Abstract 302: Multiple distinct populations of myeloid derived suppressor cells in IMA901 treated renal cell cancer patients correlate with survival and with T-cell dysfunctions
Authors: Walter Steffen , Hilf Norbert , Mendrzyk Regina , Maurer Dominik , Weinschenk Toni , Kirner Alexandra , Bronte Vincenzo , Mandruzzato Susanna , Stenzl Arnulf , Reinhardt Carsten , Singh Harpreet 
Published: June 2012

Abstract
IMA901 is a therapeutic cancer vaccine for the treatment of renal cell cancer patients based on the selection of naturally presented tumor-associated peptides. A previous phase I study (N=28 patients) showed significant correlations of clinical benefit with T-cell responses to multiple IMA901 peptides. Based on this experience, a randomized phase II study was designed to explore the biological and clinical efficacy of IMA901. Different regulatory cell populations were assessed in patients prior to vaccination, including 6 phenotypically defined populations of myeloid derived suppressor cells (MDSCs).
A total of 68 HLA-A*02-positive RCC patients with documented progression during or after first-line therapy with cytokines or TKI were randomized to receive or not a single infusion of low-dose cyclophosphamide (CY; 300 mg/m2) three days prior to start repeated i.d. vaccinations with IMA901 in association with 75 µg GM-CSF i.d. Among them, 64 pts were eligible according to the pre-specified, per-protocol analysis. Patients receiving a single infusion of CY had a significant decrease of FoxP3-positive regulatory T cells (Tregs) after 3 days (p=0.014), particularly in Ki67+ (proliferating) Tregs (p=0.006). Patients receiving low-dose CY also showed a trend for improved overall survival (OS) as compared to the non-CY group (OS not reached after 25 months of follow-up vs. 16 months, respectively; p=0.086). Marginally significantly better OS rates were seen in immune responders compared to non-responders in the overall population (p=0.048), but highly significantly so in the subgroup of patients randomized to CY (p=0.006).
6 previously reported MDSC populations were analyzed from cryopreserved PBMCs by a single multi-color flow cytometry staining panel. A high overlap (&gt;25%) was found for only 2 MDSC populations, so 6 populations represented five distinct MDSC subtypes. MDSC levels were significantly increased in patient samples as compared to matched healthy donors (p&lt;0.0001 to p=0.0043). Interestingly, two populations designated MDSC4 (CD14+ HLA-DR-) and MDSC5 (CD14- CD11b+ CD15+) were negatively correlated with survival (p=0.033 and p=0.005) in the patients of this trial prior to immunotherapy intervention. Analysis of dysfunctionality of T cells characterized by decreased levels of TCR zeta chain expression revealed that patients had lower levels of TCR zeta chain expression than matched healthy donors (p&lt;0.0001) and that low levels of TCR zeta chain were correlated with high levels of 4 MDSC phenotypes (p&lt;0.0001 to p=0.04), suggesting that MDSC levels are linked to the suppression of T cells in RCC patients.
To our knowledge, this is the first study assessing the impact of MDSC levels on the survival of cancer patients by employing a novel method that can differentiate five distinct MDSC populations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 302. doi:10.1158/1538-7445.AM2011-302