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. 2015 Oct 29;5(5):e1108511.
doi: 10.1080/2162402X.2015.1108511. eCollection 2016 May.

Long-term Survival Correlates With Immunological Responses in Renal Cell Carcinoma Patients Treated With mRNA-based Immunotherapy

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Free PMC article

Long-term Survival Correlates With Immunological Responses in Renal Cell Carcinoma Patients Treated With mRNA-based Immunotherapy

Susanne M Rittig et al. Oncoimmunology. .
Free PMC article

Abstract

Renal cell carcinoma (RCC) is an immunogenic tumor for which immunotherapeutic approaches could be associated with clinically relevant responses. It was recently shown, that induction of T-cell responses against multiple tumor-associated antigen (TAA) epitopes results in prolonged overall survival in RCC patients. In 2003-2005, we performed a phase I/II trial testing an mRNA-based vaccine formulation consisting of a mixture of in vitro transcribed RNA coding for six different TAAs (MUC1, CEA, Her2/neu, telomerase, survivin, MAGE-A1) in 30 metastatic RCC (mRCC) patients. In the first 14 patients, vaccinations were applied i.d. on days 0, 14, 28, and 42. In the consecutive 16 patients, an intensified protocol consisting of i.d. injections (daily on days 0-3, 7-10, 28, and 42) was used. After the respective induction periods, patients in both cohorts were vaccinated monthly until tumor progression. At survival update performed in July 2015, one of the 30 patients was still alive. One patient was lost to follow-up. Median survival of 24.5 mo (all patients) and 89 mo (favorable risk patients) exceeded predicted survival according to Memorial Sloan Kettering Cancer Center (MSKCC) risk score. Impressively, long-term survivors displayed immunological responses to the applied antigens while vice versa no patient without detectable immune response had survived more than 33 mo. The current survival update shows a clear correlation between survival and immunological responses to TAAs encoded by the naked mRNA vaccine. This is one of the first vaccination studies and the only RNA trial that reports on safety and efficacy after a follow-up of more than 10 y.

Keywords: Cancer; RNA; dendritic cell; human; immunotherapy; phase I/II; renal cell carcinoma; survival; trial; vaccine.

Figures

Figure 1.
Figure 1.
Overall survival is depicted in Kaplan–Meier Plots (GraphPad Prism). The current update revealed median (mean) survival of 24.5 (43.1) mo for all patients included in the study based on timepoint of study entry (A). Overall survival of patients treated in cohort A versus cohort B. p = 0.9 (logrank test), Kaplan–Meier Plots (GraphPad Prism) (B). Overall survival based on the date of documented stage IV disease. Median (mean) survival reached 35.5 (55.9) mo as depicted in Kaplan–Meier Plots (GraphPad Prism) (C). Overall survival of patients with detectable immunological responses to the vaccinated TAA was significantly prolonged compared to patients with negative immunological assays (89 mo vs. 14 mo, p = 0.002, logrank test) as displayed. Of note, immunological assays could only be performed in 20 out of 30 patients (D).
Figure 2.
Figure 2.
Exemplary Immunological Assays in long-term Survivors. Cytotoxic T cells (CTL) were generated out of the patients (HLA-A2-) PBMC (obtained after onset of vaccination as mentioned) by stimulation with autologous DC transfected with an RNA-Mix (containing RNA coding for the vaccinated TAAs MAGE-A1, MUC1, CEA, and survivin). After re-stimulations CTL were used as effector cells in 51-chromium release assays. These vaccine-induced CTL efficiently lysed autologous DC electroporated with the RNA-Mix as well as the tumor cell line Caki-2 (RCC, HLA-A2-) while DC electroporated with irrelevant EGFP-RNA were not lysed. K562 was used to exclude NK-cell mediated toxicity.

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References

    1. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K.. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18:767-811; PMID:10837075; http://dx.doi.org/10.1146/annurev.immunol.18.1.767 - DOI - PubMed
    1. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Xiangming C, Iwashige H, Aridome K, Hokita S, Aikou T.. Clinical impact of intratumoral natural killer cell and dendritic cell infiltration in gastric cancer. Cancer Lett 2000; 159:103-8; PMID:10974412; http://dx.doi.org/10.1016/S0304-3835(00)00542-5 - DOI - PubMed
    1. Ishigami S, Natsugoe S, Matsumoto M, Okumura H, Sakita H, Nakashima S, Takao S, Aikou T.. Clinical implications of intratumoral dendritic cell infiltration in esophageal squamous cell carcinoma. Oncol Rep 2003; 10:1237-40; PMID:12883687; http://dx.doi.org/10.3892/or.10.5.1237 - DOI - PubMed
    1. Iwamoto M, Shinohara H, Miyamoto A, Okuzawa M, Mabuchi H, Nohara T, Gon G, Toyoda M, Tanigawa N. Prognostic value of tumor-infiltrating dendritic cells expressing CD83 in human breast carcinomas. Int J Cancer 2003; 104:92-7; PMID:12532424; http://dx.doi.org/1883647310.1002/ijc.10915 - DOI - PubMed
    1. Chaput N, Conforti R, Viaud S, Spatz A, Zitvogel L.. The Janus face of dendritic cells in cancer. Oncogene 2008; 27:5920-31; PMID:18836473; http://dx.doi.org/10.1038/onc.2008.270 - DOI - PubMed
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