Cell therapy could unlock next cancer revolution for AstraZeneca

12 February 2024

In this week’s Executive Interview, we speak with Mark Cobbold, vice president discovery and head of Cell Therapy, Oncology R&D, at AstraZeneca, and Carsten Linnemann, chief executive officer of Neogene Therapeutics, part of AstraZeneca.

This article has been commissioned and funded by AstraZeneca.

Since the approval of the first CAR-T in 2017, T cell therapies have revolutionized the treatment of some blood cancers, and are one of the few cancer treatments to drive cures. Over recent years there has been huge investment and growth in cell therapies, but success beyond blood cancers has so far been limited.

AstraZeneca is on a mission to change this and is steadily building their expertise and capabilities with the aim of bringing the transformative potential of T cell therapies to more patients living with cancer.

Extending the potential of Cell Therapy

Developing effective cell therapies for the treatment of solid tumors has proved challenging, due to the dense, immune-supressing environment that protects cancer cells from attack by the immune system.

This key difference between solid and liquid tumors, has given rise to treatment challenges, such as how to engineer cell therapies that can penetrate, and retain their activity in the solid tumor tissue.

As AstraZeneca’s Mark Cobbold explains: “One difference is that solid tumors have a bedded-down micro-environment, and that allows those tumors to defend themselves against attack from T cells.”

AstraZeneca wants to find a way to harness the benefits of cell therapies for solid tumors, an ambition which could see the company breaking ground in a very significant new market.

Dr Cobbold, head of cell therapy, Oncology R&D says the company is aiming to “bring in armoring to T cells, and not only modify how T cells recognize tumors, but allow them to be protected from the mechanisms that tumors use to subvert immunity.”

While other companies are also exploring armoring approaches, AstraZeneca has a unique set of innovations, including novel mechanisms that aim to make T cells more effective.

Looking ahead to clinical progress with armored CAR-Ts, as well as initial research targeting liver cancer, Dr Cobbold says the company has: “a program that will be starting this year in prostate cancer.”

“We have a program that targets STEAP2, an antigen that's never been targeted before by any other academic group or pharmaceutical company,” he says, adding: “in terms of some of our future plans, we are also looking at combination approaches designed from the ground up to achieve transformational benefits.”

AstraZeneca’s focus on cell therapies could give rise to significant advances in treatment outcomes.

The company’s commitment to the modality has been made clear through strategic investments in cell therapy research, not least the acquisition of Neogene Therapeutics.

By joining with leaders in the field, including Neogene, AbelZeta, Cellectis and Gracell Biotechnologies, AstraZeneca has the goal of together achieving more for patients than each company can do in isolation.

Neogene – the emerging promise of T cell receptor therapies

Speaking with The Pharma Letter from his base in Amsterdam, Neogene co-founder and chief executive officer Carsten Linnemann says Neogene’s goal, “very early on, was to deliver cures where none exist.”

Dr Linnemann says Neogene is working “to transform cutting edge science, at the frontier of what can be done in cell therapy today, into novel treatment options for solid tumors.”

The company with offices in the United States and the Netherlands is pioneering T-cell receptor (TCR) therapies, whereby neoantigen-specific TCR genes are identified and engineered into patient-derived T cells, primed to attack the cancer of each unique patient.

Neogene’s most advanced platform aims to develop TCR-T cell products capable of containing up to five different neoantigen-specific TCRs. The approach is currently being evaluated in a Phase I trial, taking place at the Netherlands Cancer Institute (NKI) which is enrolling people with various types of solid tumors.

Beyond this, the company has advanced novel TCR-T cell products targeting key cancer drivers, including TP53 and KRAS mutations into clinical testing.

Advancing research

AstraZeneca has been building up cell therapy capabilities for several years, and partnering with ground-breaking biotechs such as Neogene, the acquisition of which was completed last year, was the next logical step forward.

When the clinical potential of the T-cell therapies first became evident over a decade ago, it was clear the impact researchers could have in creating what Dr Cobbold calls “a kind of synthetic immunology, putting a chimeric antigen receptor on the surface of a T cell.”

However, he says, “really how T cells naturally recognize threats is through a T cell receptor,” adding: “What Neogene is doing is harnessing how T cells physiologically operate, by identifying T cell receptors from patients with cancer.”

In effect, this means the company is able to identify “the best T cell receptors that are out there,” and then allow cells to “re-express those T cell receptors to target those intracellular molecules.”

Dr Linnemann adds: “We know that T cells have the capability to mediate a deep and durable regression of solid tumors. I think what T cell receptor therapies can bring to the table is a very, very broad space of targets that can be pursued.”

Broadening access

Currently approved cell therapies are difficult to manufacture at scale, with products being created for each patient individually.

AstraZeneca wants to change that.

Dr Linnemann says: “Our long term vision is to provide cell therapies as an off-the-shelf therapy - very similar to other drugs that are readily available to patients.”

Scalability is at the forefront of the company’s thinking for this new frontier of treatment in oncology.

As Dr Cobbold explains, “having the capacity and infrastructure to deliver these therapies is a challenge for the industry.”

“Manufacturing enough of these products, when they're all made on a patient-by-patient basis, is a huge challenge, not just for industry, but actually for the healthcare system.”

The company plans to “disrupt that” he says.

Given the size of the patient populations involved, finding a way to scale up manufacturing will be a prerequisite for addressing these opportunities.

In oncology, a combination of leveraging proven treatment modalities while investing heavily to create new ones has been shown to be a winning formula, and one which may continue to bear fruit.

The company’s intensifying focus on cell therapies in cancer could follow the same playbook, with a combination approach likely to be necessary for many patients.

As Dr Cobbold says: “There's going to be an aspect of personalization, and we’re probably going to need multiple therapies in some patients. Targeting both surface antigens and the intracellular compartment provides the best chance of being successful and transforming what it means to be diagnosed with cancer.”