Dendritic cells are potent antigen presenting cells capable of stimulating tumor immunity. Despite their promise as vectors for cancer vaccines, limited clinical efficacy has been observed to date. We have identified a fundamental metabolic pathway that is triggered within the melanoma microenvironment and that results in the potent suppression of dendritic cell function.
After identifying a fatty acid transporter as playing a critical role in this pathway, we have determined that the pharmacological inhibition of this transporter is capable of reversing this process of dendritic cell tolerization and significantly enhancing T cell activation. Based on these findings, we now propose to engineer a dendritic cell-based cancer vaccine that has been genetically silenced for this transporter and to test the impact of this modification both in a transgenic melanoma model as well as in advanced melanoma patients who are refractory to checkpoint inhibitor immunotherapy. In addition to generating more potent ex vivo DC-based vaccines, this work is aimed at validating this recently identified fatty acid transporter as a genetic target for future in vivo DC-targeted treatment strategies.
Significant strides have been made in the treatment of solid tumors using viruses designed to attack and kill tumors (Oncolytic Viruses: OV) following direct injection into a detectable tumor mass. Tumor cell killing releases tumor-related proteins capable of inducing anti-tumor immunity, potentially eliminating similar tumor masses throughout the body.
The first OV to achieve FDA approval is an oncolytic herpes simplex virus (oHSV) whose use in treatment of late-stage melanoma achieved a significant “cure” rate (~50%) when administered in combination with antibodies that enhance tumor rejection. Here we propose to create substantially improved oHSV vectors that will be extraordinarily safe (tumor targeted) and highly resistant to pre-existing anti-HSV immunity common in the human population. The advanced vector design will allow intravenous administration of a “heat-seeking missile” that targets metastatic cancer for destruction and consequently induces protective immunity against relapse.
Recent clinical successes have revealed that the immune system can be successfully harnessed to fight cancer. Various strategies are utilized, including enhancing a patient’s ‘natural’ response to cancer as well as ‘redirecting’ a patient’s immune cells (‘T cells’) to the tumor using genetic engineering. While these T cell therapies have had major success in leukemias, they have not yet shown promise in the treatment of solid tumors.
T cells require an enormous amount of fuel to perform their tumor-killing functions. However, we have recently shown that in solid tumors, cancer cells evade immune responses in part by depriving the T cell of the ability to generate energy and depleting the local environment of nutrients.
In this Alliance for Cancer Gene Therapy funded research program, we will utilize genetic engineering to metabolically ‘reprogram’ tumor-specific T cells. Using this technology, they will become more fit to fight cancer for an extended period of time. We will test these T cells in animal models and translate these findings into human T cells as well. The goal is to generate super-soldier type T cells, those that can be both redirected to the tumor site, but also bolstered metabolically to support long-term and durable responses.
This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America.
Melanoma is the most aggressive primary skin cancer affecting adolescents and adults. The incidence of melanoma of the skin has been steadily increasing over the past 10 years (76,100 estimated new cases in the United States alone in 2014). Despite the improvements in outcome over the last decade for those with early-stage disease, the outcome remains extremely poor for those with advanced stage disease at diagnosis.
With the current standard therapy, 10-year survival for patients with metastatic melanoma is less than 10%. It is therefore desirable to develop novel therapies that could improve these disappointing outcomes. Immune system-based therapies have the potential to fulfill this dire need. The high specificity of such immune-based therapies will also make them less toxic, reducing the organ toxicities and other long-term adverse effects endured by cancer survivors.
Melanoma cells express tumor-specific molecules on their surface referred to as ‘antigens’. Some of these antigens can be used for developing targeted therapies that will specifically recognize and kill the tumor cells without affecting the other healthy cells in the body. We are working on generating immune cells (T cells) from melanoma patients that are specific for two antigens, HER2 and GD2 expressed on melanoma tumor cell surface. Expression of these surface antigens is variable from one patient to the other and in fact, within a single tumor (e.g., some cells will be both HER2 and GD2 positive while others may express either HER2 or GD2 only).
We and others have found that using T cells specific for a single antigen can hence result in selective survival of those tumor cells that do not express the targeted antigen. This leads to cancer recurrence after therapy. We have previously shown that simultaneous targeting of two tumor-specific antigens using bispecific T cell products improves tumor control. We now propose to target two melanoma antigens, HER2 and GD2, simultaneously, with the goal of decreasing the risk of tumor recurrence.
To achieve this, we will genetically modify the T cells with a novel bispecific molecule that we have designed and constructed in our laboratory, called ‘TanCAR’. We will further test the function of these bispecific T cells against melanoma cells in the lab and in animal models. Knowledge gained from the current proposal will be used to justify and develop a clinical trial to treat patients with melanoma. Furthermore, the obtained information could have applicability for T cell therapy of other cancers as well.
