Immunotherapy With RNA Vaccination Coding For TAA In Renal Cell Carcinoma: Update On Immunological Responses and Correlation With Survival
Authors: Rittig Susanne M , Häntschel Maik , Weimer Katrin J , Heine Annkristin , Müller Martin R , Brugger Wolfram , Horger Marius , Maksimovic Olga , Stenzl Arnulf , Hoerr Ingmar , Rammensee Hans-Georg , Holderried Tobias A.W. , Kanz Lothar , Pascolo Steve , Brossart Peter 
Published: October 2019

Abstract

Introduction
Recently Walter et al. (Nature med 2012) demonstrated that induction of T cell responses to tumor-associated antigens (TAA) after peptide vaccination (IMA901) is associated with significantly prolonged overall survival in patients with advanced renal cell carcinoma (RCC). Between August 2003 and November 2005 we performed a phase I/II non-randomized study to analyze the feasibility and safety of an mRNA-based vaccination as well as immunological and clinical responses in patients with stage IV RCC (Rittig et al., Mol Ther. 2011). Here we provide an update on survival and correlative analyses of immunological responses and survival. Methods: In vitro transcribed naked mRNA coding for the TAAs mucin 1, carcinoembryonic antigen (CEA), human epidermal growth factor receptor (EGFR) 2, telomerase, survivin, and melanoma-associated antigen 1 was administered to a total of 30 patients. In the first 14 patients (cohort A), vaccinations were applied on days 0, 14, 28, and 42 (20 µg of each antigen). In the consecutive 16 patients (cohort B), an intensified protocol consisting of injections at days 0-3, 7-10, 28, and 42 with 50 µg/antigen was used. After the respective induction periods, patients in both cohorts received monthly vaccinations until tumor progression according to RECIST. Results: In October 2010 monitoring had revealed a survival in cohort A ranging from 3 to 85 months with 4/14 patients (29%) being alive, while survival in cohort B ranged from 2 to 71 months with 4/16 (25%) patients being alive. Follow up was re-assessed in March 2013. In cohort A, 3 patients were still alive (21%) with survival ranging from 105 to 115 months. Two of these surviving patients had intermediate and one had favourable risk according to Motzer score at enrolment. These respective patients had received between 13 and 32 doses of RNA. In cohort B, three patients (19%) were found to be alive, of which two had favourable and one had intermediate risk according to Motzer score at enrolment. Survival in cohort B ranged from 95 to 97 months, and between 10 and 22 doses of the vaccine had been applied to the patients. Impressively and similar to the findings of Walter et al. with the IMA901 peptide vaccine, all six patients that currently are alive displayed immunological responses to the applied antigens in cytotoxic T cell or ELISpot assays, while vice versa no patient without detectable immune response had survived more than 33 months. Conclusion: The current survival update revealed long term survival (>8 years) in about 20% of patients in this small cohort suffering from stage IV RCC. Notably, in line with data obtained after peptide vaccination, prolonged survival after treatment with our RNA vaccine also showed a clear correlation with in vitro detectable immunological responses to the applied TAA.

Disclosures:
No relevant conflicts of interest to declare.