Solid tumors represent approximately 90% of cancers but with some notable exceptions, adoptive cell therapy (ACT) has demonstrated limited success treating these types of cancer. Our goal is to address the barriers that limit consistent, reliable and curative responses. To do this, we are focused on developing therapies that overcome T cell exhaustion and loss of durable stemness, which includes proliferative capacity, ability to self-renew and ability to differentiate.
We believe we can overcome these barriers through our proprietary epigenetic and genetic reprogramming technologies, which are designed to enable the “active ingredient” of ACT. We develop our autologous T cell therapies by elucidating and optimizing the immune cell, the basic unit of efficacy in ACT, and are developing new therapeutic solutions to generate improved, durable clinical outcomes that are potentially curative.
We have developed two technology platforms to address two major barriers to effective solid tumor ACT. Gen-R to overcome loss of T cell function attributable to an exhausted state, and Epi-R to create T cell populations with properties of durable stemness, while also maintaining polyclonality, an advantage of tumor-infiltrating lymphocyte (TIL) ACT.
T cell exhaustion, a key mechanism of ACT failure, results from transcriptional and epigenetic changes that occur as T cells differentiate into a dysfunctional state. A strategy to prevent T cells from becoming exhausted would be ideal for improving the effectiveness of ACT against solid tumors. Our scientific co-founder Dr. Mackall identified such a strategy to utilize ex vivo genetic reprogramming to overcome the problem of T cell exhaustion by genetically modifying T cells to overexpress c-JUN. Overexpression of c-JUN in CAR T cells restores their antitumor activity in preclinical solid tumor models where the same CAR T cells that do not overexpress c-JUN exhaust and fail to eliminate the tumor. We have continued and expanded upon Dr. Mackall’s work, and as applied in our product candidates, we term the optimized overexpression of c-JUN our Gen-R technology.
Emerging research has made clear that a key requirement of effective cellular immunotherapy is the presence of a population of T cells with specific characteristics of stemness as well as activation of effector functions to produce clinical responses. The frequency of this T cell population correlates with responses to cancer immunotherapy, including TIL, ACT and immune checkpoint blockade therapy.
Epi-R is our ex vivo epigenetic reprogramming technology designed to generate populations of T cells which have the properties of durable stemness. Durable stemness describes the ability of a population of T cells to maintain the sustained ability to self-renew and proliferate, even after being subjected to demands of activation and proliferation upon encountering target antigens expressed by tumor cells. In order to achieve meaningful and long-term clinical responses, we believe that a population of T cells with durable stemness that are continually replenished, allowing them to generate all memory and effector T cell differentiation states, is required.
We believe our scientists have been able to intentionally and reproducibly produce T cell populations with durable stemness with our Epi-R technology platform. The resulting Epi-R T cell populations have in vitro and preclinical in vivo properties which suggest that they are significantly more potent than those generated by standard approaches to manufacturing T cells for ACT.
Our work has built upon the groundbreaking science of Dr. Restifo spanning over thirty years at the NCI, and then actuated by him and his colleagues at Lyell. Our ultimate goal is to characterize, identify, optimize and consistently produce T cell immunotherapies with enhanced proliferative capacities, as well as ability to engraft, persist and destroy tumor masses through our proprietary Epi-R technology.