PURPOSE: Immunotherapy directed toward cell surface antigens may provide a novel approach to the eradication of chemoresistant micrometastatic disease in patients with small-cell lung cancer (SCLC). Studies in SCLC cell lines and human tissues suggest that the ganglioside fucosyl GM1 is an abundant yet specific target. A prior clinical study demonstrated the potent immunogenicity of fucosyl GM-1 derived from bovine thyroid gland, conjugated to keyhole limpet hemocyanin (KLH) and administered with QS-21 adjuvant. EXPERIMENTAL DESIGN: We tested the immunogenicity of three different doses of a synthetic version of fucosyl-GM1 in patients with SCLC after a major response to initial therapy. The primary end point was to establish the lowest effective dose capable of inducing antibody production. RESULTS: Five of six patients at the 30-microg dose and three of five patients at the 10-microg dose mounted IgM responses of 1:80 or greater. These antibodies were confirmed by flow cytometry in seven of eight cases. None of the patients at the 3-microg dose had titers above 1:80. One patient at the 30-microg dose had an IgG response with a titer of 1:80. The sera from six of the eight responders induced potent complement-mediated cytotoxicity of tumor cells. CONCLUSIONS: Vaccination with the synthetic fucosyl GM1-KLH conjugate induces an IgM antibody response against fucosyl GM1 and tumor cells expressing fucosyl GM1, comparable with the response induced by the bovine derivative. We plan to combine synthetic fucosyl GM1 vaccine at a dose of 30 microg with vaccines against three other antigens-GM2, Globo H, and polysialic acid-to test in patients with SCLC after initial chemotherapy.
PURPOSE: Immunotherapy directed toward cell surface antigens may provide a novel approach to the eradication of chemoresistant micrometastatic disease in patients with small-cell lung cancer (SCLC). Studies in SCLC cell lines and human tissues suggest that the ganglioside fucosyl GM1 is an abundant yet specific target. A prior clinical study demonstrated the potent immunogenicity of fucosyl GM-1 derived from bovine thyroid gland, conjugated to keyhole limpet hemocyanin (KLH) and administered with QS-21 adjuvant. EXPERIMENTAL DESIGN: We tested the immunogenicity of three different doses of a synthetic version of fucosyl-GM1 in patients with SCLC after a major response to initial therapy. The primary end point was to establish the lowest effective dose capable of inducing antibody production. RESULTS: Five of six patients at the 30-microg dose and three of five patients at the 10-microg dose mounted IgM responses of 1:80 or greater. These antibodies were confirmed by flow cytometry in seven of eight cases. None of the patients at the 3-microg dose had titers above 1:80. One patient at the 30-microg dose had an IgG response with a titer of 1:80. The sera from six of the eight responders induced potent complement-mediated cytotoxicity of tumor cells. CONCLUSIONS: Vaccination with the synthetic fucosyl GM1-KLH conjugate induces an IgM antibody response against fucosyl GM1 and tumor cells expressing fucosyl GM1, comparable with the response induced by the bovine derivative. We plan to combine synthetic fucosyl GM1 vaccine at a dose of 30 microg with vaccines against three other antigens-GM2, Globo H, and polysialic acid-to test in patients with SCLC after initial chemotherapy.
Authors: Paul A Bunn; John D Minna; Alexander Augustyn; Adi F Gazdar; Youcef Ouadah; Mark A Krasnow; Anton Berns; Elisabeth Brambilla; Natasha Rekhtman; Pierre P Massion; Matthew Niederst; Martin Peifer; Jun Yokota; Ramaswamy Govindan; John T Poirier; Lauren A Byers; Murry W Wynes; David G McFadden; David MacPherson; Christine L Hann; Anna F Farago; Caroline Dive; Beverly A Teicher; Craig D Peacock; Jane E Johnson; Melanie H Cobb; Hans-Guido Wendel; David Spigel; Julien Sage; Ping Yang; M Catherine Pietanza; Lee M Krug; John Heymach; Peter Ujhazy; Caicun Zhou; Koichi Goto; Afshin Dowlati; Camilla Laulund Christensen; Keunchil Park; Lawrence H Einhorn; Martin J Edelman; Giuseppe Giaccone; David E Gerber; Ravi Salgia; Taofeek Owonikoko; Shakun Malik; Niki Karachaliou; David R Gandara; Ben J Slotman; Fiona Blackhall; Glenwood Goss; Roman Thomas; Charles M Rudin; Fred R Hirsch Journal: J Thorac Oncol Date: 2016-01-30 Impact factor: 15.609
Authors: Lee M Krug; Govind Ragupathi; Chandra Hood; Constantine George; Feng Hong; Ronglai Shen; Lauren Abrey; Harold J Jennings; Mark G Kris; Philip O Livingston Journal: Cancer Immunol Immunother Date: 2011-08-03 Impact factor: 6.968