A new wave of therapies based on a unique type of immune cells, called gamma delta T cells, is promising to improve the way we can treat cancer. Meet the players using these cells to target difficult to treat tumors with stronger responses and less side effects.

Immunotherapies based on T cells are becoming a huge trend in the treatment of cancer. Especially CAR-T cells, genetically-modified T cells that have shown remarkable remission rates in patients that did not respond to many other treatments.

Still, they have limitations. CAR-T cells come with strong, sometimes deadly side effects, and their capacity to target solid tumors is limited.

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Among the various solutions emerging, there is a wave of research focusing on a specific subtype of T cells. Called gamma delta T cells, they only amount to up to 5% of all T cells in our body, but they play an important role against cancer. A study published in Nature Medicine in 2015 revealed that the infiltration of gamma delta T cells in a tumor was the best predictor of a favorable outcome for the patient.

Unlike the alpha beta T cells commonly used in CAR-T therapy, gamma delta cells play a role in the innate immune response, which constitutes the first, faster line of defense of the immune system.

“As gamma delta T cells are part of the innate immune system, they are already pre-programmed to locate and destroy cells that are ‘stressed’ by cancer-associated transformation. Unmodified alpha beta T cells do not possess this innate function,” said Michael Leek, CEO of TC Biopharm.

gamma delta t cells

Responses from gamma delta T cells are faster than from alpha beta T cells

Leek’s company is seeking to exploit this function of gamma delta T cells in order to make a new form of CAR-T therapy. “By modifying gamma delta T lymphocytes with a CAR, it’s possible to create a supercharged cell with significantly increased cytotoxicity against cancerous tissues,” Leek told me.

Thanks to their natural ability to target cancer cells, gamma delta T cells could provide a safer version of CAR-T therapy thanks to what Leek calls a “dual activation system” where the CAR-T cell only attacks those cells that have undergone cancer transformation and have the specific antigen against which the CAR-T cell is primed. “This means that large doses of oncolytic cells can be administered to the patient without healthy cells being targeted,” added Leek.

Another key advantage of gamma delta T cells is that their ability to recognize antigens does not rely on the presence of a specific major histocompatibility complex (MHC) — a type of molecule located on the cell surface that present antigens to white blood cells. MHCs vary among individuals and are the basis of donor compatibility in transplantation.

As opposed to alpha beta T cells, gamma delta T cells are able to recognize an antigen independently of the MHC that presents it. That makes them a great candidate for the development of “off-the-shelf’ CAR-T cells that are derived from donors instead of from the patient, an approach that could make the therapy much faster and more affordable.  

gamma delta t cells

T cell receptor binding an antigen presented by the major histocompatibility complex

The unique receptors of gamma delta T cells could also make a difference in the creation of CAR-T cells for targeting solid tumors. Whereas alpha beta T cells target primarily peptide antigens, gamma delta T cells can recognize non-peptide antigens, which are mostly phosphorylated metabolites that are found at higher levels in cancer cells.

“These new targets mean solid tumours may for the first time be addressed by a CAR-T approach, using the patient’s own immune system to attack the tumour,” Shelley Margetson, CEO of Gadeta, told me. Her company, based in the Netherlands, is about to start its first clinical trials with gamma delta T cell technology.

Despite all these advantages, gamma delta T cells are still a relatively new area of research with its own challenges. “Clinical trials to date with gamma delta T cells have shown an overall good safety profile but limited clinical efficacy,” Margetson said.

To get around this problem, Gadeta’s approach to CAR-T therapy consists of engineering alpha beta T cells with T cell receptors derived from gamma delta T cells. “This combines the strengths of both the different types of T cells, whilst overcoming their respective weaknesses,” explained Margetson.

Gadeta gamma delta t cells

Gadeta’s gamma delta T cell approach

Another solution may lie in selecting specific subtypes of gamma delta T cells. “Historically, clinical use of gamma delta T cells has been limited to the blood resident Vγ2δ9 subtype of gamma delta T cells, which require constant antigen stimulation and are prone to die upon activation,” said Natalie Mount, CSO of GammaDelta Therapeutics, a spin-out of King’s College London that has a $100M deal with Takeda for the development of its gamma delta T cell technology.

GammaDelta Therapeutics focuses instead on a subtype of cells known as Vγ1 that are located inside tissues instead of in the bloodstream. “These tissue resident cells have excellent potential for treatment of solid tumours as they are primed to reside in tissue within a low nutrient and hypoxic environment, where they can carry out tissue surveillance, moving through tissues and recognizing and eliminating transformed cells,” Mount told me.

The promises seem big, but all these approaches will need to be tested in clinical trials to confirm their potential to treat cancer. Still, the trend of gamma delta T cells will likely not be fading any time soon. “Gamma delta T cells are gaining attention fast and we expect to see numbers of clinical trials increase significantly,” said Gadeta’s Shelley Margetson. And with an increasing number of different approaches being tested, our chances to finally beat difficult to treat forms of cancers are slightly higher every day.


Images via Shutterstock; Gadeta

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