The Challenges and Promise of CAR T-Cell Therapy in Oncology

Chimeric antigen receptor T-cell therapy (CAR T) has provided substantial benefit to patients with certain hematological malignancies and has significant opportunity for growth. As of 2024, the global CAR T-cell therapy market is valued at $4.6 billion and is projected to reach $15.2 billion by 2035. Despite this, CAR T-cell therapies are currently limited to treating B-cell malignancies, and most patients do not achieve progression-free survival. Such challenges highlight a significant unmet need and call for further advancements in the field.

Vittoria Biotherapeutics is a clinical-stage cell therapy company that incorporates the latest advancements in cell therapy and gene editing with a unique approach that potentially overcomes some of the issues with this therapeutic modality. Its therapeutic pipeline targets unmet needs in oncology and autoimmune disease. Vittoria aims to harness the potential of cell therapy to cure chronic diseases, enhance the potency and efficacy of treatments, and expand their applications across various indications. Vittoria’s investigational CAR-T therapy leverages gene editing to modulate the CD5 signaling pathway and a shorter manufacturing time to enhance efficacy and improve manufacturing efficiencies and vein-to-vein time.

In a recent interview with Xtalks, Nicholas Siciliano, PhD, CEO and Co-Founder of Vittoria Biotherapeutics, shared his journey and the mission driving his innovative biotech company. With a PhD in immunology and a career rooted in Philadelphia, Nick’s path was inspired by his interactions with prolific life science executives and witnessing groundbreaking innovations from institutions like Penn and the Children’s Hospital of Philadelphia (CHOP). It was here that Dr. Siciliano ventured into the forefront of therapeutic innovation, particularly in cell therapy for oncology.

XTALKS CLINICAL EDGE: Issue 3 — Interview with CTTI

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“I’m a firm believer that cell therapy, and the modality in general, is going to be the future of medicine and has the potential to be curative for chronic diseases that in the past, we could at best, hope to manage,” he stated.

One of the significant hurdles in advancing gene-edited CAR T-cell therapies is the gene editing process. This introduces an additional unit operation in manufacturing, requiring precise delivery of nucleases and ensuring that guide RNAs don’t have off target implications.

While this process can add a layer of complexity, including the need for robust safety and analytical measures, Dr. Siciliano emphasized the net benefit and future potential of leveraging gene editing in CAR T development. “Gene-editing will become part and parcel to next-generation cell therapies,” he noted, describing how improving cell exhaustion — when immune cells such as T cells are unable to identify and eradicate cancerous or infected cells — and enhancing effector function — which is the interaction between an effector T cell and target antigen — far outweigh the challenges.

The CD5 Pathway

CD5 is highly expressed on T cells and the CD5 signaling pathway plays an immunosuppressive role in T-cell effector function, making it a significant target for excision from CAR T-cell therapies for enhanced activity.

“There’s a tremendous amount of evidence in the literature and even in clinical data that shows that CD5 is an important modulator of naturally occurring anti-tumor T cells in patients,” said Dr. Siciliano. Vittoria’s scientific founder, Dr. Marco Ruella, a physician-scientist at the University of Pennsylvania, recently published a seminal study describing the impact of knocking out the CD5 receptor to improve the anti-tumor activity of CAR T cells in Science Immunology. The study showed enhanced efficacy and reduced exhaustion markers in CD5 knockout CAR T cells, leading to better tumor control in vivo.

Removing the CD5 receptor from the CAR T treatment is central to Vittoria’s approach, and in combination with Vittoria’s proprietary five-day manufacturing process, offers multiple functional benefits. These include enhanced early proliferation, which allows the potential for lower dosing, reduced manufacturing failures and shorter production times. Additionally, it confers resistance to exhaustion in solid tumor models, a critical factor for achieving success with CAR T therapies in solid tumor cancers.

However, the CD5 pathway is not fully elucidated despite its potentially pivotal role in mediating T-cell effector function. Vittoria’s unique perspective on modulating this pathway has revealed numerous functional benefits, making their approach distinctive. “We haven’t seen such a marked improvement in function with any other single gene edit that we’ve explored, or frankly, that’s been explored by others in the literature. So that’s really exciting,” Dr. Siciliano explained.

VIPER-101 vs. Traditional CAR T Methods

“T-cell lymphoma, historically, has been a very difficult disease to treat. Conventional treatments don’t yield great response rates. A large percentage of patients ultimately become relapsed or refractory to frontline chemotherapies. Delivering an effective and durable therapeutic to these patients would really be game-changing for this indication,” said Dr. Siciliano, setting the stage for the unique advantages of their lead program, VIPER-101, particularly in treating T-cell lymphoma.

Vittoria’s VIPER-101 therapy potentially offers a solution with its novel, dual population therapeutic approach. “One of the big challenges with delivering a CAR T against a T-cell malignancy is that you’re using T cells to target T cells,” Dr. Siciliano highlighted. One population in our therapy is the effector population that has the CAR and targets CD5 on malignant T cells, while the other is a population engineered to be nearly identical to the native T cell population but with CD5 deleted. This second population of CD5 deleted healthy T cells can function as a patch for T-cell cytopenia or T-cell aplasia during the effector phase of the therapy.

By avoiding the destruction of healthy, CD5 knockout T cells, VIPER-101 can target malignant cells expressing CD5 while reducing the impact on the patient’s healthy T cell compartment. This unique approach also prevents the CAR T product from attacking itself via fratricide, thereby preventing fratricide-mediated suppression of the drug product and reducing manufacturing challenges.

A standout feature of VIPER-101 is its innovative, five-day manufacturing process that is enabled by Vittoria’s Senza5^TM platform technology. Traditional CAR T manufacturing can take 14 days or more, but the company has developed a rapid process that significantly shortens this timeline and confers a functional benefit to the resulting CAR T-cell therapy. The quicker turn-around improves cell stemness and improves manufacturing efficiencies. Combining this with CD5 knock-out provides additional advantages.

“Modulating the CD5 pathway allows us to dose orders of magnitude lower than conventional CAR T. We don’t need the expansion that other cell products do,” added Dr. Siciliano. Lower dosing requirements can reduce the incidence of manufacturing failures.

Another key challenge in CAR T therapy is antigen escape, where cancer cells mutate to evade treatment. Dr. Siciliano explained that early and robust expansion of CAR T cells in patients helps prevent this. “We believe that by targeting the cancer cells early on during the treatment and getting a robust cytotoxic effect from the drug, we will be able to potentially avoid antigen escape,” he said. This proactive approach ensures that the therapy remains effective over time, reducing the likelihood of cancer recurrence.

Senza5^TM Platform for Manufacturing CAR T Therapies

The Senza5 platform, Vittoria’s proprietary technology, demonstrates unprecedented utility and superior anti-tumor efficacy across multiple distinct liquid and solid tumor models. By modulating the CD5 pathway, Senza5 addresses early expansion, durability and resistance to exhaustion.

“Shorter autologous manufacturing times confer better stemness and durability to the drug product. The less time that a patient’s T cells spend in an in vitro foreign environment, the better they do when they go back into the patient,” Dr. Siciliano explained. The shorter manufacturing process not only improves the quality of the product but also accelerates the treatment timeline, making it more efficient and effective.

Senza5’s enhances early CAR T in vivo expansion and functional persistence. “Because of what we’ve elucidated about the CD5 pathway, and due to the functional benefits, its modulation confers like early expansion, we can allow the expansion to happen in the patient rather than in culture,” Dr. Siciliano noted, emphasizing the platform’s advantages.

Beyond T-cell lymphoma, the Senza5 platform holds promise for various oncology and immunology applications. Vittoria’s Phase I trial, which is currently enrolling patients, will provide valuable insights into the platform’s broader potential. The company is also exploring innovative approaches to distinguish between pathogenic and healthy cells, potentially offering safer and more effective treatments for a wide range of conditions.

Navigating the Regulatory Landscape

Regulations for novel therapies like CAR T are complex.

Dr. Siciliano emphasized the importance of proactive and thoughtful engagement with regulatory agencies. “One of the things we’ve seen from the agency is they’ve been proactive and very thoughtful about developing policies, regulations, constantly communicating about new guidance to try to help drug developers bring these, what I believe to be transformative, therapies to market and to patients,” he said. This collaboration is essential for ensuring that new therapies meet safety and efficacy standards while also facilitating timely access for patients.

This emerging field of next-generation CAR T therapies combines potency and efficacy improvements with streamlined manufacturing processes. As cell and gene therapies advance, the regulatory landscape will hopefully evolve, improving their accessibility. Dr. Siciliano highlighted the need for a balance between rigorous testing and the urgency of delivering potentially curative treatments to patients. Vittoria is at the forefront of what Dr. Siciliano describes as the “enabled-autologous” category of cell therapies.

Vittoria aims to influence the broader oncology treatment landscape, offering new hope for patients with challenging conditions.