The immune system has many mechanisms to fight cancer, one of which is T cells. A common reason for failure of the immune system to eliminate tumors is that it does not recognize and kill “self” cancer cells. It is now possible to use gene engineering to introduce synthetic molecules, such as chimeric antigen receptors (CARs) into T cells allowing them to target tumor cells for destruction. The gene-engineered cells are then grown for clinical use and infused back into the patient’s body to attack and destroy chemotherapy-resistant disease.
While this approach has been highly successful for blood cancers, the field awaits a clear demonstration of effectiveness against solid tumors, such as prostate cancer, the most common malignancy among men. A major barrier to the success of CAR T cell therapy for solid tumors is that the engineered T cells must do battle in a toxic microenvironment that creates a “nutrient desert,” which suppresses T cell function, preventing robust immune responses.
Glucose in one major nutrient of limited availability in the tumor microenvironment, and T cells require glucose uptake and metabolism for normal survival and function. Aberrant glucose signaling and epigenetic deregulation, two common cancer hallmarks, have been extensively reported in many solid tumors, including prostate cancer. However, the molecular switches coupling nutrient availability to epigenetic imprinting and the downstream signaling that potentiates the antitumor potency of CAR T cells are largely unknown.
By elucidating the effect that glucose signaling has on anticancer epigenetic programing in T cells, such as 5-hydroxymethylcytosine (5hmC) DNA marks, this proposal will ultimately provide a link between glucose availability in prostate tumors, the loss of 5hmC marks and antitumor activity of CAR T cells. Thus, we propose to address a major metabolic/epigenetic resistance mechanism of this therapy.
Our approach involves the development of next generation therapies with CAR T cells, involving innovative combinations of metabolic as well as epigenetic modifiers of the aforementioned checkpoint switches and genetic technology to be tested in rigorous preclinical models. Furthermore, using cutting-edge genome editing tools such as CRISPR/Cas9, and novel biomanufacturing strategies, we will create CAR T cells capable of inducing safe, long-term complete remissions in patients with advanced prostate cancer. This project is relevant to ACGT’s mission of “supporting revolutionary scientific research into the treatment of cancer using cells and genes as medicine.” If successful, our proposed studies will undoubtedly provide a tumor-attack roadmap for the treatment of many other cancers as well, including those of the lungs, ovaries, skin, breast, pancreas, brain, etc.