T Cell Therapy: A Revolution
The immune system is critical for our defense against infection and cancer. Growing insight into the immune system’s mechanisms for fighting cancer has led to a recent explosion in the development of immunotherapies. In particular, companies are now able to engineer patients’ own living T cells with chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) to target specific cancer antigens and kill tumor cells. In 2017, upon the first approval of a CAR-T therapy by the FDA, Commissioner Gottlieb was quoted saying “We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer.”
We founded our company to build on these early T cell therapy innovations while addressing their limitations and making our product candidates available to a broader patient population.
The Complete T-Cell Receptor Targets and Controls the T-Cell Response
T cells are the elite soldiers of the immune system. They have evolved as the most potent killers of tumor cells with activities driven by the TCR complex.
Upon binding to specific tumor antigens, the TCR catalyzes a highly complex signaling cascade that leads to the killing of the T-cell target. Each of the six subunits of the TCR and their phosphorylation motifs (ITAMs) play a unique and critical role in T cell signaling. By engaging the complete TCR complex, T cells can unleash their full range of weapons against cancer, the totality of which is particularly critical for overcoming the hostile immunosuppressive microenvironment of solid tumors.
Existing CAR and Engineered TCR Therapies Have Key Limitations
CAR-T therapies have achieved remarkable response rates in certain hematologic cancers and gained two FDA approvals in 2017; however, CAR-T cells have struggled to show efficacy against solid tumors and have high rates of severe side effects, including patient deaths. We believe this is because they do not benefit from all of the activation and regulatory elements of the natural TCR complex.
Engineered TCR-T cells which utilize the complete TCR have shown clinical activity in solid tumors, but have major limitations. TCR-T cells require tumors to express HLA to bind tumor antigens. HLA is often downregulated in cancers, preventing T cell detection. In addition, each specific TCR-T cell therapy can only be used in patients with one of several specific HLA subtypes, limiting universal applicability of this approach and increasing the time and cost of patient enrollment.
Lack of efficacy in solid tumors
High rate of severe cytokine release syndrome
High rate of neurotoxicity
HLA downregulation or antigen loss
Number of addressable patients limited by HLA matching
Time and cost of patient enrollment increased
The TRuC™ Platform
TRuC-T Cells are designed to incorporate the best features of CAR-T and TCR-T cell therapies and overcome their limitations. The TRuC platform is a novel T cell therapy platform, which uses the complete TCR complex without the need for HLA matching.
By conjugating the tumor antigen binder to the TCR complex, the TRuC construct can recognize highly expressed surface antigens on tumor cells without the need for HLA and engage the complete TCR machinery to drive the totality of T cell functions required for potent, modulated and durable tumor killing.
The TRuC™ Platform Features
Our platform enables the design of TRuC-T cells with a number of advantages over currently engineered T cell approaches. TRuC-T cells have demonstrated superior anti-tumor activity in vivo compared to CAR-T cells while releasing lower levels of cytokines in preclinical studies.
These data are encouraging for solid tumors where CAR-T cells have not shown significant clinical activity due to very short persistence and for hematologic tumors where a high incidence of severe cytokine release syndrome remains a major concern.
TRuC T-cells have demonstrated superior traits compared to CAR-T cells in our preclinical studies, which we believe are due to the engagement of the entire TCR signaling complex:
Faster migration to the tumor
Faster tumor killing
Lower cytokine release
TRuC T-cells have demonstrated a differential phenotype compared to CAR-T cells in our preclinical studies, including:
Increased metabolic fitness
Enhanced tumor penetration
The versatility of our TRuC-T cell platform allows us to address a broad patient population without the need for HLA matching, and to program our TRuC-T cells with various enhancements including:
Dual TRuC-T cells – to target multiple tumor antigens at once
“Off-the-shelf” allogenic TRuC-T cells – to improve therapy cost and convenience
Accessories – to avoid the suppressive effects of the tumor microenvironment