CD70 on alloreactive T cells in patients treated with off-the-shelf CAR T cells with our specifically designed CAR is another unique and differentiating feature of ALLO-329 and underlies our proprietary Dagger® Technology. This clinically validated technology could enable ALLO-329 to overcome one of the biggest anticipated barriers to CAR T therapy in autoimmune disorders: lymphodepletion. We believe this unique feature of ALLO-329 will allow us to reduce or eliminate the need for lymphodepleting chemotherapy, which we believe could expand adoption of ALLO-329 beyond the most severe cases of autoimmune disease.
What advantages do you see for your allogeneic approach compared to autologous CAR T therapies in development?
Beyond its technical strengths, ALLO-329 is designed as an "off-the-shelf" and “once-and-done” solution, which differentiates ALLO-329 from autologous CAR T or bispecific TCE and allows us to potentially reach these larger patient populations with autoimmune disease. Given the number of potential patients with treatable autoimmune disorders, especially if patients with more moderate disease symptoms are addressable with CAR T, meeting that scale will be next to impossible to do with bespoke manufactured autologous CAR T products. In addition, allogeneic cells may be better suited than autologous cells to perform the immune reset believed to be at the heart of CAR T efficacy in autoimmunity. Because they are eventually rejected by the patient’s immune system, long term risks such as prolonged B cell aplasia and secondary malignancies may be minimized. While reports of secondary malignancies with the use of autologous CAR T therapies are rare, it nevertheless becomes an advantage to have a product that will quickly be eliminated by the body once it has completed its task. Our "off-the-shelf" allogeneic approach, using T cells from healthy donors, addresses these limitations.
How do you see ALLO-329 potentially changing the treatment paradigm for autoimmune diseases
We believe ALLO-329 has the potential to revolutionize the treatment paradigm for autoimmune diseases. Unlike competitors in the space, we are tackling a broader spectrum of autoimmune mechanisms, which could significantly enhance therapeutic outcomes and expand the range of autoimmune diseases we can address.
This "off-the-shelf" therapy, coupled with encouraging preclinical findings in models of systemic lupus erythematosus (SLE), offers a more accessible treatment option with the potential to significantly improve patient outcomes and quality of life across multiple autoimmune conditions.