Vaccination with dendritic cells showed no effect in patients treated by us. In our study, the results achieved by other groups could not be confirmed.
Vaccination with Dendritic Cells in the Treatment of Metastasized Renal Carcinoma
Karl-Horst Bichler
Department of Urology, Eberhard-Karls University, Tübingen, Germany
Prephase
The paper is given in memory of earliest investigations to kill kidney tumor cells by dendritic cells (2002)
Key Words:
vaccination Renal cell carcinoma, metastasized • Immunotherapy • Dendritic cells • Tumor
Abstract
Introduction: The 5-year survival rate in advanced stages of renal cell carcinoma (RCC) is only 10%. Chemotherapy and radiation therapy are not successful.
Immunotherapy regimens using interleukin-2, interferon as well as combinations with chemotherapy show partly high response rates, but long range successes cannot be confirmed. Patients and Methods: We examined in our study 23 patients with metastasized RCC. 11 patients were not treated with a vaccine because of several exclusionary criteria. 12 patients were vaccinated. 6 of them fulfilled the criteria of the study. 6 patients received the vaccine in an individual treatment approach. A new therapy approach is the attempt of tumor vaccination with fused allogenic dendritic cells from healthy donors. Results: Patients (in study): 2 x no change, 4 x progression; patients (in an individual treatment approach): 1 x mixed response, 5 x progression. Conclusion:
Vaccination with dendritic cells showed no effect in patients treated by us. In our study, the results achieved in Gottingen could not be confirmed.
Introduction:
Nowadays kidney tumors are diagnosed and operated on earlier in localized stages because of routinely applied sonography. Due to the absence of any specific symptoms as many as 50% of patients are already metastasized at the time of diagnosis [1]. Recurrences are possible even after surgery of localized kidney tumors.
Prognosis is dependent upon stage (Table 1). The five-year survival rate applies to only 10% of patients in an advanced stage [1-3].
Therapeutic possibilities in metastasized RCC are considerably limited in contrast to treatment of localized tumors. Because of polychemotherapeutic resistance, such treatment schemata show response rates of under 10% [4, 5]. Radiation of metastases is feasible only in static-endangered bone or brain metastases. Local tumor control of soft tissue metastases requires levels of radiation which would lead to unacceptable damage to neighboring structures [6].
In view of the frequent occurrence of dysproteinaemia on patients (especially in metastasized RCC) [7, 8], because of the successful removal of solitary metastases after removal of primary tumor, and because of repeatedly reported spontaneous remissions, the issue of possible immunomodulation of patients with RCC has been apparent for many years [9].
Immunotherapies have been carried out in the past 20 years using interleukin-2, interferon, lymphokin-activated killer cells and other immunomodulating substances [2, 4, 10, 11]. The highest rates of response were observed by using interleukin-2 in combination with interferon-alpha-2a. Long-range results in immunotherapy so far show rates of response of up to 40%, but a statistically significant survival rate has not been demonstrated. Initially high rates of response could not be confirmed in longer-range observation [2, 11-14]. Our own not yet published examinations using the combination of interferon-alpha-2a with vinblastin showed rates of response of up to 23% [15]. Other studies showed similar results [16].
A more recent approach to therapy is Vaccination of the tumor with fused autologous dendritic cells from healthy donors with homologous kidney tumor cells [17].
Dendritic cells were used for presentation of own kidney tumor cell antigens in order to engender an immunity response of the kidney tumor.
Dendritic cells are components of the antigen-presenting system. Their function is to incorporate, process and present antigens. They are highly mobile white blood cells located at the entry ports of the body [18].
Kidney tumor cells taken from the patient by way of tumor nephrectomy or by removal of a metastasis are electrofused with dendritic cells from a healthy blood donor. Thereafter the dendritic cell shares with the tumor cell a common cell surface and can thus present tumor antigens (Illustration 1). Because of the mechanical characteristics of vaccine production, bone metastases are not suitable. Production of vaccine requires approximately 4 weeks.
After injection, naive T-lymphocytes are activated Illustration 2a). The binding location of the naive T-lymphocytes and the fused dendritic cells consists of a T-cell receptor, a RCC antigen that is presented by a MHC class I or Il molecule (MHC = major histocompatibility complex), and co-stimulatory peptides.
Activated T-lymphocytes with specific antigen receptors for the individual kidney tumor antigen bind to the tumor antigens of the kidney tumor metastases. Subsequently there is a lysis of the tumor cells via cytotoxic T-cells (Illustration 2b). On the basis of this theoretical starting point and the generally detrimental situation in the treatment of metastasized kidney tumors, we have, in the framework of a study, treated patients with metastasized RCC with fused dendritic cells.
Materials and Methodes
Included in this study were patients with primary or secondary metastasized RCC who, for purposes of control had a measurable lesion.
Another precondition was a positive Multitest immignost ®1). (This test is a delaytype hypersensitivity test for common antigens. It examines the competence of the body toward an immune reaction of a later type, i. e. of cellular immune response). A further requirement was a life expectancy of 3 months.
Patients with metastases of the central nervous system, with a second tumor, with chemo- or immunotherapy within the past 3 months, with a Karnofsky-index of < 70, and patients over 70 years of age were excluded from the study (Table 2). After the tumor material yield, the tumor cells were fused with dendritic cells of healthy blood donors. A tumor volume of at least 10 ml vital tumor tissue was required.
Before tumor material was extracted and at the time of each vaccination a staging was done.
Altogether, 23 patients were operated on having metastasized kidney tumors.
11 patients were not treated because of several exclusionary criteria. 12 patients were vaccinated, and of these only 6 fulfilled the case study criteria. The other 6 patients received the vaccination therapy because effective therapy modalities were unavailable and were carried out as individual treatment attempts.
Production of the vaccine was carried out in the Medical Department of the university of Tübingen (Laboratory of Dr. G. Stuhler). Dendritic cells from peripheral blood of healthy donors were isolated and fused with tumor cells via electrical impulse. The fused cells (10ml) were injected into subcutaneous tissue of the patient 4 weeks after the operation. Monthly injections followed until the material was used up.
1) Biosyn D-70734 Fellbach
Results
Of the 6 patients fulfilling case study criteria, 2 patients had a no-change status for 8 weeks, followed by a progression of metastases. In 4 patients metastases progressed while undergoing therapy. Of the 6 patients treated in individual attempts, one patient (aged 70 years) showed mixed response. 5 patients showed progression while in therapy. No side effects were observed (Table 3).
Conclusion
For our study we applied stringent inclusion and exclusion criteria. Very few patients with metastasized kidney cell tumors fulfilled these criteria (6 of 23).
This therapy is generally not suitable for patients with large tumor volume or CNS metastases.
Summarized we can say that tumor vaccination with fused dendritic cells is theoretically a suitable immunotherapeutic approach, but in clinical application, patients treated with this method have not shown positive effects. Thus far, data of the Göttingen procedure could not be verified in this study [17].
This work was done with help of Wolfgang Loeser, Gerhard Feil, Tobias Schäfer
References
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3. Bichler K-H, Wechsel HW: The problematic nature of metastasized renal cell carcinoma. Anticancer Res 1999;19:1463-1466.
4. Bichler K-H, Kleinknecht S, Strohmaier WL: Immune status and immune therapy of renal cell carcinoma. Urol Int 1990;45:269-283.
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9. Bichler K-H, Ax W, Tautz C: Cell-mediated immunity in patients with renal adenocarcinoma. Eur Urol 1975;1:231-234.
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11. Strohmaier WL, Bichler K-H, Kleinknecht S, Wilbert DM. : Individualisierte Immuntherapie des Nierenkarzinoms - Ableitung aus dem Immunstatus. Z Urologie Poster 1989 Feb.
12. Rosenberg, SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS Parkinson DR, Seipp CA, Einhorn JH, White DE: Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 1994;271:907-913.
13. Minasian LM, Motzer RJ, Gluck L, Mazumdar M, Vlamis V, Krown SE: Interferon alpha-2a in advanced renal cell carcinoma: Treatment results and survival in 159 patients with long-term follow-up. J Clin Oncol 1993;11:1368-1375.
14. Fossa SD, Krammar A, Droz JP: Prognostic factors and survival in patients with metastatic renal cell carcinoma treated with chemotherapy or interferonalpha. Eur J Cancer 1994;30A:1310-1314.
15. Loser W, Bichler K-H, Feil G, Schäfer T, Zumbrägel A: Kombinierte Immunchemotherapie mit Interferon und Vinbalstin bei Patienten mit metastasiertem Nierenzellkarzinom. Vortrag Südwestdeutcher Urologenkongress, Offenburg 2001.
16. Strohmaier WL, Bichler K-H, Schreiber M: Immundiagnostisch flankierte Interferon-Cisplatintherapie beim metastasierendem Nierenkarzinom. Verhandlungsberichte der DGU, 1987. Stuttgart, Springer, 1988, 269-272.
17. Kugler A, Stuhler G, Walden P, Zöller G, Zobywalski A, Brossart P, Trefzer U, Ullrich S, Müller CA, Becker V, Gross AJ, Hemmerlein B, Kanz L, Müller G, Ringert R-H. : Regression of human metatastic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids. Nature Medicine 2000;3:332-336.
18. Esche C, Shurin MR, Lotze MT: The use of dendritic cells for cancer vaccination. Curr Opin Mol Ther 1999;1:72-81.
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Table 1.Survival rate of patients with RCC (acc. to [3]).
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Table 2. Exclusion criteria of study
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Table 3. Results.
Legends
Illustration 1. Production of vaccines.
Illustration 2a + 2b. Effects of procedures.
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Illustrations are not included in the reading sample
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