Lung cancer is the leading cause of cancer death in the United States. It presents mostly in incurable stages and death is typical within 2 years. There are two basic types of lung cancer. Small cell lung cancer is the rarer and more aggressive form. Non-small cell lung cancer is less aggressive than small cell, but still one of the most aggressive human cancers. One of the most important recent advances against lung cancer is immunotherapy. Currently available immunotherapy works by activating immune cells called “T cells.” T cells each attack cells bearing a single foreign element that they recognize; many foreign elements can be attacked because the body has a library of T cells active against different targets.

When immunotherapy is added to chemotherapy, cancer control and survival are improved. However, by 2 years, while chemotherapy + immunotherapy remains superior to chemotherapy alone, only 22% of patients remain free from both cancer growth and death. Biologically, a common strategy utilized by cancer cells to evade the immune system is to stop making HLA, a protein used to show the immune system what the cell is making. This is an important and powerful resistance mechanism because T cells can only recognize foreign elements when they are presented by HLA. Few approaches can overcome this, but a technology called CAR-T can. CAR-T involves genetically engineering a virus to infect T immune cells and change their target. Importantly, these modified T cells can recognize foreign material even when not presented by HLA. The approach has had dramatic success in certain lymphomas, and we now seek to apply it to lung cancer. We have already shown that a high proportion of both types of lung cancer already express a molecule called GD2. We have already shown in a laboratory dish and in laboratory animals that we can manufacture the CAR-T against GD2 and that it can kill cancer cells. We now seek to test whether it can help human patients. Our product has two unique properties that we believe increase the probability of success. First, the product expresses IL-15, which increases its ability to self-perpetuate and thus increase efficacy. Second, it expresses a “kill switch” that will allow us to eliminate all the cells in case of side effects, thus increasing safety.

If the clinical trial is successful, we would move from the phase 1 to phase 2 study. Depending on preliminary efficacy, we could do this in non-small cell lung cancer, in small-cell lung cancer, or in both. Aim 3 seeks to use another drug to increase the expression of GD2. This could make this treatment effective for a greater proportion of patients and might further improve response in those who already respond. Greater scientific understanding of the biologic activity of the CAR-T from aim 2 could allow us to optimize the phase 2 study. Further, the work in aim 3 might be applied to other cancers.

The preclinical work described herein as background was funded by a successful Jimmy V Foundation grant completed on time. Our cancer center has sped progress to phase 1 by funding protocol generation and regulatory submissions in parallel with this grant application. We expect to complete the proposed clinical trial in 18 months, and our cancer center has again committed funding to accelerate subsequent study in the case of success. As a consequence, we believe that we could bring this therapy to larger scale trials and ultimately approval in a compressed timeline. Because lung cancer disproportionally affects military Service Members and Veterans and because the outcomes in lung cancer are inferior for these populations, any advances against lung cancer are particularly relevant to them. While we are excited about targeted therapies that have improved care for non-smoking lung cancers, we believe that, with higher smoking rates, military Service Members and Veterans with lung cancer have been left behind. We hope to bring a different type of targeted therapy to these patients and dramatically improve their cancer outcomes.