We are expanding the possibilities for cancer patients by fully engaging the T-cell receptor (TCR) complex, which identifies tumor cells and directs the immune system to fight them.
Our first solid tumor target is mesothelin. We aim to extend our baseline approach to many other targets while also innovating our TRuC-T cell therapies to traffic more effectively into different tumor types, persist longer in the body, better deal with relapse caused by antigen escape and leave behind a memory phenotype.
- TRuCs: What They are
and How They Work - Our Manufacturing Process
- Our Publications
The Power of the TCR
Our complex immune system evolved to defend the body from pathogens such as bacteria and viruses, but it can also be harnessed to fight cancerous and pre-cancerous cells. Its most potent weapons are T cells, which can track down abnormal cells and eliminate them through the utilization of T cell receptors (TCRs) – clusters of proteins on every T cell that identify specific antigens displayed on the outside of cells.
Once a TCR has identified a cell that needs to be eliminated, it binds to it through the coordinated action of the TCR and the αβ-TCRs recognizing their associated tumor antigens, specifically only when presented on human leukocyte antigens (HLA), cell-surface proteins responsible for the regulation of the immune system. Then, the TCR sends up an alarm – catalyzing a highly complex and broad signaling cascade that leads other T cells to activate and multiply, ultimately killing the abnormal cell and protecting the body against similar threats in the future.
The TCR is composed of eight parts or subunits. Two of them recognize other cells – TCR-α and TCR-β. The remaining six are proteins that each play unique and critical roles in T-cell signaling (i.e. CD3γ/CD3ϵ, CD3δ/CD3ϵ and CD3ζ/CD3ζ). They are not redundant or interchangeable – each of the TCR subunits makes distinct contributions to the activation and regulation of T cells, and only the combination of all the TCR subunits can optimally activate and control all functions of T cells.
In essence, T cells are the key to cancer immune surveillance.
The Power of the TCR
Our complex immune system evolved to defend the body from pathogens such as bacteria and viruses, but it can also be harnessed to fight cancerous and pre-cancerous cells. Its most potent weapons are T cells, which can track down abnormal cells and eliminate them through the utilization of T cell receptors (TCRs) – clusters of proteins on every T cell that identify specific antigens displayed on the outside of cells.
Once a TCR has identified a cell that needs to be eliminated, it binds to it through the coordinated action of the TCR and the αβ-TCRs recognizing their associated tumor antigens, specifically only when presented on human leukocyte antigens (HLA), cell-surface proteins responsible for the regulation of the immune system. Then, the TCR sends up an alarm – catalyzing a highly complex and broad signaling cascade that leads other T cells to activate and multiply, ultimately killing the abnormal cell and protecting the body against similar threats in the future.
The TCR is composed of eight parts or subunits. Two of them recognize other cells – TCR-α and TCR-β. The remaining six are proteins that each play unique and critical roles in T-cell signaling (i.e. CD3γ/CD3ϵ, CD3δ/CD3ϵ and CD3ζ/CD3ζ). They are not redundant or interchangeable – each of the TCR subunits makes distinct contributions to the activation and regulation of T cells, and only the combination of all the TCR subunits can optimally activate and control all functions of T cells.
In essence, T cells are the key to cancer immune surveillance.
TRuC-T Cells: Engineered for Maximum Impact
We engineer our TCR Fusion Construct T cells (TRuC-T cells) to recognize cancer cells as biological threats through a three-step process. First, after receiving cells from patients, we identify a cancer antigen recognition domain, or a “homing device”, tailored to recognize that patient’s specific tumor antigen and fuse it directly to a TCR subunit. Then, we use a lentiviral vector to transfer the genetic information for the TRuC construct into that patient’s own T cells where it naturally integrates into the native TCR complex. We then re-administer these engineered T cells equipped with the new homing device back into the patient, giving them the ability to detect and destroy cancer cells. Upon antigen engagement, these T cells harness the entire TCR to produce a more powerful yet controlled T cell response against cancer.
Many engineered T cell therapies are only able to use one subunit or two of the eight parts of T-cell receptors, while others are restricted to a patient’s HLA subtype (an immune identifier analogous to blood type). In contrast, our engineered T cells use all the parts of the TCR and work across all HLA types to produce a powerful yet precise defense against cancer that can persist in the hostile, immunosuppressive microenvironment of solid tumors. In both preclinical and clinical studies, we have seen these properties translate into more durable responses with potentially fewer adverse events for patients with cancer.
These emerging data are very encouraging when we consider that other types of cell therapies such as CAR-Ts have struggled to show efficacy against solid tumors and have high rates of severe side effects in some patients, including cytokine release syndrome and neurotoxicity. Other forms of engineered TCR-T cells have limitations as well – specifically, each one can only be used in patients with one of several specific HLA subtypes, limiting their use and increasing the time and cost of patient enrollment.
TRuC-T Cells: Engineered for Maximum Impact
We engineer our TCR Fusion Construct T cells (TRuC-T cells) to recognize cancer cells as biological threats through a three-step process. First, after receiving cells from patients, we identify a cancer antigen recognition domain, or a “homing device”, tailored to recognize that patient’s specific tumor antigen and fuse it directly to a TCR subunit. Then, we use a lentiviral vector to transfer the genetic information for the TRuC construct into that patient’s own T cells where it naturally integrates into the native TCR complex. We then re-administer these engineered T cells equipped with the new homing device back into the patient, giving them the ability to detect and destroy cancer cells. Upon antigen engagement, these T cells harness the entire TCR to produce a more powerful yet controlled T cell response against cancer.
Many engineered T cell therapies are only able to use one subunit or two of the eight parts of T-cell receptors, while others are restricted to a patient’s HLA subtype (an immune identifier analogous to blood type). In contrast, our engineered T cells use all the parts of the TCR and work across all HLA types to produce a powerful yet precise defense against cancer that can persist in the hostile, immunosuppressive microenvironment of solid tumors. In both preclinical and clinical studies, we have seen these properties translate into more durable responses with potentially fewer adverse events for patients with cancer.
These emerging data are very encouraging when we consider that other types of cell therapies such as CAR-Ts have struggled to show efficacy against solid tumors and have high rates of severe side effects in some patients, including cytokine release syndrome and neurotoxicity. Other forms of engineered TCR-T cells have limitations as well – specifically, each one can only be used in patients with one of several specific HLA subtypes, limiting their use and increasing the time and cost of patient enrollment.
Improving T Cell Therapies
We are leading the TCR cell therapy space by utilizing our TRuC-T cells which incorporate the best features of T cell therapies while overcoming their limitations, specifically by using the full, regulated TCR complex and conjugating the tumor antigen binder to the TCR complex, eliminating the need for HLA matching. These unique characteristics of our validated platform enable us to transform cell therapies by:
- Pursuing indications previously untreatable by earlier cell therapies due to adverse events from cytokine release syndrome or a lack of ability to persist through the hostile solid tumor microenvironment
- Treating any patient with the specific tumor antigen since TRuC-T cells are not limited by HLA subtype, providing patients suffering from cancer hope for better, healthier lives
Our approach allows the TRuC construct to recognize highly expressed surface antigens on tumor cells, activating all of the subunits of the complete TCR machinery to generate a broad and controlled response allowing for more potent tumor cell killing, faster migration to the tumor, and longer persistence. Observed in clinical and preclinical studies, these properties can translate into more durable responses with potentially fewer adverse events for patients with cancer.
Advantages of TRuC-T Cells
Efficacy
Our TRuC-T cells are designed with an increased number of homing receptors, enabling them to find tumors and migrate there quickly so they can get to work. They are also designed to carefully target and preferentially kill cancer cells with rapid kinetics, reducing tumor size while leaving healthy cells intact and functioning.
Migration
Some cell therapies, in particular CAR-Ts, have an inability to traffic to solid tumors and need to be administered locally to the site of the tumor in order to overcome their innate biology. Our TRuC-T cells are dynamic and have demonstrated that after intravenous administration, they are capable of trafficking to the site of the tumor, expanding and killing the tumor cell.
Durability
For cell therapies to work against cancer, they need to be able to persist in the hostile tumor microenvironment instead of being quickly destroyed or suppressed by it. Our TRuC-T cells are designed with an enhanced metabolism that gives them an increased lifespan and memory phenotype.
Our Manufacturing Process
The process of manufacturing cell therapies is highly complex which is why our strategy focuses on quality and consistency. Since the beginning of the company, our semi-automated and functionally closed systems have provided an economical, reliable, and highly scalable manufacturing platform with a small footprint. We devote extensive resources to process development and manufacturing to optimize the reliability of our TRuC-T cell therapies and reduce manufacturing costs. We continue to be focused on reducing vein-to-vein time for patients to maximize the potential benefit of our TRuC therapies.
ElevateBio. In November 2020, we partnered with ElevateBio – an innovative organization with significant expertise in the cell and gene therapy field – to provide clinical manufacturing capacity for our gavo-cel program. This partnership gives us immediate access to the extensive technical capabilities at ElevateBio BaseCamp, a world-class cell and gene therapy manufacturing facility based in Waltham, MA. Our partnership increases and diversifies our capacity, grows our technical capabilities, and allows us to meet potential manufacturing demand for the Phase 2 expansion portion of the gavo-cel clinical trial.
