Advancing CAR-T therapy: how CD5 modulation is shaping cancer treatment

What potential advantages does the CD5 modulation strategy offer over traditional CAR-T therapies?

MR: Chimeric antigen receptor T-cell (CAR-T) therapy is very effective in treating patients with B-cell lymphoma, leukemia, and multiple myeloma, where we have six FDA-approved drugs. However, these treatments will eventually fail for the majority of patients, so there is a strong need for better CAR therapies. Our approach of CRISPR-Cas9 deletion (a gene-editing technology) of CD5 (a specific cluster expresses on the surface of T cells) gives the CAR T cell a higher activation and higher proliferation in vivo that leads to much stronger anti-tumour activity. We think that, over the traditional CAR product, a product that uses gene editing, using CRISPR gene knockout of CD5, would potentially lead to stronger anti-tumour effects in multiple cancer models. We’re starting with T-cell lymphoma – which is a step further compared to traditional CAR T cells that targets only B cell neoplasm – and then we are planning to expand this approach to solid cancers, where CAR-T therapy has not yet succeeded in leading to prolonged remissions.

How might the CD5 knockout approach impact the treatment of other types of cancers beyond T-cell lymphoma?

MR: We started by focusing on T-cell lymphoma because it is an orphan disease with very limited effective therapies, but, importantly, we think that CD5 deletion enhances any type of CAR T cell treatment. As a matter of fact, in the paper we show up to six different models of cancer using CAR T cell and TCR-edited T cells. In all the models we show that, even in solid cancers, CD5-deleted CARs have a better anti-tumour effect. We think that the key point is that CD5 enhances CAR T-cell activation and function even within the immunosuppressive tumour microenvironment, which means this approach is going to be particularly important for cancers such as solid cancer where the immune microenvironment is terribly toxic to the CAR T cells. We are planning on expanding this approach from T-cell lymphoma to solid cancers and potentially other types of haematological cancers where we do not have a CAR product approved; for example, adult acute myeloid leukemia (AML).

How is Vittoria Biotherapeutics leveraging the findings about CD5 to develop their lead program, VIPER-101, for T-cell lymphoma?

NS: Vittoria Biotherapeutics is pioneering the application of CD5 modulation through its Senza5^TM platform to enhance CAR T-cell therapies, exemplified by our lead program, VIPER-101. By simultaneously deleting CD5 and expressing a CD5-targeting CAR into engineered patient T cells, VIPER-101 offers a novel approach for treating T-cell lymphoma. This program uses our proprietary Senza5 technology to remove CD5 from the surfaces of engineered T cells, significantly enhancing the cytotoxic activity of engineered CAR T cells that target this same antigen on tumours, thus preventing T-cell fratricide while conferring enhanced effector function. The result is a therapy that addresses the aggressive nature of T-cell lymphoma with both improved potency and a unique safety feature. This approach has the potential to be transformative for T-cell lymphoma patients, as they currently face limited treatment options with only modest response rates.

Can you explain the key features and benefits of the Senza5 platform developed by Vittoria Biotherapeutics?

NS: The Senza5 platform, developed by our team, represents a significant advancement in CAR-T therapy. It integrates gene editing to remove the CD5 molecule from engineered T cells and a rapid five-day manufacturing process that synergises to enhance effector function and preserve cellular ‘stemness’, essential for long-term efficacy and durability in patients. This platform not only increases the potency of CAR-T therapies, but also reduces potential risks, making treatments safer and more effective for a broader range of cancers, including solid tumours.

What future developments and innovations can be expected from Vittoria Biotherapeutics in the field of CAR-T therapies?

NS: Looking ahead, Vittoria is committed to expanding the frontier of CAR-T therapies. We are continuously exploring ways to enhance our Senza5 platform, focusing on increasing target antigen diversity and improving the scalability of our manufacturing processes. Future innovations will likely include developing solid-tumour-directed CAR-T therapies and augmenting the lymphodepletion process. Additionally, we aim to extend our technologies to tackle other challenging conditions, like autoimmune diseases, providing patients with more effective, potentially curative treatment options for chronic diseases.