NIH grant for CWRU professors could enable new directions for cancer immunotherapies

Nicole Steinmetz, PhD, Associate Professor of Biomedical Engineering, Radiology, member of the Case Comprehensive Cancer Center and the Center for RNA Science and Therapeutics in the Division of General Medical Sciences at Case Western Reserve University School of Medicine and the holder of the George J. Picha Designated Professor in Biomaterials, has received a major grant from the National Institutes of Health to help understand how a virus-like particle from plants stimulates potent anti-tumor responses.

The new U01 award, totaling nearly $3 million, is provided by the National Cancer Institute. For the funded study, Steinmetz is teamed up with Steve Fiering, PhD, professor of microbiology and immunology at Geisel Medical School at Dartmouth. They will also collaborate with Julian Kim, MD and Sourabh Shukla, PhD, members of the Case Comprehensive Cancer Center, as well as P. Jack Hoopes DVM, PhD, a veterinarian and cancer researcher at Geisel.

"This research is aimed at giving the body's own cancer-fighting capacity a major 'lift and push,'" said Steinmetz. "It also offers potential to fight cancer in dogs, who are of course members of our families as well. We are very grateful to the National Institutes of Health for supporting this potentially transformative work."

Under the grant, Steinmetz and colleagues will further test a tiny nanoparticle-based therapeutic that her team developed which targets the body's own cancer immunity cycle. The therapeutic, derived from a virus-like particle from plants, is about 30 nanometers in diameter; in comparison, a human hair is about 75,000 nanometers in diameter.

"In recent years the funding of grants with multiple leaders, such as this one, has been increasingly supported by the National Institutes of Health," said Fiering. "This work is a great example of how scientists with different expertise can work together and accomplish much more than either lab could by itself."

Researchers have long known that a person's immune system has the potential to recognize and destroy tumor cells. With tumor growth, cancer cells release substances known as tumor-associated antigens into the blood stream. These antigens have a unique molecular "zip code" that is recognized by specific immune cells called antigen-presenting cells, also circulating in the blood on "patrol." The antigen-presenting cells capture the tumor-associated antigens and transport them to another class of specialized immune cells known as cytotoxic T lymphocytes. The antigen-presenting cells "train" the cytotoxic T lymphocytes (killer T cells) to recognize and kill the tumor cells using the tumor-associated antigens. Traveling through the blood stream, the activated killer T cells, in turn, recognize the cancer cells (based on the tumor-associated antigen training) and proceed to kill the cancer cells. During this last step, additional tumor-associated antigens are released and the cycle repeats itself.

But as a tumor progresses, it may respond to the body's natural immunity system by activating immune-suppressive mechanisms, essentially turning off the body's own cancer-defense mechanisms. Conversely, the Steinmetz immunotherapy strategy can "flip the switch" by turning off the immune-suppressive environment and turning on the cancer immunity cycle to elicit a potent immune response against the tumor.

"Recent FDA approvals of immune-based cancer therapies make it clear that using patients' own immune systems to attack cancer is now a major new approach to treating potentially every type of cancer, but we are just at the beginning of understanding immune approaches," said Fiering. "Immune therapy is a huge step forward in cancer treatment and it is exciting to work with the Steinmetz lab to make significant contribution to this field. The studies funded by this proposal will enable us to understand the mechanisms that generate the effective treatment we have documented and this understanding is needed to enable this therapy to be used to treat patients."

Data by Steinmetz and Fiering [Steinmetz, Fiering, Nature Nanotechnology, 2016] show that the proposed nanoparticle cancer immunotherapy generates a highly potent anti-tumor immunity response even in cancers such as melanomas, which are resistant to attack by the immune system. In addition to melanoma, the proposed therapy exhibits clear treatment efficacy and similar anti-tumor immunity performance in metastatic ovarian and metastatic breast tumor models.

"Most importantly, our data indicate that this immune-stimulation is sustainable, that is, the stimulation is able to generate an immune memory that prevents further tumor progression, metastasis, and recurrence," said Steinmetz. "Prevention of relapse and metastatic cancer development, even before physicians are able to detect its onset, represents a major leap in the field."

Steinmetz and her colleagues will study the proposed therapeutic using mouse models of cancer as well as experimental treatments of companion dogs with melanoma. Basic immunological investigation will be used to probe which molecular features of the virus provoke the anti-tumor therapeutic effect, which cells are involved, and which pathways are activated.