OUR SCIENCE
What is CAR T?
CARs (Chimeric Antigen Receptors) are artificial modular proteins, that are used to direct immune cell reactivity towards a target of interest.
The term chimeric indicates the presence of various components from various sources. The extracellular antigen binding, hinge transmembrane, and the intracellular activation domain make up CARs.
The single chain variable fragment (scFv) of a monoclonal antibody made up of the VL and VH region connected to a spacer, which is capable of recognising the tumour associated antigens (TAAs), makes up the extracellular antigen binding domain. The extracellular antigen binding domain and the intracellular cytoplasmic signalling domain are connected by a transmembrane hinge region that is connected to the cell membrane by a spacer.
CAR-T cells can be produced from a patient's own blood (autologous) or from the healthy T cells of a different donor (allogeneic). These T cells are isolated from a person and genetically modified to express a particular CAR, which instructs them to target an antigen found on the surface of tumours.
In order to ensure safety, CAR-T cells are designed to be specific to an antigen that is expressed on tumours but not on healthy cells.
Current Approach ?
Adoptive cell immunotherapy has advanced tremendously in the past decade by primarily using autologous NK and T cells.
In this treatment approach, the patient’s blood is collected and T cells are isolated, engineered to introduce the CAR gene, followed by expansion of these CAR T cells in vitro and introduction into the patient to fight against cancer.
Unfortunately, this approach carries certain limitations, for example; most cancer patients receive chemotherapy as a first line treatment and this significantly limits availability of competent T cells from these patients and often this results in exhausted, less potent cellular products.
Additionally, autologous immunotherapies are labor intensive and costly.
Our Approach?
The development of widely used cell therapies that are established, functionally validated, cryopreserved and can be applied across HLA barriers would improve the consistency and availability of adoptive cell therapy and reduce costs.
We are addressing issues of constant supply, regular replenishment, vein-to-vein delays, and dependence on patient-derived T cells, by establishing a platform from HLA matched clonal hypoimmunogenic iPSC bank (truly off-the-shelf).
Our iPSCs will be a perpetual source for CAR-engineered immune cells.
Induced Pluripotent Stem Cells
The generation of iPSCs from somatic cells has opened up a myriad of possibilities: iPSCs can proliferate indefinitely and can be differentiated into a variety of cell types when exposed to an appropriate microenvironment. These attributes of iPSCs have opened up a myriad of possibilities in medicine with applications in immunotherapy, regenerative medicine, disease research, drug discovery, and other therapeutic modalities.
iPSCs as a source are inexpensive (limited patient dependency), suitable for accurate replication of physiological and disease states, clonal expansion (with similar pharmacological profiles), and genetic engineering. Leveraging our expertise in induced pluripotent stem cell technology, we plan to initially establish an iPSC stem cell platform to generate allogeneic NK and γδ-CAR T cells for immunotherapy.
γδ T cells
γδ (gamma delta) T cells represent a unique set of T cells (1-5% of total CD3 cells) characterized by expression of the γδ T cell receptor. Unlike ⍺β T cells, they do not express CD4 or CD8 on their surface and are not restricted by MHC for antigen recognition and hence act as conventional antigen-presenting cells.
The innate ability of γδ T cells for immune surveillance, increased cytokine secretion, tissue infiltration and their presence in TIL (tumor infiltrating lymphocyte) populations make them attractive candidates for immunotherapy.
By exploiting this duality of these cells' innate and MHC-based recognition of antigens, our iPSC-derived CAR-modified γδ T cells are a convenient and inexpensive complementary source in immunotherapy regimens. Further enhancement of these cellular interactions can be improved by combinatorial therapy with ⍺β-T cells and bi-specific antigen binding (biTES).
NK cells
First identified by their intrinsic ability to kill target cells without prior sensitization, the potential of Natural Killers (NKs) has been demonstrated in the allogeneic immunotherapy for blood cancers.
NKs recognize and kill transformed, pathogen-infected, or stressed cells in tissues using a variety of germline-encoded receptors without the requirement of antigen presentation.
NKs have many attributes that make them attractive for cell therapy. These include: a unique receptor repertoire, that is independent from HLA dependent antigen presentation and its restrictive antigenic specificity, rapid cytotoxicity, minimal graft-versus-host disease, moderate cytokine release syndrome (CRS), and cytokines that can augment host immune response.
The relative ease in engineering NKs and ability to generate NKs from iPSCs represents a unique opportunity to utilise conspecific NK cells as an “off the shelf “ immunotherapy approach .
