Cryoimmunotherapy with 'Sticky' Interleukin-12

Even when detected early, with stage I disease, the chance of a lung cancer patient surviving for 5 years with current treatments is essentially a coin flip. Although initially effective, up to half of early-stage lung cancer patients will experience a tumor recurrence following surgical removal of a lung tumor. For a significant fraction of patients, recurrence leads to progression, metastasis, and death.

Cryoablation is a surgical alternative that involves freezing, and hence killing, tissue via the insertion of a cryoprobe needle that is cooled by circulating liquefied gases, e.g., argon or nitrogen. Cryoablation is minimally invasive, which allows quicker patient recovery and shorter hospital stays compared to surgical resection of tumors. It is not as effective as surgical resection in controlling primary tumors. However, unlike surgery, cryoablation can induce a vaccine-like response using fragments of killed tumor, capable of training cells of the immune system to attack tumor cells. In order to enhance the strength and frequency of this vaccine-like response, this project will evaluate the addition of a novel immune-stimulating therapeutic to cryoablation.

Interleukin-12 (IL-12) is a member of a family of proteins (the interleukins) that immune cells use to signal one another and coordinate immune responses. IL-12 is a master regulator of the immune system, able to both activate effector immune cells (those cells that attack targets) while at the same time inhibiting the function of suppressive cells recruited by lung cancer cells as a defense mechanism. IL-12 given intravenously has been tried as a cancer therapy in the past; however, given its potency to activate the immune system, it was associated with excessive toxicity and abandoned as a treatment strategy.

To overcome toxicity hurdles, we propose to build a novel molecule in which IL-12 is fused to a protein fragment that binds to collagen. Collagen is a structural protein that lung tumors make in abundance. It has been shown to protect lung cancers and act as a barrier to immune cells. The collagen-binding IL-12 can be injected directly into a cryoablated tumor where it will 'stick' to collagen and not leak into systemic circulation where it can be toxic. The attached IL-12 can then amplify the antitumor immune response induced by cryoablation. Immune cells generated by this combination approach are expected to patrol the body and eliminate hidden or escaped tumor cells that might otherwise become a recurrent tumor. Thus, the cryo-immunotherapy combination can be as effective as surgery at controlling primary tumors, but more effective in eliminating residual or hidden tumor cells that are left behind by surgery and existing adjuvant therapies.

The major objectives of this project are to (1) develop and validate the novel collagen-binding IL-12 therapeutics and (2) determine whether cryo-immunotherapy is better than surgery plus immunotherapy at inhibiting lung cancer metastasis. The long-term goal of this research is to increase survival rates by replacing surgery with cryo-immunotherapy as a first line treatment for lung cancer. To this end, if this project is successful, testing will progress to evaluate cryo-immunotherapy in clinically relevant humanized tumor models as well as large animal models with our collaborators at the UNC Lineberger Cancer Center, the Durham VA Medical Center, and the NC State College of Veterinary Medicine in the next 2-4 years. Results from these translational studies will inform clinical trial development.

Because military personnel carry a higher risk of developing lung cancer due to increased rates of smoking and occupational exposure to carcinogens, more effective therapies for lung cancer would prolong and enhance the lives of military veterans and their families.

The proposed research addresses two LCRP Areas of Emphasis. The combination of cryoablation and collagen-binding IL-12 is an 'innovative strategy for the treatment of lung cancer.' Furthermore, because this locoregional therapy is expected to induce systemic antitumor immunity, this approach also represents an 'innovative strategy for the prevention of recurrence of or metastases from lung cancer.'