Researchers take a new approach to immunotherapy for mRCC

Dendritic cells and carbonic anhydrase 9 (CA9) have become the focus of new research directed towards discovering new immunotherapies for metastatic renal cell cancer (RCC), according to results from some early clinical research presented here at the Sixteenth International Kidney Cancer Symposium, in Miami, FL.

“We wanted to use a different approach of activating the immune system in a more targeted way. Initially, we studied our patients, and did a tissue microarray, and tried to identify specific markers that are characteristic for kidney cancer,” said lead researcher Alexandra Drakaki, MD, PhD, assistant professor of medicine and urology, and director, Genitourinary Medical Oncology Program, University of California, Los Angeles.

“We were interested in studying carbonic anhydrase 9 (CA9) as a potential target, because it is a transmembrane protein and has access to a similar domain that can be easily recognized by the immune system,” she added.

Upon analysis of 500 tissue samples from patients with renal cancer to determine CA9 expression, they found that not only was CA9 overexpressed, but was also a marker of kidney cancer.

Dr. Drakaki and colleagues are conducting this phase I, open-label, dose-escalation, cohort expansion study to assess both the safety and immune response to autologous dendritic cells transduced with the fusion protein granulocyte-macrophage colony-stimulating factor and carbonic anhydrase IX (GMCA-9) (AdGMCA9) in patients with metastatic renal cell carcinoma.

“Dendritic cells are the professional antigen presenting cells. We took CA9, which is the protein of interest, and we developed this fusion gene with granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to stimulate the immune system. After we developed the fusion gene, we used an adenovirus vector and transduced the dendritic cells,” explained Dr. Drakaki.

Blood from patients with mRCC underwent apheresis, and Dr. Drakaki and colleagues isolated peripheral blood mononuclear cells (PBMCs), and cultured them with granulocyte/macrophage-colony-stimulating factor and interleukin-4 (GM-CSF/IL-4) to induce maturation.

“Then, within 7 days, we are able to do the transduction with the adenovirus vector into those dendritic cells. So by day 7, our vaccine is ready to be used for patients,” said Dr. Drakaki.

At 3 months, all nine patients had stable disease, and at 6 months, four of the nine had stable disease. According to Dr. Drakaki, early safety and efficacy results have been promising. No serious adverse events occurred, and adverse events were few.

“The treatment has been very well tolerated,” noted Dr. Drakaki.

They are currently doing an expansion cohort, in which they hope to be able to identify more responders.

“We are planning to continue our work, and we are seeing already—from our tissue analysis—that this specific vaccine stimulates the immune system. Hopefully in the future, we can have combination studies with other agents, such as immune checkpoint inhibitors,” noted Dr. Drakaki.

“CA9, a protein that has been studied a lot in kidney cancer, could be a potential therapeutic target for kidney cancer. The development of the vaccine is feasible, it’s safe, it’s well tolerated, and patients on the highest dose can have stable disease,” she concluded.