Enhancing CAR T cells with small molecule targeted protein modulation is the scientific foundation of DeCART. Our goal is to modify the underlying CAR T cell biology ex vivo using small molecules to control levels of certain proteins in the T cells. This ex vivo control of protein levels improves the phenotype of the T cells, which we referred to as drug-enhanced CAR T cells which we believe improves CAR T cell therapies and will improve cancer patient outcomes.
Current Limitations of CAR T Cell Therapies
1. T CELL EXPANSION
Pharmacologic studies in lymphoma and leukemia have shown that the engraftment, peak concentration of CAR T cells, and persistence are associated with durability of tumor control.
2. TUMOR ESCAPE
In the presence of fully functional CAR T cells, tumor cells can develop adaptive resistance to avoid being eliminated by the immune system.
Together with the remarkable clinical activity, adoptive transfer of CAR T cells has demonstrated significant and unique toxicities.
4. T CELL DYSFUNCTION
Dysfunction, including exhaustion, anergy, and senescence, arises during many chronic infections and cancer is driven in part by chronic persistence of antigen.
Target Protein Modulation
DeCART uses small molecules to modulate certain protein levels that affect T cell biology. These compounds are either an E3 ligase inhibitor or a bi-functional molecule called a chimeric targeting molecule (or CTM) that binds to both an E3 ligase and a protein that is targeted to be degraded. The E3 ligase inhibitor is used to increase the levels of the target protein while the CTM is used to decrease the levels of the target protein.
Harnessing the ubiquitin proteasome system to control protein levels
DeCART’s first small molecule T cell protein modulator is a CBL-B inhibitor which increases the levels of certain proteins that are important for T cell function. The use of the CBL-B inhibitor during the ex vivo production of CAR T cells improves the phenotype and function of the resulting CAR T cells.
A complex set of tumor, host, and environmental factors govern strength and timing of anti-cancer immune responses
Immune Cell Activation
Stepping on the Gas
- CD28 independent T cell activation (CBLi)
- Resistance to anergy (KO & CBLi)
- T cell proliferation (CBLi)
- Enhanced T cell cytokine production (KO & CBLi)
- Antigen recall in vitro & in vivo (CBLi)
Impedes Inhibitory Signals
Hitting the Brakes
- Rescues T cell exhaustion (CBLi)
- Resistant to TGFβ-driven Immune suppression (KO)
CAR T Therapy
CAR T therapies have unveiled a new treatment and hope for cancer patients. However, studies have shown there is more research needed to overcome the therapy limitations caused by the immune system and tumor microenvironment. DeCART believes that drug-enhanced CAR T cell therapy builds upon the strengths and successes while overcoming many of its current limitations.
Combining targeted protein modulation with adoptive T cell therapy
Because changes to the T cell biology using Chimeric Targeting Molecules (or CTMs) are reversible, we believe that CTMS are a safer method of enhancing CAR T cell potency than the permanent changes resulting from genome editing methods.
Our pipeline includes protein modulators in combination with novel CARs for both hematologic and solid tumor indications. DeCART’s first program is expected to use Nurix’s small molecule CBL-B inhibitor, NX-0255, for ex vivo enhancement of T cell biology throughout the processing and engineering of CAR T cells.