Many children, who are diagnosed with bone or muscle tumors (sarcomas), which have spread to more than one site in their body, cannot be cured. Thus, there is an urgent need to develop new therapies.  

We propose to develop a therapy, called immunotherapy, which uses the patient’s own immune system to destroy their sarcoma. Immunotherapies comes in many different forms, and this grant is focused on cell therapy, which consists of taking immune cells from patients, genetically engineering them to recognize and kill tumor cells, and then infusing cells back into the patient.  

Cell therapy has already been very effective for certain types of blood cancers. However, the activity of immune cell therapy against sarcoma and other solid tumors has been limited. In this Alliance for Cancer Gene Therapy funded research we will develop a novel approach to attack sarcomas with genetically engineered immune cells, which relies on attacking not only the cancer cell but also the supporting blood vessels, which are critical for tumor growth.  

In addition, we will explore if broadening the attack to target not only one, but two proteins present on sarcomas improves the anti-sarcoma activity of immune cells. State of the art technologies will be used, and we will test the anti-sarcoma activity of our immune cells in models that closely mimic human disease. At the conclusion of the research, we expect to have optimized our immune cell therapy approach for sarcoma and based on our results are planning to develop a clinical study.  

This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America and Wendy Walk.

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.