Research from the University of Michigan Rogel Cancer Center could provide a new approach to treating an aggressive form of breast cancer.
A study conducted by Duxin Sun, Ph.D., found that targeting the immune microenvironment to lymph nodes and tumors simultaneously resulted in long-term tumor remission in mouse models of metastatic triple-negative breast cancer. Additionally, the use of nanoparticles to deliver these immune-modifying drugs increases the efficacy of the treatment. These results appear in Science Translational Medicine.
Immunotherapy plus chemotherapy has long been approved as a standard treatment option for triple-negative breast cancer, but shows only limited response in patients. Many believe that the immunosuppressive microenvironment of the tumor is one of the main factors contributing to poor responses in people with TNBC.
Sun, Charles R. Walgreen Jr. Professor of Pharmacy and Professor of Pharmaceutical Sciences at the UM College of Pharmacy, claims that previously developed immunomodulators work well in animal models, but fail in clinical trials. He and his team wanted to come up with a better approach that would treat TNBC patients long term and could withstand the rigors of clinical trials. To do this, they had to look beyond the tumor microenvironment, to the lymph nodes.
“People don’t pay enough attention to the lymph node microenvironment,” Sun said. “But it’s just as important. Lymph nodes play a crucial role in initiating cancer progression and metastasis.”
Sun and his team, with co-lead author Wei Gao, Ph.D., investigated strategies to modulate both tumor and lymph node microenvironments to improve treatment response. Based on 15 years of experience, Sun knew that a type of nanomedicine could be used to deliver immune modulators to these microenvironments to alter their macrophages, a type of immune system white blood cell that fights pathogens, such as cancer cells.
Sun’s team treated mouse models of breast cancer with an albumin nanoparticle, a type of nanomedicine, called Nano-PI, in combination with immunotherapies, to reshape the microenvironment in the lymph nodes and tumors. Nano-PI not only enhanced the delivery of both immunomodulators to lymph nodes and tumors, but also enhanced drug accumulation in macrophages of these two tissues.
“What we found was striking,” Sun said. “If we used this nanoparticle to deliver drugs to modulate the tumor and the lymph nodes, we would achieve long-term tumor remission and eliminate lung metastases, which we had never seen before.”
Without Nano-PI, Sun says the drugs worked well but the results were poor. But once they implemented the nanoparticle in this way, the team achieved almost 200 days without the tumor growing back, compared to most mouse models where the tumor comes back in 90 days.
“It’s not a cure,” Sun quickly added, “but it does represent a promising candidate for future clinical trials and tells us that we may be able to achieve long-term tumor remission.”
In this study, Sun used different design criteria to develop the Nano-PI, which is drug, nanocarrier, target cell and disease specific, to deliver drugs into macrophages of two types of tissues. . Specifically, Nano-PI was able to target M2 macrophages, which are one of the major immunosuppressive factors requiring regulation to treat metastatic breast cancer. The designs presented in Nano-PI suggest the possibility of increased efficacy of immunotherapy to achieve long-term complete tumor remission which may have better clinical translation in patients with TNBC.
Sun says nanomedicine in general hasn’t had much success in treating cancer, largely due to poor clinical translation of preclinical models to cancer patients. But in this study, Sun and his team found a possible way to increase the efficiency of this nanotechnology.
“Our findings suggest that previous nanomedicine design principles may themselves be in error.”
Sun and his team used new design criteria for drug-specific nanomedicine, meaning they should be used to solve a specific problem in a specific context.
“You can’t have one-size-fits-all nanomedicine to perform one-size-fits-all tasks,” Sun said. “It cannot solve all problems for all drugs. The old design principle sees nanomedicine as universal, but this does not succeed when translated from mouse models to clinical trials. We find that it must be specific to a drug, to a nanocarrier, to a type of cell. Each nanocarrier will have its own property and can only do certain things to be effective for patients.
To further test this new philosophy and continue to explore the effectiveness of targeting lymph nodes and tumors simultaneously, Sun hopes these findings can progress to a clinical trial.
“The technology is mature enough that we can make this nanomedicine that would provide drugs to see if it will translate to a human trial and really achieve long-term remission.”
Article quoted: “Albumin nanoparticle containing PI3Kγ inhibitor and paclitaxel in combination with α-PD1 induces tumor remission of breast cancer in mice”, Science translational medicine. DOI: 10.1126/scitranslmed.abl364
