Immune checkpoint inhibitor therapy, which activates T cells to kill tumor cells, is an effective way to treat some cancer types. But it does not work for every patient; many develop disease progression after their initial response to immunotherapy. And immune checkpoint inhibitor therapy is less effective in "cold tumors," where there are no T cells.
"Our goal is to build a team of immune cells to overcome tumor resistance to immune checkpoint inhibitor therapy," says Fumito Ito, MD, PhD, FACS, Associate Professor of Oncology at Roswell Park Comprehensive Cancer Center.
While T cells are important for immunotherapy, another key player in the immune system, known as dendritic cells, can uptake tumor antigens, process and present them to T cells, and initiate the antitumor immune response.
"Let's say, if T cells are an army of specialized cells to kill tumor cells, the dendritic cell is a commander in chief or a quarterback in the immune system," says Dr. Ito. "One caveat is that there are various types of dendritic cells with different activating T cells' abilities. So, we needed to find good ones. Recent evidence demonstrated that among various subsets of dendritic cells, conventional-type 1 dendritic cells, cDC1s, are critical for antitumor immunity. We came up with a three-step approach to maximize the engagement of cDC1s in the tumor."
Dr. Ito and his team hypothesized that induction and activation of intratumoral cDC1s could overcome resistance to immune checkpoint inhibitor therapy. They developed a combinatorial regimen that consisted of:
- Intratumoral injections of a cytokine
- Flt3L to recruit cDC1s in the tumor
- Radiotherapy to release tumor antigens
- Two immune-stimulating medications to activate cDC1s for the generation of T cells attacking the tumor.
"We found that this regimen significantly increased T cells in the tumor, mediated effective regression not only of primary but also untreated distant tumors, and that the tumors became responsive to immune checkpoint inhibitor therapy," says Dr. Ito. "The key takeaway from the preclinical study is that cDC1s in tumors play a critical role in enhancing antitumor immunity and overcoming resistance to immune checkpoint inhibitor therapy."
Based on encouraging results from preclinical studies, Roswell Park is planning to conduct a phase I clinical trial for patients with stage IV breast cancer. Patients with unresectable and metastatic breast cancer who have injectable lesions are eligible. If you have patients with unresectable and metastatic stage IV breast cancer, please contact Roswell Park at physicianresources.roswellpark.org for more info about eligibility criteria.
