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. 

Recently, the use of tumor-killing viruses has gained favor in cancer gene therapy in an approach that has become known as “virotherapy.” Virotherapy exploits viruses that are able to target and destroy cancer cells, while sparing the surrounding normal tissue. We are developing a virotherapy approach for the treatment of prostate cancer based on infection with Sindbis virus.  

The ability of Sindbis virus to travel rapidly throughout the body in the bloodstream will improve access to metastasized cancer cells. We intend first to develop and test these agents in cultured cells. We will then test and optimize the ability of the virus to cure prostate cancer.

Dr. Griffith’s research has moved on in looking at the application of the TRAIL gene and other T-cell therapies in treating all types of cancer, not just prostate cancer. His lab has developed a method of inducing tumor cell death through the administration of full-length TRAIL cDNA (called Ad-TRAIL) into cells using non-replicative adenoviral vectors. Incorporating this vector into tumor cells induces apoptosis, or cell death.  

This research seems to be making some promising strides and an extremely beneficial finding has been that the use of TRAIL is nontoxic against normal cells and tissues unlike other similar genes that have been employed in the same way. Dr. Griffith and his lab plan to continue their work with the TRAIL gene as well as investigating how apoptotic (dying) cells can have an impact on the immune response. 

Prostate Cancer is the second leading cause of cancer death among men in the United States. We are studying and testing a new means of inhibiting the formation of prostate tumors, using an agent called TRAIL to induce the death of tumor cells. The TRAIL gene is transferred into a cell with Ad5-TRAIL, a genetically engineered virus known as a viral vector. The vector used the cell’s own machinery to produce the TRAIL protein and induce tumor cell death. Studies with laboratory animals have shown that this form of gene therapy results in the death of tumor cells.  

My lab is currently studying Ad5-TRAIL’s ability to activate the immune system’s anti-tumor responses. Tumor cells can deceive the body’s immune system into perceiving them as normal cells rather than foreign invaders but introducing genes into a tumor can counteract this. Determining the effect of Ad5-Trail-induced apoptosis (programmed cell death) on the activation of the immune system in patients with localized prostate cancer is the next step in this ongoing research and is anticipated to begin this year. The goal is to use this type of gene therapy to achieve tumor rejection, and tumor-free survival for the patients.