Gamma delta (γδ) T cells hold significant potential for unmet medical needs. Yet they are more challenging to source than other T cells, representing as little as 1% to 5% of the total CD3+ T-cell population in peripheral blood.1 Crucially, the mechanism of action of gamma delta T cells means they can operate in an HLA-independent manner and have potential as an “off-the-shelf” allogeneic therapy.
The cell therapy market is expected to surge in the coming years. While CAR-T therapies are becoming increasingly important in oncology for treatment of so-called liquid tumors and perhaps also for treatment of autoimmune diseases, gamma delta T cells — a less conventional subset — are emerging as an exciting treatment for solid tumors and, quite recently, also autoimmune diseases.
However, there remain challenges in procuring the rare gamma delta T cells and scaling up manufacturing effectively. To meet demand, pioneering research is furthering the development of potentially lifesaving therapy using these cells.
Gamma delta vs alpha beta T cells: What’s the difference?
Gamma delta T cells are a small subset of white blood cells. They are especially effective for cancer treatment because they are activated by stress signals expressed by tumor cells, not by a single specific antigen on a tissue type.
This means that gamma delta T cells express little or no toxicity toward healthy cells that may express the same antigens as cancer cells, offering a safety advantage over conventional CAR T cells. Furthermore, gamma delta T cells can enhance other cells in the immune system to strengthen the body’s natural ability to attack cancer cells.
“If you look at the market right now, there are a lot of solid tumor applications [for gamma delta T cells], which CAR-T therapies have so far failed to address,” says Stuart Gibb, head of scientific strategy for cell and gene therapies at Terumo Blood and Cell Technologies.
According to GlobalData’s Clinical Trials Analytics database, solid tumors remain the top indicator for the pharma industry going forward, with approximately 6,570 trials underway worldwide.2 This suggests a huge window of opportunity for gamma delta therapies, which can also treat “liquid cancers” — namely, those affecting the blood and blood marrow. Additionally, this year, the first clinical trial was registered to investigate the use of gamma delta T cells for treating autoimmune disorders.
Yet despite the enormous potential of gamma delta T cells, challenges remain over their scalability. Given that most trials have not progressed beyond Phase II, Gibb warns against expecting too much too soon while knowledge is still developing.
“We’re at Phase II. So, there’s guesswork, there’s informed speculation. To say gamma deltas definitely have a better safety profile [than CAR-T cells] is overreaching,” he says. “But I think there is certainly potential that gamma deltas could meet and supersede the current autologous CAR-T space because of the different mechanisms in how they act.”
The scale of the manufacturing challenge
Like most other cell therapies available today, gamma delta T-cell therapies are autologous. Cells must originate from each individual patient being treated. The therapy involves complex logistics, as the cells are taken from the patient and then later readministered to them after processing. With existing manufacturing processes, these methods are both costly and time-consuming, posing a significant obstacle to the successful scale-up of cell therapies.
However, gamma delta T cells are even more difficult to extract from patients because they represent a very small proportion of the body’s white blood cells.3 While higher percentages are present in the gut and lungs, the extraction processes would be far more invasive and complex than taking blood.
“There’s a limited number of cells in the bloodstream that you can isolate,” explains Gibb. “Scaling up is a two-stage approach. In one approach, you need to go from that small amount of starting material to a sufficient amount for genetic modification. Then there’s a second stage of expansion that you can either do with feeder cells or feeder-free.
“Compare and contrast to regular T cells, which follow a more linear expansion process. But I believe scaling up gamma deltas is ultimately achievable.”
Addressing the quantity-over-quality issue
Because of the small quantity of biological material available for use, expanding gamma delta T-cell production is a different conversation from the regular T-cell approach. In the future, the careful handling of this finite and valuable material could potentially be enhanced with artificial intelligence (AI).
“On the autologous CAR-T side, we’re acutely aware of the right phenotype. That’s not really been addressed for gamma deltas at the moment,” says Gibb. “But once we’ve got to a base treatment, for the device manufacturers, AI is going to come into play for feed rates and other critical parameters for processing.
“Right now, we’re kind of in this weird space with gamma delta T cells, where quantity is overriding quality. As soon as we start getting more realistic clinical data, that’s when AI is going to really step up and improve quality.”
Currently, heterogeneous protocols are in place for expanding gamma delta T-cell processes. Gibb advises manufacturers to take a step back and take time to analyze datasets and preclinical processes to understand the best route for large-scale production.
Prospects remain optimistic for gamma delta T cells
Despite the challenges, the market outlook remains exciting. Gibb believes in the past year, the number of companies in the gamma delta space has increased from 10 to 15 — an uptick of 50%. In this rapidly evolving field, manufacturers seeking to innovate will need to find the right partners who can support successful scale-up.
“Once the Phase II trials close, we can work out how many [gamma delta] cells we need. Because we don’t necessarily need the same amount as we’ve needed for CAR-T cells,” adds Gibb. “It could be less, because you don’t have certain problems that CAR-T cells present — the graft-versus-host disease is not a consideration. From the clinical reports I’ve read, [gamma deltas] also have a lower incidence of cytokine release syndrome.”
With cancer and autoimmune conditions remaining prevalent worldwide, the potential impact of gamma delta T cells as treatment could be enormous. In the long term, they could far surpass the effectiveness of CAR-T cell therapies.
“There have been efforts to [produce] allogeneic CAR T cells through CRISPR or editing. But with gamma deltas, we don’t have to do any fancy genetic manipulations,” notes Gibb. “If everything pans out, they absolutely have the potential to meet and exceed where CAR-T is at the moment.”
To learn more about how Terumo Blood and Cell Technologies can support cell and gene therapy scale-up, download the exclusive report below.
References:
1. Hu Y, Hu Q, Li Y, et al. γδ T cells: origin and fate, subsets, diseases and immunotherapy. Signal Transduct Target Therapy. 2023; 8:434. doi: 10.1038/s41392-023-01653-8
2. GlobalData. Number of ongoing clinical trials (for drugs) involving solid tumor by phase. October 2021. Accessed 15 October 2024. https://www.globaldata.com/data-insights/healthcare/number-of-ongoing-clinical-trials-for-drugs-involving-solid-tumorby-phase-503550/.
3. Meraviglia S, Lo Presti E, Tosolini M, et al. Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer. OncoImmunology. 2017;6(10). doi: 10.1080/2162402X.2017.1347742
