Can immune cell-based therapies become mainstream in oncology?

Developing an allogeneic cell therapy is not without its challenges, including avoiding destruction by the patient’s immune system

There have been two successful cell therapies that target the so called ‘liquid tumours’ (leukaemia and lymphoma). Both are chimeric antigen receptor (CAR) T cells -- Novartis’ Kymriah and Gilead Sciences’ Yescarta -- and both demonstrate initial high response rates that convert to durable clinical responses in a subset of patients. While the early success of these therapies is promising, the next generation of cell therapies needs to contribute to the treatment of patients with solid tumours.

There were ~176,000 new patients diagnosed as having liquid tumours in the USA in 2019, compared with ~1.6 million (almost a ten-fold increase) new patients diagnosed as having solid tumours. In addition, because Kymriah and Yescarta are autologous therapies (manufactured using the patient’s own cells), the cost of an individual treatment is high — $475,000 (Kymriah) and $373,000 (Yescarta) — and potentially prohibitive to healthcare budgets. By comparison, an average cancer drug costs in the region of $10,000 per month. So, can cell-based therapeutics become a mainstream treatment for cancer patients and what changes might make this feasible?

Gene editing — for transitioning cell-based therapies into solid tumours?

Although cell-based therapy is a complex form of cancer treatment, targeting liquid tumours is more straightforward. Leukaemia and lymphoma cells can be accessed via the blood stream, meaning that there is no requirement to target the cell therapy to a specific tissue or organ. Neither is there the challenge of navigating a disorganised capillary network and persisting within an immunosuppressive and hypoxic solid tumour microenvironment. It is widely believed that cell therapies will need to be armed to navigate and survive these challenges and have a substantial impact on patient survival. 

Avoiding off-target chromosomal translocations

Precise modulation of the therapeutic cell to increase survival, proliferation, and persistence is required, and is likely to involve multiple gene edits. While CRISPR-Cas, the popular gene editor, is robust when delivering single genetic changes, it does so by generating DNA double-strand breaks (DSBs), which can cause off-target chromosomal translocations in the cell. With correct guide design and careful use, such changes are rare with single or double edits; however, where multiple genes need to be edited, the risk of generating chromosomal translocations and other genetic aberrations increases. Such changes could lead to an oncogenic therapeutic cell — a potential disaster for the patient. For one or perhaps two gene editing events, such translocations can be screened out and precisely edited cells identified for therapeutic use in the patient. However, beyond a couple of editing events, identifying a precisely edited cell becomes more troublesome and the risk of missing an oncogenic translocation increases too. 

Base editors: avoiding double-strand breaks

Base editing is a relative newcomer to the gene editing arena that is catching people’s attention. Base editors can consistently deliver gene editing in primary cells with high efficiency without using a nuclease introducing a DNA DSB. Base editing works by generating a nick (or single-stand break) in the DNA and altering a specific base pair using a deaminase enzyme. This can enable the effective knockout of genes by introducing a stop codon in early coding exons. The impact of base editing on cell therapy development should become apparent over the next few years, and it is likely that much of this will be realised in the development of allogeneic as opposed to autologous cell therapies. 

Off-the-shelf allogeneic cell therapy?

Allogeneic cell therapies use healthy donors to develop off-the-shelf therapeutic cells. These can be manufactured at scale and stored in central hubs until required for treatment. Developing an allogeneic cell therapy is not without its challenges, including avoiding destruction by the patient’s immune system. To avoid this, an allogeneic cell therapy must be modified to achieve a stealth-mode where it is seen as “self” by the patient’s immune system. To develop such a cell, multiple genes will need to be modified and most likely knocked out. It is anticipated that base editors will play a crucial part in editing multiple genes to enable prolonged survival of allogeneic therapeutic cells in patients without the use of immunosuppressive drugs. 

Allogeneic cell therapies should also be cheaper than their autologous cousins because the supply chain is simpler and easier to manufacture at scale. Indeed, healthcare economic research indicates allogeneic cell therapies could be reduced to $7,500 per dose if an economy of scale is achieved. Such a reduction in price will help drive the democratisation of cell therapy as a mainstream treatment. 

Delivering cell therapy to all patients

Cell therapies with high efficacy driving durable clinical responses is an attainable goal. In oncology we need to translate the successes of immune cell-based therapies in liquid tumours to solid tumours through modifying immune cells to withstand the more challenging solid tumour microenvironment and reduce costs of such therapies. Both can be achieved with the application of efficient and effective gene editing to develop allogeneic cell therapies. While CRISPR-Cas is being used in the development of these cells, owing to an anticipated improved safety profile, future allogeneic cell therapies are likely to make use of base editors to introduce genetic changes.

Author:  Jonathan Frampton is Corporate Development Partner at Horizon Discovery horizondiscovery.com