Fusion vaccine plus surgery may prove potent combination in renal cell cancer
Renal cell cancer (RCC) is a life-threatening malignancy considered incurable in the metastatic setting. While standard chemotherapy has proved largely ineffective, biological-based treatments, such as vaccines, do hold promise. In prior studies, for example, fusion vaccines — made of dendritic cells fused with tumor cells, both derived from the patient — were well-tolerated and demonstrated clinical response in a subset of patients. David Avigan, MD (BIDMC), is now leading a clinical trial to confirm the safety of fusion cell vaccination, to investigate its impact in combination with GM-CSF, and most importantly, to test whether vaccination following surgery improves its efficacy.
Why this study is important
This phase I/II trial is one of a new generation of cancer vaccine studies looking at ways to “manipulate the environment” in the patient to better respond to the vaccine, explains Avigan. “We wanted to take advantage of improved outcomes in metastatic disease following nephrectomy, due in part to the increased immune effects of removing bulk lesion from the patient.” His hope is that the combination of vaccination and surgery will improve immunologic response and clinical outcomes.
Patients with previously untreated metastatic RCC who have undergone nephrectomy (or resection of other accessible lesions) receive 3 vaccinations of fused cells by subcutaneous injection at 3-week intervals, starting one to two months after surgery. One cohort, now closed, received the vaccine alone, and those who tolerated it proceeded to the second cohort. All subjects enrolled on the study since the first cohort closed received both the vaccine and GM-CSF, a protein that stimulates the immune system.
The vaccine contains patient-derived antigen-presenting dendritic cells and the patient’s own tumor antigens, a fusion that Avigan believes can provoke a broad-based immunologic response that makes it more difficult for the tumor to escape detection. Tumors have evolved strategies to evade, mute, or disable the immune system, and fusion vaccines are an attempt to “reeducate” immune cells so that they can more effectively recognize tumor cells and eradicate them. “The vaccine is also created outside the patient,” he adds, “and thus away from the inhibitory influences of the tumor.” The addition of GM-CSF, which has been studied in other vaccine trials as well, is part of the effort to amplify response to the vaccine and may even recruit other dendritic cells in the patient, suggests Avigan.
Before and after vaccination, investigators count the patient’s tumor-reactive lymphocytes to determine whether the vaccine induced a rise in the number of these cells. “We quantify immunologic response by measuring the expression of these cytokines for their ability to become functionally active again,” says Avigan. Since some investigators hypothesize that debulking the tumor might also decrease the number of regulatory cells (involved in immunosuppression), the study is measuring those as well. “But our main focus is evidence of regression after vaccination,” says Avigan.
The open-label study, which began accruing patients in 2004, is ongoing, but preliminary evidence of immunologic and disease response has been seen in some patients, says Avigan. “Our hope is to extend that phenomenon into clinically meaningful outcomes that result in stable disease or eradication.”
Vaccination of Patients With Renal Cell Cancer With Dendritic Cell Tumor Fusions and GM-CSF
David Avigan, MD
For eligibility criteria, contact information, and sites, go to NCT00458536 on ClinicalTrials.gov.