Abstract
On the basis of compelling preclinical data in cats and dogs we initiated a clinical gene therapy study in nine patients with advanced solid tumors using xenogeneic fibroblasts secreting human IL-2 (Vero-IL-2 cells). Cohorts of three successive patients with tumors accessible to CT- or ultrasound-guided injection were treated repeatedly with 5 × 105, 5 × 106, or 5 × 107 Vero-IL-2 cells. Endpoints of the study were feasibility, toxicity, and clinical and biological effects of this novel approach to immunotherapy of cancer. Histopathological, immunological and molecular analyses were performed on biopsy specimens of tumors and blood samples from before, during and after treatment. Low levels of serum antibodies to Vero cells developed in 2/9 patients. Analysis of tumor biopsies showed increased expression of CD3 mRNA and enhanced tumor infiltration with varying lymphocyte subpopulations after treatment. In addition, monoclonal alterations of the TCR repertoire of blood and tumor lymphocytes were observed. Treatment was well tolerated and toxicity consisted of transient fever in one patient and short-lived, mild itching and erythema in two others. One patient with soft tissue sarcoma showed a more than 90% and more than 50% reduction of the volume of two distant, non-injected metastases, respectively, lasting for 22+ months. Four other patients showed stabilization of their disease for three to nine months, among whom was a patient with melanoma who developed marked vitiligo. We conclude that repeated injection of up to 5 × 107 Vero-IL-2 cells was safe and showed biological and clinical activity in heavily pretreated patients with advanced solid tumors.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Roth C, Rochlitz CF, Kourilsky P, 1994; Immune response against tumors. Adv. Immunol. 57, 281–351.
Roth JA, Cristiano RJ, 1997; Gene therapy for cancer: what have we done and where are we going? J. Natl. Cancer Inst. 89, 21–39.
Roth C, Mir LM, Cressent M, Quintin-Colonna F, Ley V, Fradelizi D, et al., 1992; Inhibition of tumor growth by histoincompatible cells expressing interleukin-2. Int. Immunol. 4, 1429–1436.
Quintin-Colonna F, Devauchelle P, Fradelizi D, Mourot B, Faure T, Kourilsky P, et al., 1996; Gene therapy of spontaneous canine melanoma and feline fibrosarcoma by intratumoral administration of histoincompatible cells expressing human interleukin-2. Gene Ther. 3, 1104–1112.
Pannetier C, Cochet M, Darche S, Casrouge A, Zöller M, Kourilsky P., 1993; The sizes of the CD3 hyper-variable regions of the murine T-cell receptor beta chains vary as a function of the recombined germ-line segments. Proc. Natl. Acad. Sci. U S A 90, 4319–4323.
Dietrich PY, Caignard A, Diu A, Genevée C, Pico JL, Henry-Amar M, et al., 1992; Analysis of T cell receptor variability in transplanted patients with human cutaneous acute graft versus host disease. Blood, 80, 2419–2424.
Dietrich PY, Caignard A, Lim A, Chung V, Pico JL, Pannetier C, et al., 1994; In vivo T-cell clonal amplification in human acute graft versus host disease. Blood, 84, 2815–2820.
van-Hille B, Lohri A, Reuter J, Herrmann R., 1995; Nonradioactive quantification of mdrl mRNA by polymerase chain reaction amplification coupled with HPLC. Clin. Chem., 41, 1087–1093.
Lüscher U, Filgueira L, Juretic A, Zuber M, Lüscher NJ, Heberer M, et al., 1994; The pattern of cytokine expression in freshly excised human metastatic melanoma suggests a state of reversible anergy tumor-infiltrating lymphocytes. Int. J. Cancer, 57, 612–619.
Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, et al., 1994; Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus in-terleukin 2. JAMA, 271, 907–913.
Fearon ER, Pardoll DM, Itaya T, Golumbek P, Levitsky HI, Simons JW, et al., 1990; Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell, 60, 397–403.
Gansbacher B, Zier K, Daniels B, Cronin K, Bannerji R, Gilboa E., 1990; Interleukin 2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity. J. Exp. Med., 172, 1217–1224.
Bubenik J, Simova J, Jandlova T., 1990; Immunotherapy of cancer using local administration of lymphoid cells expressing IL-2 cDNA and constitutively producing IL-2. Immunol. Let, 23, 287–292.
Wölfel T, Klehmann E, Müller C, Schutt K-H, Meyer zum Büschenfelde K-H, Knuth A., 1989; Lysis of human melanoma cells by autologous cytolytic T cell clones. J. Exp. Med., 170, 797–810.
Rosenberg SA., 1997; Cancer vaccines based on the identification of genes encoding cancer regression antigens. Immunol. Today, 18, 175–182.
Rosenberg SA, White DE., 1996; Vitiligo in patients with melanoma: Normal tissue antigens can be targets for cancer immunotherapy. J. Immunother., 19, 81–84.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1998 Springer Science+Business Media New York
About this chapter
Cite this chapter
Rochlitz, C.F. et al. (1998). Gene Therapy with Cytokine-Transfected Xenogeneic Cells in Metastatic Tumors. In: Walden, P., Trefzer, U., Sterry, W., Farzaneh, F., Zambon, P. (eds) Gene Therapy of Cancer. Advances in Experimental Medicine and Biology, vol 451. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5357-1_82
Download citation
DOI: https://doi.org/10.1007/978-1-4615-5357-1_82
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-7444-2
Online ISBN: 978-1-4615-5357-1
eBook Packages: Springer Book Archive