Share This Article:

CD8 T cell response in a phase I study of therapeutic vaccination of advanced NSCLC with allogeneic tumor cells secreting endoplasmic reticulum-chaperone gp96-Ig-peptide complexes

DOI: 10.4236/alc.2013.21002    3,642 Downloads   8,788 Views   Citations

ABSTRACT

Antigen containing, allogeneic cells secreting the genetically modified protein and peptide-chaperone gp96-Ig cross, prime and expand antigen specific CD8 T cells with therapeutic antitumor activity in mice. In a first in man phase I study, we now report the results of therapeutic vaccination of non-small cell lung cancer (NSCLC) patients with an established, allogeneic non-small cell lung adenocarcinoma cell line secreting gp96-Ig. Advanced NSCLC-patients stage IIIB or IV of any histological subtype were enrolled and treated with up to 36 vaccinations over the course of 18 weeks. Primary endpoint was safety, secondary endpoints tumor response and overall survival. Measurement of tumor antigen specific CD8 CTL responses is precluded by the lack of known NSCLC associated antigens. Therefore, we measured patient CD8 T cell-IFN-γ responses to allo-antigens of the vaccine cells as surrogate for tumor antigen specific CD8 CTL. In 7 of 18 treated patients tumor growth was stabilized, however none of the 18 patients had an objective tumor response by RECIST criteria. Of 15 patients evaluable for immune response, 11 responded to vaccination with more than twofold increase in CD8-IFN-γ frequency above baseline. These patients had a median survival time of 16.5 months. Four patients who had no CD8 response above base line had survival times from 2.1 to 6.7 months. Our data are consistent with the concept that generation of CD8 CTL by therapeutic vaccination may delay tumor growth and progression and mediate prolonged survival even in the absence of objective tumor responses. Further studies will be required to test this concept and promising result.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Raez, L., Walker, G., Baldie, P., Fisher, E., Gomez, J., Tolba, K., Santos, E. and Podack, E. (2013) CD8 T cell response in a phase I study of therapeutic vaccination of advanced NSCLC with allogeneic tumor cells secreting endoplasmic reticulum-chaperone gp96-Ig-peptide complexes. Advances in Lung Cancer, 2, 9-18. doi: 10.4236/alc.2013.21002.

References

[1] Raez, L.E., Cassileth, P.A., Schlesselman, J.J., Sridhar, K., Padmanabhan, S., Fisher, E.Z., Baldie, P.A., Podack and E.R. (2004) Allogeneic vaccination with a B7.1 HLA-A gene-modified adenocarcinoma cell line in patients with advanced non-small-cell lung cancer. Journal of Clinical Oncology, Official Journal of the American Society of Clinical Oncology, 22, 2800-2807. doi:10.1200/JCO.2004.10.197
[2] Srivastava, P.K., DeLeo, A.B. and Old, L.J. (1986) Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proceedings of the National Academy of Sciences of the United States of America, 83, 3407-3411. doi:10.1073/pnas.83.10.3407
[3] Udono, H., Levey, D.L. and Srivastava, P.K. (1994) Cellular requirements for tumor-specific immunity elicited by heat shock proteins: Tumor rejection antigen gp96 primes CD8+ T cells in vivo. Proceedings of the National Academy of Sciences of the United States of America, 91, 3077-3081. doi:10.1073/pnas.91.8.3077
[4] Udono, H. and Srivastava, P.K. (1993) Heat shock protein 70-associated peptides elicit specific cancer immunity. The Journal of Experimental Medicine, 178, 1391-1396. doi:10.1084/jem.178.4.1391
[5] Udono, H. and Srivastava, P.K. (1994) Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70. Journal of Immunology, 152, 5398-5403.
[6] Binder, R.J. and Srivastava, P.K. (2005) Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cells. Nature Immunology, 6, 593-599. doi:10.1038/ni1201
[7] Yang, Y., Liu, B., Dai, J., Srivastava, P.K., Zammit, D.J., Lefrancois, L. and Li, Z. (2007) Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity, 26, 215-226. doi:10.1016/j.immuni.2006.12.005
[8] Li, Z. and Srivastava, P.K. (1993) Tumor rejection antigen grp96/ grp94 is an ATPase: Implications for protein folding and antigen presentation. The EMBO Journal, 12, 3143-3151.
[9] Arnold, D., Faath, S., Rammensee, H. and Schild, H. (1995) Cross-priming of minor histocompatibility antigen-specific cytotoxic T cells upon immunization with the heat shock protein gp96. The Journal of Experimental Medicine, 182, 885-889. doi:10.1084/jem.182.3.885
[10] Vabulas, R.M., Braedel, S., Hilf, N., Singh-Jasuja, H., Herter, S., Ahmad-Nejad, P., Kirschning, C.J., Da Costa, C., Rammensee, H.G., Wagner, H., et al. (2002) The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. The Journal of Biological Chemistry, 277, 20847-20853. doi:10.1074/jbc.M200425200
[11] Binder, R.J., Han, D.K. and Srivastava, P.K. (2000) CD91: A receptor for heat shock protein gp96. Nature Immunology, 1, 151-155. doi:10.1038/77835
[12] Matzinger, P. and Bevan, M.J. (1977) Induction of H-2-restricted cytotoxic T cells: In vivo induction has the appearance of being unrestricted. Cellular Immunology, 33, 92-100. doi:10.1016/0008-8749(77)90137-X
[13] Testori, A., Richards, J., Whitman, E., Mann, G.B., Lutzky J, Camacho, L., Parmiani, G., Tosti, G., Kirkwood, J.M., Hoos, A., et al. (2008) Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician’s choice of treatment for stage IV melanoma: The C-100-21 Study Group. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 26, 955-962. doi:10.1200/JCO.2007.11.9941
[14] Yamazaki, K., Nguyen, T. and Podack, E.R. (1999) Cutting edge: Tumor secreted heat shock-fusion protein elicits CD8 cells for rejection. Journal of Immunology, 163, 5178-5182.
[15] Oizumi, S., Strbo, N., Pahwa, S., Deyev, V. and Podack, E.R. (2007) Molecular and cellular requirements for enhanced antigen cross-presentation to CD8 cytotoxic T lymphocytes. Journal of Immunology, 179, 2310-2317.
[16] Strbo, N., Oizumi, S., Sotosek-Tokmadzic, V. and Podack, E.R. (2003) Perforin is required for innate and adaptive immunity induced by heat shock protein gp96. Immunity, 18, 381-390. doi:10.1016/S1074-7613(03)00056-6
[17] Strbo, N., Vaccari, M., Pahwa, S., Kolber, M.A., Fisher, E., Gonzalez, L., Doster, M.N., Hryniewicz, A., Felber, B.K., Pavlakis, G.N., et al. (2011) Gp96 SIV Ig immunization induces potent polyepitope specific, multifunctional memory responses in rectal and vaginal mucosa. Vaccine, 29, 2619-2625. doi:10.1016/j.vaccine.2011.01.044
[18] Sang, M., Wang, L., Ding, C., Zhou, X., Wang, B., Wang, L., Lian, Y. and Shan, B. (2011) Melanoma-associated antigen genes—An update. Cancer Letters, 302, 85-90. doi:10.1016/j.canlet.2010.10.021
[19] Gajewski, T.F. and Fallarino, F. (1995) Rational development of tumour antigen-specific immunization in melanoma. Therapeutic Immunology, 2, 211-225.
[20] Bystryn, J.C. (1995) Clinical activity of a polyvalent melanoma antigen vaccine. Recent Results in Cancer Research Fortschritte der Krebsforschung Progres dans les Recherches sur le Cancer, 139, 337-348. doi:10.1007/978-3-642-78771-3_26
[21] Glazer, C.A., Smith, I.M., Ochs, M.F., Begum, S., Westra, W., Chang, S.S., Sun, W., Bhan, S., Khan, Z., Ahrendt, S., et al. (2009) Integrative discovery of epigenetically derepressed cancer testis antigens in NSCLC. PloS One, 4, e8189. doi:10.1371/journal.pone.0008189
[22] Yamazaki, K., Spruill, G., Rhoderick, J., Spielman, J., Savaraj, N. and Podack, E.R. (1999) Small cell lung carcinomas express shared and private tumor antigens presented by HLA-A1 or HLA-A2. Cancer Research, 59, 4642-4650.
[23] Oizumi, S., Deyev, V., Yamazaki, K., Schreiber, T., Strbo, N., Rosenblatt, J. and Podack, E.R. (2008) Surmounting tumor-induced immune suppression by frequent vaccinetion or immunization in the absence of B cells. Journal of Immunotherapy, 31, 394-401. doi:10.1097/CJI.0b013e31816bc74d
[24] Schreiber, T.H., Deyev, V.V., Rosenblatt, J.D. and Podack, E.R. (2009) Tumor-induced suppression of CTL expansion and subjugation by gp96-Ig vaccination. Cancer Research, 69, 2026-2033. doi:10.1158/0008-5472.CAN-08-3706
[25] http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-029771.pdf
[26] Bonomi, P.D., Finkelstein, D.M., Ruckdeschel, J.C., Blum, R.H., Green, M.D., Mason, B., Hahn, R., Tormey, D.C., Harris, J., Comis, R. et al. (1989) Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: A study of the Eastern Cooperative Oncology Group. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 7, 1602-1613.
[27] Schiller, J.H., Harrington, D., Belani, C.P., Langer, C., Sandler, A., Krook, J., Zhu, J. and Johnson, D.H. (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. The New England Journal of Medicine, 346, 92-98. doi:10.1056/NEJMoa011954
[28] Weick, J.K., Crowley, J., Natale, R.B., Hom, B.L., Rivkin, S., Coltman Jr., C.A., Taylor, S.A. and Livingston, R.B. (1991) A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: A Southwest Oncology Group study. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 9, 1157-1162.
[29] Miller, V.A. O.C.P., Soh, C. and Kabbinavar, F. A (2009) randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 27, LBA8002.
[30] Reck, M., von Pawel, J., Zatloukal, P., Ramlau, R., Gorbounova, V., Hirsh, V., Leighl, N., Mezger, J., Archer, V., Moore, N., et al. (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 27, 1227- 1234. doi:10.1200/JCO.2007.14.5466
[31] Sandler, A., Gray, R., Perry, M.C., Brahmer, J., Schiller, J.H., Dowlati, A., Lilenbaum, R. and Johnson, D.H. (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. The New England Journal of Medicine, 355, 2542-2550. doi:10.1056/NEJMoa061884
[32] Scagliotti, G., Novello, S., von Pawel, J., Reck, M., Pereira, J.R., Thomas, M., Abrao Miziara, J.E., Balint, B., De Marinis, F., Keller, A. et al. (2010) Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 28, 1835-1842. doi:10.1200/JCO.2009.26.1321
[33] Treat, J.S.G., Peng, G., Monberg, M.J., Obasaju, C.K. and Socinski, M.A. (2011) Comparison of pemetrexed plus cisplatin with other first-line doublets in advanced non-small cell lung cancer (NSCLC): A combined analysis of three phase 3 trials. Lung Cancer. http://www.ncbi.nlm.nih.gov/pubmed/22115704.
[34] De Smet, C., Lurquin, C., De Plaen, E., Brasseur, F., Zarour H, De Backer, O., Coulie, P.G. and Boon, T. (1997) Genes coding for melanoma antigens recognised by cy- tolytic T lymphocytes. Eye (Lond), 11, 243-248. doi:10.1038/eye.1997.59
[35] Riley, J.P., Rosenberg, S.A. and Parkhurst, M.R. (2001) Identification of a New Shared HLA-A2.1 Restricted Epitope From the Melanoma Antigen Tyrosinase. Journal of Immunotherapy (1991), 24, 212-220.
[36] Singhal, S., Miller, D., Ramalingam, S. and Sun, S.Y. (2008) Gene expression profiling of non-small cell lung cancer. Lung Cancer, 60, 313-324. doi:10.1016/j.lungcan.2008.03.007
[37] Strbo, N., Pahwa, S., Kolber, M.A., Gonzalez, L., Fisher, E. and Podack, E.R. (2010) Cell-secreted Gp96-Ig-peptide complexes induce lamina propria and intraepithelial CD8+ cytotoxic T lymphocytes in the intestinal mucosa. Mucosal Immunology, 3, 182-192. doi:10.1038/mi.2009.127
[38] Collett, D. (2003) In Modeling Survival Data in Medical Research, 2nd Edition, CRC Press, New York.
[39] Schreiber, R.D., Old, L.J. and Smyth, M.J. (2011) Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science, 331, 1565-1570. doi:10.1126/science.1203486
[40] Koebel, C.M., Vermi, W., Swann, J.B., Zerafa, N., Rodig, S.J., Old, L.J., Smyth, M.J. and Schreiber, R.D. (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature, 450, 903-907. doi:10.1038/nature06309
[41] North, R.J. and Bursuker, I. (1984) T cell-mediated suppression of the concomitant antitumor immune response as an example of transplantation tolerance. Transplantation Proceedings, 16, 463-469.
[42] North, R.J. and DiGiacomo, A. (1986) Generation and Suppression of the Immune Resoponse to Immunogenic Tumors. In: Steinman, R.M. and North, R.J., Eds., Mechanisms of Host Resistance to Infectious Agents, Tumors, and Allografts, The Rockefeller University Press, New York, 387-396.

  
comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.