Ionic control of T cell function

We previously found that ↑[K⁺]_e within the TME acts as an ionic checkpoint on T cell anti-tumor activity, inducing dysfunction. This work established extracellular potassium concentration as a novel means of tumor-induced immune evasion and manipulation of ion transport as a means to control T cell function (Eil R, et al. Nature 2016). Ensuing work focused on the downstream consequences upon T cell function and maturation following exposure to ↑[K⁺]_e, and revealed that ↑[K⁺]_e durably alters T cell metabolism and epigenetic programs that determine behavior (Vodnala SK* & Eil R* et al. Science 2019). Despite these observations, prior models defining K⁺ in T cells, cannot account for these observations. 

Prior models ascribed K⁺ transport in T cells to be solely a facilitator of T cell receptor induced Ca²⁺ influx. However, our prior findings and ongoing work in the lab implicate K⁺ abundance and transport as central to T cell metabolism and homeostasis.  We continue to actively pursuing this line of research with both a depth (hypothesis directed interrogations) and breadth (in vivo CRISPR-Cas9 functional screens), along with the development of novel reporters and reagents to study K⁺ dynamics in T cells. Our ongoing work in this area suggests that intracellular K⁺ concentration acts as a central regulator of homeostasis and metabolism required for T cell antitumor function. We are actively leveraging these ongoing findings into novel and proprietary approaches to engineer T cell function.  

Safe treatment of metastatic solid cancers with chimeric antigen receptor (CAR) T cells

The recent development of a new type of cancer therapy involving the transfer of a patient’s own T cells that have been genetically engineered to recognize their cancer has produced remarkable results – curing patients of advanced cancer that previously were untreatable. This approach, using viral based engineering approaches to introduce a chimeric antigen receptor (CAR) into T cells, has met significant success in the setting of hematologic (liquid) malignancies. Fifty percent, or more, of patients with chemotherapy resistant lymphoma or myeloma receiving T cells genetically engineered to express a CAR targeting blood cancer antigens (i.e. CD19, BCMA) are rendered cancer free. However, the use of this technique has not been possible in solid cancers – which account for ninety percent of cancer related deaths in the United States. While T cell “dysfunction” can limit tumor destruction, the primary barrier preventing the use of CAR-T cells for the treatment of solid cancers remains the recognition of the ‘target’ on normal, healthy tissues – even at low levels of expression. In prior instances where genetically engineered T cells were used to treat solid cancers in humans, recognition of their target “off-tumor” produced unacceptable toxicities (death, severe colitis, blindness, hearing loss) – or no activity at all was appreciated.

As this “off-tumor” toxicity remains the primary barrier to the clinical application of CAR-T cell transfer for solid cancers (a potentially curative treatment), the Eil Lab is actively pursuing novel approaches to control the function of T cells outside of the tumor site. To date, this includes several ongoing projects that have seen rapid progress. We have generated multiple chimeric receptors independently in our lab along with validation of our approach to limit their function outside of the tumor site. While many investigators test their human CAR-T cells in immunodeficient mice, these systems are blind to “off-tumor” toxicities by design. As such, we have also developed a mouse model revolving around a CAR targeting a tumor antigen that is expressed in multiple visceral organ sites. We are actively using this model as platform to develop and test new strategies to control CAR-T function.

In concert, we have designed and validated a humanized chimeric receptor in tandem with safety strategies to limit off tumor toxicity. We are in the process of obtaining intellectual property protection for these inventions and aim to open an investigator initiated clinical trial in patients with cancer involving the liver within the next 12-18 months. This approach coalesces the clinical and scientific components of Dr. Eil’s expertise and aims to make tangible progress in patient outcomes.