Fraietta

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. 

Powell

Ovarian cancer is the most lethal gynecologic cancer. However, women with evidence of immune cells in their ovarian cancer, specifically T cells, have an improved overall survival. This suggests that T cells control ovarian cancer growth.  

Patient T cells can now be grown to large numbers outside of the body and then reinfused back into the same patient in a process referred to as adoptive T cell therapy. To allow these T cells to “see” the cancer cells, they are engineered outside of the body to express a tumor-sensor called a CAR. Patient T cells genetically engineered to express a CAR can recognize a cancer antigen, such as CD19. Transfer of these anti-CD19 CAR T cells back to terminally diseased patients results in cancer remission in ~90% of treated patients with certain forms of leukemia.  

In order to bring this form of therapy to women with ovarian cancer, we propose to engineer patient T cells to recognize an antigen called folate receptor-alpha, which is expressed by up to 90% of ovarian cancers, and use them to treat women with recurrent ovarian cancer, a disease which kills more than 14,000 women each year, and for which there are no effective treatment options. These CAR T cells can effectively and comprehensibly kill human ovarian cancer cells in mice. The opportunity now exists to provide this form of cancer gene therapy for our patients. Here, we propose conducting a clinical trial to test whether these CAR T cells are safe and effective in women with recurrent ovarian cancer.

June

Ovarian cancer is the leading cause of gynecologic cancer death, and though most patients respond to initial chemotherapy, the majority will eventually relapse and die of chemotherapy resistant disease. Despite the advent of newer chemotherapies, the five-year survival for patients with advanced disease remains only 25 percent, and few patients are cured.  

In preliminary studies, we have developed genetically engineered T cells as a complementary immunotherapy to augment traditional treatment strategies. The engineered T cells eradicate large tumors in pre-clinical experiments.  

In this project, we will conduct FDA-mandated pre-clinical experiments, manufacture clinical grade vector, obtain local IRB approval and FDA and NIH/OBA RAC federal approval for the protocol, and then conduct the clinical protocol.  

The protocol will test whether the T cells that are designed to withstand the toxic effects of the tumor are able to mediate tumor regression in patients with advanced ovarian cancer that has failed to regress after chemotherapy.