Abstract A82: Metronomic cyclophosphamide followed by a multi-peptide folate receptor vaccine for ovarian and breast cancer immunotherapy in the setting of minimal residual disease - a feasibility study
Authors: Kalli Kimberly R. , Erskine Courtney L. , Krempski James W. , Benson Linda M. , Suman Vera J. , Padley Douglas J. , Dietz Allan B. , Hobday Timothy J. , Degnim Amy C. , Hartmann Lynn C. , Block Matthew S. , Knutson Keith L. 
Published: August 2014

Abstract
Background: Current options to prevent ovarian and breast cancer recurrence are limited. However, signs of anti-tumor immunity are associated with improved survival in patients who have experienced a number of different malignancies. After identifying folate receptor alpha (FR)-derived class II-binding peptides recognized by lymphocytes from patients who previously had breast or ovarian cancer, we developed a multi-peptide vaccine with five peptides, each of which was recognized by more than 25% of the patients. We combined this vaccine with metronomic cyclophosphamide in an attempt to selectively reduce T regulatory cells in the periphery and the tumor microenvironment.
Methods: We obtained an Investigational New Drug approval from the Food and Drug Administration to perform a phase I study in 22 patients who were currently in remission from their breast or ovarian cancer. Participants were required to be at least 90 days past any treatment for their disease (other than hormonal treatment, if applicable) and show no current evidence of disease. After 28 days of metronomic cyclophosphamide, six monthly intradermal injections of the vaccine were given. The primary endpoints of the trial are safety and immunogenicity.
Results: To date, 15 of 22 patients have enrolled (7 breast and 8 ovarian cancer patients). 4 breast and 2 ovarian cancer patients are available for toxicity evaluation. No serious major adverse events have been observed, with the expected injection site reactions being the primary toxicity experienced by most participants; grade 2 decreased white blood cell counts were observed in 3 patients at completion of cyclophosphamide. Two patients went off study prior to completing all six vaccinations, one for vision changes, and one for disease progression. Immune monitoring is underway, with major assays being ELISAs for high-affinity IgG targeting the FR and FR-peptide specific ELIspots. These data will be presented at the meeting.
Conclusions: Metronomic cyclophosphamide followed by intradermal vaccinations with a multi-peptide vaccine targeting the tumor antigen FR appears to be a tolerable regimen at this preliminary point of the study. With the exception of vision changes in one patient, no serious safety concerns have arisen. Pursuit of this strategy in further clinical study will require demonstration of FR-specific immune responses, an acceptable toxicity profile, and demonstration that T regulatory cells are altered in the periphery.
Citation Format: Kimberly R. Kalli, Courtney L. Erskine, James W. Krempski, Linda M. Benson, Vera J. Suman, Douglas J. Padley, Allan B. Dietz, Timothy J. Hobday, Amy C. Degnim, Lynn C. Hartmann, Matthew S. Block, Keith L. Knutson. Metronomic cyclophosphamide followed by a multi-peptide folate receptor vaccine for ovarian and breast cancer immunotherapy in the setting of minimal residual disease - a feasibility study. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A82.