Paolo Paoletti, CEO of GammaDelta Therapeutics celebrated in the 2019 Maserati 100 Innovators of the year award.

A look inside the science

Until recently, the development of new therapies for malignant disease had paid relatively little attention to the roles played by γδ T cells. This partly reflected an incomplete understanding of the mechanisms by which γδ T respond to tumours, coupled to the challenge of obtaining sufficient numbers of high quality γδ T cells for clinical-scale administration. GammaDelta Therapeutics has a unique position enabling us for the first time to isolate large numbers of high quality, tissue-resident γδ T cells from human tissues and to develop all appropriate steps to test their use in the clinical setting.

Gamma Delta T Cells


Gamma Delta (γδ) T cells are lymphocytes which, along with B cells and alpha beta T cells, form part of our adaptive immune system. This system of three cell types forming the adaptive system is conserved across species, all the way to jawless fish, thus underscoring its evolutionary importance.

γδ T cells, however, have unique properties that enable them to combine the specificity of an adaptive immune response with the speed of an innate cellular response. Alpha beta T cells and B cells are selected upon their capacity to recognise specific foreign antigens, which they do by travelling through the body’s lymphatic system before they can be recruited to sites of infection. On the other hand, γδ T cells are able to recognise molecular patterns of dysregulation in stressed, infected or transformed cells and are already resident in tissues such as the skin or the colon, as well as the blood, to carry out tissue surveillance and maintain homeostasis. Once γδ T cells recognise alterations of physiological self, they respond in situ and very quickly without the need for priming by antigen presenting cells or clonal expansion in the lymphatic system. They can kill transformed or infected cells immediately, attract the conventional adaptive immune system or present antigen themselves in order to start a fully developed systemic immune response.

Gamma Delta T Cell Function


The power of T cell based immunotherapy has already been demonstrated clinically; for example in the context of haematological cancers where genetically modified alpha beta T cells have elucidated profound clinical responses. The challenge however, of an effective cellular immunotherapy for solid tumours remains, as these tumours are effectively ‘hidden’ in an often hypoxic environment which is difficult to penetrate with blood resident cells.

Tissue-resident γδ T cells represent a compelling new approach as these cells home to and reside within tissue where they respond to perturbation of ‘normal self’. To this end, γδ T cells recognise so-called “stress antigens” which are indicative of infection or malignant transformation. Thus, rather than relying on the expression of specific antigens, for example those that distinguish measles from influenza, γδ T cells can respond to generic sentinels of dysregulation. This provides distinct advantages in the context of a cancer therapy, since they can recognise several different tumour types. Moreover, tumours cannot evade detection by their down-regulation of specific antigens, as is the case for cancer recognition by conventional T cells. Additionally, γδ T cell recognition does not depend on Major Histocompatibility Complex (MHC) presentation. Hence, a person’s γδ T cells may work equally well in another person. This may extend the cells’ potential beyond patient-specific, autologous therapy, to “off-the-shelf” allogeneic therapy. Furthermore, when tissue-resident γδ T cells respond, they often do so en masse, without the requirement to be selected or clonally expanded. This provides γδ T cells the power to combine the selectivity of the adaptive immune response with the speed of an innate response.

Tissue and Blood Resident Gamma Delta T Cells


Some mammals, but especially humans and higher primates, have a signature γδ T cell population residing in the blood. These invariant T cells (identifiable via their Vδ2γ9 antigen-recognising surface T cell receptor) largely respond to the same stimulus, namely a group of small phospho-moieties which include human metabolites that are produced in abundance by many malignant cells. With the help of a drug group called bisphosphonates, which boost the accumulation of metabolites in cancer cells even further, blood resident γδ T cells can recognise and kill tumour cells. Although powerful in theory, these cells need constant stimulation which can lead to exhaustion. Moreover, their biology suggests that they are evolutionarily primed to live and act within blood and studies of these cells have failed to show that they can efficiently leave the blood and migrate to tissues in order to target solid tumours.

Human tissue resident γδ T cells, on the other hand, express a specific set of T cell receptors that differ from blood derived Vδ2 T cells. These cells migrate and stay within human tissue (e.g. skin and colon) after their development and are not only equipped to migrate to and through tissue but also to cope with the very different environment that is found within tissues, such as reduced oxygen levels. They survey cells of the tissues they live in for any signs of stress, such as infection or transformation and respond to malignant cells immediately by killing them. A single γδ T cell can respond to a variety of different tumour cells but will spare healthy tissue cells.

Exploiting the function of Tissue derived Gamma Delta T Cells: Our unique approach


Laboratory studies have shown that tissue resident γδ T cells perform a critical immune-surveillance function in tissue, directly recognising and killing a variety of tumour cells. The importance of this has been shown in mice where defects in γδ T cells lead to a significant increase in tumour occurrence and severity. Interestingly, mice have a very minor blood γδ T cell compartment and this strongly suggests that the protective effect is mediated by their tissue resident γδ T cells.

Furthermore, human epidemiological studies showed a high γδ T cell signal to be the major positive prognostic factor for 5 year and overall survival across 39 tumour types examined in 18,000 cancer patients.

Tissue resident γδ T cells have been an intriguing focus of immuno-oncological research for a while but their biological nature, that is their residency in tissues, made them hard to study and even harder to isolate and grow in a laboratory or clinical setting.

We have developed unique methods to enable the isolation and expansion of these cells, allowing for the first time their growth in large numbers. As a result, we now have a compelling opportunity to fully exploit the capabilities of these cells, enabling us to bring forward new therapies for patients with cancers and other serious diseases.