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Cancer immunotherapy empowers a patient’s own immune system to fight back against tumor cells. Multiple therapeutic strategies for immunotherapy have been clinically tested to a beneficial extent, including cell therapy, immune checkpoint blockade and cancer vaccination. However, many times the long-term benefits of each of these strategies are limited when used individually.

In an attempt to boost the immune system’s complete ability to bombard cancer growth and progression, Julian Zhu, Ph.D., member of the Developmental Therapeutics research program at VCU Massey Cancer Center, recently developed a novel vaccine that successfully treated colorectal cancer cells in combination with immune checkpoint inhibitors, which are drugs that inhibit the function of specific proteins. In pre-clinical experiments, the combination demonstrated a complete regression without recurrence in about 60 percent of cancer cells, as indicated by research findings published in Science Advances.

“This is a war between cancer cells and the immune system,” Zhu said. “We’re trying to help the immune system to tilt the balance against cancer and elicit a more effective and durable response.”

Cancer vaccines are typically comprised of two types of molecules: an adjuvant and an antigen. An adjuvant is a molecule that can initiate an innate immune response, the body’s first line of defense against foreign invaders. This immune response serves mainly to contain and prevent the spread of foreign pathogens but is not specific to any type of cell and cannot distinguish a cancer cell from a healthy cell. Conversely, an antigen is a molecule that often prompts an immune response to target and kill invasive cells of specific viruses or diseases.

“An effective cancer vaccine often needs adjuvants and antigens to work together in order to provoke a durable and antitumor-specific immune response,” said Zhu, who is also an assistant professor in the Department of Pharmaceutics at the VCU School of Pharmacy and KL2 Scholar at the Wright Center for Clinical and Translational Research.

Not many cancer vaccines have been successfully used in clinic because many conventional cancer antigens are found in both tumor cells and healthy cells. What this means is that if the immune system is directed to fight one of these antigens it might also target the body’s normal cells as well.

“In other words, the immune system needs to tolerate those antigens; otherwise, the antigens are going to attack our own healthy cells and cause alternate, potentially harmful immune responses,” Zhu said.

A newly discovered class of antigens called a neoantigen elicits immune responses exclusively to cancer cells. Neoantigens can be produced in the lab and delivered through a vaccine into tumor cells where they alert the immune system to attack the cancer while preserving healthy cells.

While the neoantigen acts as a signal for the immune system to detect the presence of cancer, adjuvant molecules can serve to activate an immune response pathway, a genetic route by which the immune system sends cells to respond to an infection, disease or other pathogen. However, certain immune cells can only operate through certain pathways; therefore, activating only one pathway with a single adjuvant might limit a vaccine’s overall efficacy. Traditionally, most cancer vaccines have used a single-barrel approach with just one adjuvant and have been largely ineffective.

Zhu utilized a bi-adjuvant nanovaccine to harness the power of two immune response pathways and heighten the ability of the immune system to counteract the cancer cells. A nanovaccine differs from a regular vaccine in that it is comprised of nanoparticles – multiple molecules packaged into one unit – and directly targets the cells in the body where the disease originated.

“If we add more than one type of adjuvant into a nanovaccine, we can increase its potency, take advantage of multiple immune pathways and produce a broader immune response,” Zhu said.

Think of Zhu’s nanovaccine in terms of a situation where the combined efforts of firefighters from multiple fire stations would maximize the effectiveness of putting out a fire, but the fire trucks from each station have to use different roads to arrive at the scene. Consider the neoantigen as the emergency dispatcher alerting the immune system exactly where to send responders, and the adjuvants as traffic controllers opening up roadways to access the scene of the fire. The concept of using multiple adjuvants in a nanovaccine is to open up more roads (immune pathways) to allow more of the immune system’s emergency responders to report to the fire (cancer) at the same time.

To further enhance therapeutic benefit, Zhu combined the delivery of this novel nanovaccine with an immune checkpoint blockade called anti-PD-1 (aPD-1). PD-1 is a protein that protects tumor cells from being killed by immune cells, and aPD-1 blocks the function of PD-1, thereby increasing the immune system’s ability to detect and destroy cancer cells. aPD-1 drugs represent some of the most promising cancer immunotherapies currently being tested. However, only a subset of cancer patients responds well to aPD-1 by itself because tumors are often capable of powerful immune suppression.

“If we have a nanovaccine that can now work synergistically with the immune checkpoint blockade (aPD-1) to elicit enhanced immune responses, then we can improve overall therapeutic outcomes,” Zhu said.

After Zhu treated colorectal cancer cells separately with both the bi-adjuvant nanovaccine and aPD-1, the tumors showed immediate growth reduction, but most cancer cells still grew back over time. However, when Zhu combined the nanovaccine with aPD-1, approximately 60 percent of the colorectal cancer cells in in vivo models showed complete regression and didn’t grow back.

Zhu said the next steps will be to further test the efficacy of this combination therapy in colorectal cancer as well as study this strategy in other types of cancer to see if it can be more broadly applicable. Neoantigens are specific to different tumors so a unique neoantigen will be needed for each type of cancer.

“If we wanted to kill a breast cancer cell, we would need to discover or engineer neoantigens that are specific to breast cancer,” Zhu said. “In that case, we could then use the same therapeutic strategy that we applied to colorectal cancer cells but would have to design a completely different nanovaccine.”

Zhu collaborated on this research with Ting Su, Ph.D., of the VCU School of Pharmacy; Brian Liang, Fuwu Zhang, Ph.D., Gang Niu, Guocan Yu, Ph.D., Xiaoyuan Chen, Ph.D., Yijing Liu, and Zhanton Wang, Ph.D., of the National Institute of Biomedical Imaging and Bioengineering; and Guangming Lu, Longjiang Zhang, M.D., Ph.D., and Qianqian Ni, of the Medical School of Nanjing University.

This research was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (1ZIAEB000073-09); the National Key Basic Research Program of the People’s Republic of China (2014CB744501 and 2014CB744504); the National Natural Science Foundation of China (81230032); the Major International (Regional) Joint Research Program of China (81120108013); start-up funds from the Wright Center's NCATS Clinical and Translational Science Award (no. KL2TR002648); and, in part, by a pilot grant from VCU Massey Cancer Center (P30 CA106059).

Written by: Blake Belden