2022: The year of γδ T-cells?
The adaptive immune system consists of two primary types of lymphocytes known as T-cells and B-cells. While these lymphocytes are in the same family of immune cells, they operate very differently. T-cells are produced in the bone marrow and matured in the thymus, where they are sent on two different major pathways of maturation, depending on the type of receptor complex that is developed [1,2]. CD4+ T-cells, also known as helper T-cells, help to orchestrate the activity of CD8+ T-cells, as well as other immune cells. CD8+ T-cells, which generally are known as cytotoxic T-cells, act to effectively identify and kill cells in the body that present antigens originating from infectious microorganisms or cancerous mutations [2]. The primary receptor responsible for the cytotoxic activity exhibited by T-cells is the T-cell receptor (TCR). This receptor is a complex structure, which in most T-cells is composed of an ⍺- and β chain, that together mediate the interaction with the the major histocompatibility complex I (MHC-I) that carry the presented antigens [3].
Today’s adoptively transferred T-cell therapies, that are being developed to treat cancer, are primarily based on ⍺β T-cells. However, some problems emerge when relying on T-cells to recognize and kill cancer cells in a MHC-I/⍺βTCR dependent manner. Cancer cells are known to acquire mutations that induce downregulation or total elimination of the MHC-I responsible for the presentation of cancerous antigens to the ⍺β T-cells. Over time, this greatly diminishes the effectiveness of the anti-tumoral response inherent to this class of T-cells [4].
While this problem is effectively circumvented by engineering the T-cells with chimeric antigen receptors (CARs), that recognize protein antigens on the surface of cancer cells, other problems emerge with ⍺β T-cells. Today’s FDA approved CAR-T cell therapies, and most investigational CAR-T cell therapies being tested in clinical trials, are autologous therapies, meaning that the T-cells are derived from the patients themselves. However, this is both an ineffective and extremely expensive procedure. Therefore, much research is going into the development of allogeneic, off-the-shelf CAR-T therapies. The big problem, however, manifests as the graft T-cells recognize the host’s MHC-peptide complexes as non-self, killing these cells and causing graft versus host disease (GvHD), which in the worst case can be fatal [5]. One approach to circumvent this side-effect is to induce knock-out of the TCR, rendering the T-cells unable to recognize the host’s MHC-I complexes. Nevertheless, this again is difficult and requires a precise and efficient gene editing tool, such as the CRISPR system.
Other approaches involve the use of different cell-types that exhibit an innate ability to kill cancer cells, such as macrophages, NKT-cells or natural killer (NK) cells, but do not attack host cells to cause GvHD. You can read more about NK cells and the use of these cells for cancer therapy here. Another cell type that possesses these characteristics is known as the γδ T-cell. In humans, the ⍺β TCR is present on approximately 95% of all the T-cells in the body. The remaining 5% express a TCR which is composed of a γ- and a δ-chain, hence the name γδ T-cell [6]. The γδ T-cell was first discovered in 1987, following the accidental discovery of the γ-chain in TCRs [7].
The unique aspect of this type of T-cell is that it does not recognize MHC-I through its γδ TCR. The use of the γδ TCR is still largely unknown, but it may play a role in the recognition of lipid antigens and stress induced ligands. Instead, the γδ T-cell is able to recognize cancer cells through a variety of innate receptors such as NKG2D and other natural cytotoxicity receptors (NCRs). Additionally, these T-cells are able to secrete high levels of cytokines, which also have important regulatory roles in the anti-cancer response of the immune system[7]. Furthermore, the γδ T-cell exhibits an inherent tumor-homing ability, which again increases tumor infiltration, and patients with high tumor infiltration with γδ T-cells are generally associated with better survival outcomes [8]. Collectively, these features position the γδ T-cell as a great candidate for the treatment of cancers in an allogeneic setting.
Many sub-types of γδ T-cells have been identified over the years, but not all subtypes exhibit the desired characteristics for cancer immunotherapy, and γδ T-cells have been under some scrutiny as reports have claimed γδ T-cells tumor-promoting properties in the tumor microenvironment [7]. The sub-types of γδ T-cells are generally separated into two subsets, known as effector γδ T-cells and regulatory γδ T-cells, with effectors having pro-tumor capabilities and regulators having antitumor capabilities (Figure 1) [7]. The subtype, γδ T17, is shown to be a major source of IL-17 in the tumor microenvironment, thus promoting cancer growth. Other subtypes, such as Vδ1γδT and Vδ2γδT are largely anti-tumorigenic, and these subsets are also the ones being investigated in relation to immunotherapy.
Figure 1 - The different subtypes of gamma delta T-cells [7]
Due to the promising potential and growing understanding and classification of γδ T-cells, several companies are emerging, focused on this sub-group of lymphocytes to fight cancers. While some companies develop modalities that enhance or engage the γδ T-cells, others work to genetically engineer γδ T-cells, for instance with chimeric antigen receptors (CARs) [9]. One such promising γδ T-cell company focusing on this approach is Adicet Bio [10]. The company develops CAR-engineered therapies based on the Vδ1+ subset for both hematological- and solid cancers. Recently, Adicet Bio released promising preliminary results on its development of the first ever allogeneic, off-the-shelf, γδ CAR T-cell therapy in Non-Hodgkin's lymphoma. The data showed that the company's CD20-targeting CAR-T therapy was able to achieve profound early complete responses in 2 of 4 patients with a dose of only 30 million CAR+ γδ T-cells. In addition to the two complete responses, one patient achieved a partial response that investigators characterized as a near complete response. This is very promising early stage data, which shows that γδ T-cell therapies might be a serious candidate for the future of cancer therapies. Importantly, the company reported no signs of GvHD, thus indicating that the hypothesis of γδ T-cells not eliciting GvHD may hold true. Moreover, the company reported no signs of neurotoxicity or ≥Grade 3 cytokine release syndrome (CRS), adverse events that are otherwise normally attributed to CAR-T cell therapies [11].
Another γδ T-cell company, Lava Therapeutics, is developing γδ T-cell engaging antibodies using its GammabodyTM platform. These bispecific antibodies engage the γδ T-cells, more specifically the Vγ9Vδ2-subset, in a targeted manner that allows for highly specific cytolysis of tumor cells, with little off-target impact on healthy cells[12]. Lava has one programme currently being investigated in a phase 1/2a trial, which targets CD1d in several myeloid leukemias. The company expects to deliver preliminary antitumor data in the first half of 2022 [13], and furthermore the company is taking another candidate, targeting PSMA for metastatic castration resistant prostate cancer (mCRPC), into clinical trials.
While the field has yet to mature, the promising data being reported by γδ T-cell focused companies are sure to attract a lot of capital and new interest in this emerging field of cancer therapeutics, with recent acquisitions of GammaDelta Therapeutics and Adaptate Biotherapeutics. Stargazing Bio Research has collected all of the companies engaged in both engineered γδ T-cell therapies like Adicet Bio among many others, as well as the companies actively developing γδ T-cell engagers/enhancing antibodies like Lava Therapeutics. The field is set to grow rapidly and if this promising data continues to roll out, it is important to get in early if you are looking to invest in the industry or get an overview of the competitive landscape. Upon releasing its data readout, the stock price of Adicet Bio, trading under the ticker symbol $ACET, grew 38.5% on the day.
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