2011, 8(2): 279-287. doi: 10.3934/mbe.2011.8.279

Questions from the fourth son: A clinician reflects on immunomonitoring, surrogate markers and systems biology

1. 

Wiseman Research Initiatives, LLC., 756 Fairfield Circle, Pasadena, CA 91106, United States

Received  May 2010 Revised  November 2010 Published  April 2011

The fourth son is the one who doesn't even know how to ask a question. Tumor immunology is challenged by the failure to identify reliable surrogate markers in vaccine and other experimental therapies for cancer; perhaps investigators haven't yet asked the right questions. Unlike prophylactic vaccines for infectious disease, where the development of antibody is considered a satisfactory endpoint, no such endpoint exists for human therapeutic vaccines. Why is this? Despite an extensive roster of in vitro assays that correlate immune responses to favorable clinical outcomes, no assay is sufficiently reliable to be usefully predictive for vaccine therapy. The discussion reviews some of the historical developments in tumor immunology and the problem of defining a causal relationship when strong correlations are identified. The development of mathematical models from empirical data may help inform the clinician/scientist about underlying mechanisms and help frame new testable hypotheses.
Citation: Charles Wiseman, M.D.. Questions from the fourth son: A clinician reflects on immunomonitoring, surrogate markers and systems biology. Mathematical Biosciences & Engineering, 2011, 8 (2) : 279-287. doi: 10.3934/mbe.2011.8.279
References:
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D. Berd, H. Maguire Jr. and M. Mastrangelo, Induction of cell mediated immunity to autologous melanomic cells and regression of metatases,, Cancer Research, 46 (1986), 2572.

[2]

D. Bernstein, G. E. Williams, H. Eisen, S. Mital, J. G. Wohlgemuth, T. M. Klingler, K. C. Fang, M. C. Deng and J. Kobashigawa, Gene expression profiling distinguishes a molecular signature for grade 1B mild acute cellular rejection in cardiac allograft recipients,, The Journal of Heart and Lung Transplantation, 26 (2007). doi: 10.1016/j.healun.2007.09.017.

[3]

M. M. Black, R. E. Zachrau, B. Shore, A. S. Dion and H. P. Leis Jr, Cellular emmunity to autologous breast cancer and R111-murine mammary tumor virus preparations,, Cancer Research, 38 (1978), 2068.

[4]

R. A. Blades, P. J. Keating, L. J. McWilliam, N. J. R. George and Peter L. Stern, Loss of HLA class 1 expression in prostrate cancer: implications for immunotherapy,, Urology, 46 (1995), 681. doi: 10.1016/S0090-4295(99)80301-X.

[5]

V. Bronte and S. Mocellin, Suppressive influences in the immune response to cancer,, Journal of Immunotherapy, 32 (2009), 1. doi: 10.1097/CJI.0b013e3181837276.

[6]

L. H. Butterfield, M. L. Disis, B. A. Fox, P. P. Lee, S. N. Khleif, M. Thurin, G. Trinchieri, E. Wang, J. Wigginton, D. Chaussabel, G. Coukos, M. Dhodapkar, L. H\aa kansson, S. Janetzki, T. O. Kleen, J. M. Kirkwood, C. Maccalli, H. Maecker, M. Maio, A. Malyguine, G. Masucci, A. K. Palucka, D. M. Potter, A. Ribas, L. Rivoltini, D. Schendel, B. Seliger, S. Selvan, C. L. Slingluff Jr, D. F. Stroncek, H. Streicher, X. Wu, B. Zeskind, Y. Zhao, M. B. Zocca, H. Zwierzina and F. M. Marincola, A systematic approach to biomarker discovery,, preamble to, 6 (2008).

[7]

D. L. Chao, M. P. Davenport, S. Forrest and A. S. Perelson, A stochastic model of cytotoxic T cell responses,, Journal of Theoretical Biology, 228 (2004), 227. doi: 10.1016/j.jtbi.2003.12.011.

[8]

A. G. Dalgleish and B. R. Souberbielle, The development of therapeutic vaccines for the management of malignant melanoma,, Cancer Survey, 26 (1996), 289.

[9]

L. G. de Pillis, A. E. Radunskaya and C. L. Wiseman, A validated mathematical model of cell-mediated immune response to tumor growth,, Cancer Research, 65 (2005), 7950.

[10]

A. Diefenbach, E. Jensen, A. Jamieson and D. Raulet, Rae1 and H60 ligands of the NKG2D receptor stimulate tumor immunity,, Nature, 413 (2001), 165. doi: 10.1038/35093109.

[11]

M. L. Disis, V. Goodell, K. Schiffman and K. L. Knutson, Humoral epitope-spreading following immunization with a HER-2/neu peptide based vaccine in cancer patients,, Journal of Clinical Immunology, 24 (2004), 571. doi: 10.1023/B:JOCI.0000040928.67495.52.

[12]

M. E. Dudley, J. R. Wunderlich, P. F. Robbins, J. C. Yang, P. Hwu, D. J. Schwartzentruber, S. L. Topalian, R. Sherry, N. P. Restifo, A. M. Hubicki, M. R. Robinson, M. Raffeld, P. Duray, C. A. Seipp, L. Rogers-Freezer, K. E. Morton, S. A. Mavroukakis, D. E. White and S. A. Rosenberg, Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes,, Science, 298 (2002), 850. doi: 10.1126/science.1076514.

[13]

B. Eibl, H. Schwaighofer, D. Nachbaur, C. Marth, A. Gächter, R. Knapp, G. Böck, C. Gassner, L. Schiller, F. Petersen and D. Niederwieser, Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer,, Blood, 88 (1996), 1501.

[14]

A. M. F. Fulton, A. Weise and Wei Wei-Zen, Prospects of controlling breast cancer metastasis by immune intervention,, Breast disease, 26 (2006), 115.

[15]

J. Galon, A. Costes, F. Sanchez-Cabo, A. Kirilovsky, B. Mlecnik, C. Lagorce-Pagès, M. Tosolini, M. Camus, A. Berger, P. Wind, F. Zinzindohoué, P. Bruneval, P-H Cugnenc, Z. Trajanoski, W-H Fridman and F. Pagès, Type, density, and location of immune cells within human colorectal tumors predict clinical outcome,, Science, 313 (2006), 1960. doi: 10.1126/science.1129139.

[16]

A. M. Hicks, Transferable anticancer innate immunity in spontaneous regression/complete resistance mice,, PNAS, 103 (2006), 7753. doi: 10.1073/pnas.0602382103.

[17]

K. Klages, C. T. Mayer, K. Lahl, C. Loddenkemper, M. W. L. Teng, S. F. Ngiow, M. J. Smyth, A. Hamann, J. Huehn and T. Sparwasser, Selective depletion of Foxp3$^+$ regulatory T cells improves effective therapeutic vaccination against established melanoma,, Cancer Research, 70 (2010), 7788. doi: 10.1158/0008-5472.CAN-10-1736.

[18]

K. -H. Lee, E. Wang, M. B. Nielsen, J. Wunderlich, S. Migueles, M. Connors, S. M. Steinberg, S. A. Rosenberg and F. M. Marincola, Increased vaccine-specific T cell frequency after peptide-based vaccination correlates with increased susceptibility in in-vitro stimulation but does not lead to tumor regression,, J. Immunol., 163 (1999), 6292.

[19]

T. W. T. Leung, Y. Z. Patt, L. Wan-Yee, S. K. W. Ho, S. C. H. Yu, A. T. C. Chan, T. S. K. Mok, W. Yeo, Choong-tsek Liew, N. W. Y. Leung, A. M. Y. Tang and P. J. Johnson, Complete pathological remission is possible with septemic combination chemotherapy for inoperable hepatocellular carcinoma,, Clinical Cancer Research, 5 (1999), 1676.

[20]

K. S. S. D. Mandrekar, Clinical trial designs for predictive biomarker validation: Theoretical considerations and practical challenges,, JCO, 27 (2009), 4027. doi: 10.1200/JCO.2009.22.3701.

[21]

F. M. Marincola, L. Rivoltini, M. L. Salgaller, M. Player and S. A. Rosenberg, Differential anti-MART-1/MelanA CTL activity in peripheral blook of HLA-A2 melanoma patients in comparison to healthy donors: evidence for in-vivo priming by tumor cells,, J. Immunother. Emphasis Tumor Immunol, 19 (1996), 266.

[22]

, "Mathematical Methods in Systems Biology,", Tel Aviv University, (2010), 7.

[23]

A. F. Ochsenbein, S. Sierro, B. Odermatt, M. Pericin, U. Karrer, J. Hermans, S. Hemmi, H. Hengartner and R. M. Zinkernagel, Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction [Erratum appears in Nature 2001 Sep 13;413(6852):183],, Nature, 411 (2001), 1058.

[24]

V. Rom-Kedar, "Models of the Innate Immune System: Theory and Medical Implications,'', Presentation, (2010).

[25]

S. Rosenberg, R. M. Sherry, K. E. Morton, W. J. Scharfman, J. C. Yang, S. L. Topalian, R. E. Royal, U. Kammula, N. P. Restifo, M. S. Hughes, D. Schwartzentruber, D. M. Berman, S. L. Schwarz, L. T. Ngo, S. A. Mavroukakis, D. E. White and S. M. Steinberg, Tumor progression can occur despite the induction of very high levelsof Self/Tumor antigen-specific CD8+ t cells in Patiens w Melanoma,, J immunol, 175 (2005), 6175.

[26]

J. Schlom, P. M. Arlen, J. L. Gulley, Cancer vaccines: Moving beyond current paradigms,, Clinical Cancer Research, 13 (2007), 3776. doi: 10.1158/1078-0432.CCR-07-0588.

[27]

J. Schlom, J. L. Gulley, P. M. Arlen, Paradigm shifts in cancer vaccine therapy,, Experimental Biology and Medicine, 233 (2008), 522. doi: 10.3181/0708-MR-226.

[28]

, "Smoking and Health,'', Report of the Advisory Committee to the Surgeon General of the Public Health Service, (1103).

[29]

M. Susser, What is a cause and how do we know one? A grammar for pragmatic epidemiology,, Am. J. of Epidemiology, 133 (1991), 635.

[30]

P. Tieri, S. Valensin, V. Latora, G. C. Castellani, M. Marchiori, D. Remondini and C. Franceschi, Quantifying the relevance of different mediators in the human immune cell network,, Bioinformatics, 21 (2005), 1639. doi: 10.1093/bioinformatics/bti239.

[31]

E. Wang, A. Monaco, V. MonsurrÃ, M. Sabatino, Z. Pos, L. Uccellini, J. Wang, A. Worschech, D. F. Stroncek and F. M. Marincola, Antitumor vaccines, immunotherapy and the immunological constant of rejection,, Idrugs, 12 (2009), 297.

[32]

E. Wang, A. Worschech and F. M. Marincola, The immunologic constant of rejection,, Trends in Immunology, 29 (2008), 256. doi: 10.1016/j.it.2008.03.002.

[33]

T. L. Whiteside, Anti-tumor vaccines in head and neck cancer: Targeting immune responses to the tumor,, Current Cancer Drug Targets, 7 (2007), 633. doi: 10.2174/156800907782418310.

[34]

C. Wiseman, R. Cailleau, M. Olivé, G. R. Blumenschein and J. M. Bowen, Autologous and homologous immunofluorescent antibody to established breast cancer cell lines,, In Vitro, 16 (1980), 629. doi: 10.1007/BF02618388.

[35]

C. Wiseman, C. Presant, R. Rao and J. Smith, Clinical responses to intralymphatic whole-cell melanoma vaccine augmented by in vitro incubation with alpha-interferon,, Ann. N.Y. Acad. Sci., 690 (1993), 388. doi: 10.1111/j.1749-6632.1993.tb44040.x.

[36]

C. L. Wiseman and A. Kharazi, Objective clinical regression of metastatic breast cancer in disparate sites after use of whole-cell vaccine genetically modified to release sargramostim,, Breast Journal, 12 (2006), 475. doi: 10.1111/j.1075-122X.2006.00319.x.

[37]

J. D. Wolchok and P. B. Chapman, How can we tell when cancer vaccines vaccinate,, J. Clin. Oncol., 21 (2003), 586. doi: 10.1200/JCO.2003.12.065.

[38]

J. D. Wolchok, A. Hoos, S. O'Day, J. S. Weber, O. Hamid, C. Lebbé, M. Maio, M. Binder, O. Bohnsack, G. Nichol, R. Humphrey and F. S. Hodi, Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria,, Clinical Cancer Research, 15 (2009), 7412. doi: 10.1158/1078-0432.CCR-09-1624.

[39]

A. Worschech, M. Kmieciak, K. L. Knutson, H. D. Bear, A. A. Szalay, E. Wang, F. M. Marincola and M. H. Manjili, Signatures associated with rejection or recurrence in HER-2/neu-positive mammary tumors,, Cancer Res., 68 (2008), 2436. doi: 10.1158/0008-5472.CAN-07-6822.

[40]

L. Zaritskaya, K. A. Shafer-Weaver, M. K. Gregory, S. L. Strobl, M. Baseler and A. Malyguine, Application of a flow cytometric cytotoxicity assay for monitoring cancer vaccine trials,, Journal of Immunotherapy, 32 (2009), 186. doi: 10.1097/CJI.0b013e318197b1b2.

show all references

References:
[1]

D. Berd, H. Maguire Jr. and M. Mastrangelo, Induction of cell mediated immunity to autologous melanomic cells and regression of metatases,, Cancer Research, 46 (1986), 2572.

[2]

D. Bernstein, G. E. Williams, H. Eisen, S. Mital, J. G. Wohlgemuth, T. M. Klingler, K. C. Fang, M. C. Deng and J. Kobashigawa, Gene expression profiling distinguishes a molecular signature for grade 1B mild acute cellular rejection in cardiac allograft recipients,, The Journal of Heart and Lung Transplantation, 26 (2007). doi: 10.1016/j.healun.2007.09.017.

[3]

M. M. Black, R. E. Zachrau, B. Shore, A. S. Dion and H. P. Leis Jr, Cellular emmunity to autologous breast cancer and R111-murine mammary tumor virus preparations,, Cancer Research, 38 (1978), 2068.

[4]

R. A. Blades, P. J. Keating, L. J. McWilliam, N. J. R. George and Peter L. Stern, Loss of HLA class 1 expression in prostrate cancer: implications for immunotherapy,, Urology, 46 (1995), 681. doi: 10.1016/S0090-4295(99)80301-X.

[5]

V. Bronte and S. Mocellin, Suppressive influences in the immune response to cancer,, Journal of Immunotherapy, 32 (2009), 1. doi: 10.1097/CJI.0b013e3181837276.

[6]

L. H. Butterfield, M. L. Disis, B. A. Fox, P. P. Lee, S. N. Khleif, M. Thurin, G. Trinchieri, E. Wang, J. Wigginton, D. Chaussabel, G. Coukos, M. Dhodapkar, L. H\aa kansson, S. Janetzki, T. O. Kleen, J. M. Kirkwood, C. Maccalli, H. Maecker, M. Maio, A. Malyguine, G. Masucci, A. K. Palucka, D. M. Potter, A. Ribas, L. Rivoltini, D. Schendel, B. Seliger, S. Selvan, C. L. Slingluff Jr, D. F. Stroncek, H. Streicher, X. Wu, B. Zeskind, Y. Zhao, M. B. Zocca, H. Zwierzina and F. M. Marincola, A systematic approach to biomarker discovery,, preamble to, 6 (2008).

[7]

D. L. Chao, M. P. Davenport, S. Forrest and A. S. Perelson, A stochastic model of cytotoxic T cell responses,, Journal of Theoretical Biology, 228 (2004), 227. doi: 10.1016/j.jtbi.2003.12.011.

[8]

A. G. Dalgleish and B. R. Souberbielle, The development of therapeutic vaccines for the management of malignant melanoma,, Cancer Survey, 26 (1996), 289.

[9]

L. G. de Pillis, A. E. Radunskaya and C. L. Wiseman, A validated mathematical model of cell-mediated immune response to tumor growth,, Cancer Research, 65 (2005), 7950.

[10]

A. Diefenbach, E. Jensen, A. Jamieson and D. Raulet, Rae1 and H60 ligands of the NKG2D receptor stimulate tumor immunity,, Nature, 413 (2001), 165. doi: 10.1038/35093109.

[11]

M. L. Disis, V. Goodell, K. Schiffman and K. L. Knutson, Humoral epitope-spreading following immunization with a HER-2/neu peptide based vaccine in cancer patients,, Journal of Clinical Immunology, 24 (2004), 571. doi: 10.1023/B:JOCI.0000040928.67495.52.

[12]

M. E. Dudley, J. R. Wunderlich, P. F. Robbins, J. C. Yang, P. Hwu, D. J. Schwartzentruber, S. L. Topalian, R. Sherry, N. P. Restifo, A. M. Hubicki, M. R. Robinson, M. Raffeld, P. Duray, C. A. Seipp, L. Rogers-Freezer, K. E. Morton, S. A. Mavroukakis, D. E. White and S. A. Rosenberg, Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes,, Science, 298 (2002), 850. doi: 10.1126/science.1076514.

[13]

B. Eibl, H. Schwaighofer, D. Nachbaur, C. Marth, A. Gächter, R. Knapp, G. Böck, C. Gassner, L. Schiller, F. Petersen and D. Niederwieser, Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer,, Blood, 88 (1996), 1501.

[14]

A. M. F. Fulton, A. Weise and Wei Wei-Zen, Prospects of controlling breast cancer metastasis by immune intervention,, Breast disease, 26 (2006), 115.

[15]

J. Galon, A. Costes, F. Sanchez-Cabo, A. Kirilovsky, B. Mlecnik, C. Lagorce-Pagès, M. Tosolini, M. Camus, A. Berger, P. Wind, F. Zinzindohoué, P. Bruneval, P-H Cugnenc, Z. Trajanoski, W-H Fridman and F. Pagès, Type, density, and location of immune cells within human colorectal tumors predict clinical outcome,, Science, 313 (2006), 1960. doi: 10.1126/science.1129139.

[16]

A. M. Hicks, Transferable anticancer innate immunity in spontaneous regression/complete resistance mice,, PNAS, 103 (2006), 7753. doi: 10.1073/pnas.0602382103.

[17]

K. Klages, C. T. Mayer, K. Lahl, C. Loddenkemper, M. W. L. Teng, S. F. Ngiow, M. J. Smyth, A. Hamann, J. Huehn and T. Sparwasser, Selective depletion of Foxp3$^+$ regulatory T cells improves effective therapeutic vaccination against established melanoma,, Cancer Research, 70 (2010), 7788. doi: 10.1158/0008-5472.CAN-10-1736.

[18]

K. -H. Lee, E. Wang, M. B. Nielsen, J. Wunderlich, S. Migueles, M. Connors, S. M. Steinberg, S. A. Rosenberg and F. M. Marincola, Increased vaccine-specific T cell frequency after peptide-based vaccination correlates with increased susceptibility in in-vitro stimulation but does not lead to tumor regression,, J. Immunol., 163 (1999), 6292.

[19]

T. W. T. Leung, Y. Z. Patt, L. Wan-Yee, S. K. W. Ho, S. C. H. Yu, A. T. C. Chan, T. S. K. Mok, W. Yeo, Choong-tsek Liew, N. W. Y. Leung, A. M. Y. Tang and P. J. Johnson, Complete pathological remission is possible with septemic combination chemotherapy for inoperable hepatocellular carcinoma,, Clinical Cancer Research, 5 (1999), 1676.

[20]

K. S. S. D. Mandrekar, Clinical trial designs for predictive biomarker validation: Theoretical considerations and practical challenges,, JCO, 27 (2009), 4027. doi: 10.1200/JCO.2009.22.3701.

[21]

F. M. Marincola, L. Rivoltini, M. L. Salgaller, M. Player and S. A. Rosenberg, Differential anti-MART-1/MelanA CTL activity in peripheral blook of HLA-A2 melanoma patients in comparison to healthy donors: evidence for in-vivo priming by tumor cells,, J. Immunother. Emphasis Tumor Immunol, 19 (1996), 266.

[22]

, "Mathematical Methods in Systems Biology,", Tel Aviv University, (2010), 7.

[23]

A. F. Ochsenbein, S. Sierro, B. Odermatt, M. Pericin, U. Karrer, J. Hermans, S. Hemmi, H. Hengartner and R. M. Zinkernagel, Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction [Erratum appears in Nature 2001 Sep 13;413(6852):183],, Nature, 411 (2001), 1058.

[24]

V. Rom-Kedar, "Models of the Innate Immune System: Theory and Medical Implications,'', Presentation, (2010).

[25]

S. Rosenberg, R. M. Sherry, K. E. Morton, W. J. Scharfman, J. C. Yang, S. L. Topalian, R. E. Royal, U. Kammula, N. P. Restifo, M. S. Hughes, D. Schwartzentruber, D. M. Berman, S. L. Schwarz, L. T. Ngo, S. A. Mavroukakis, D. E. White and S. M. Steinberg, Tumor progression can occur despite the induction of very high levelsof Self/Tumor antigen-specific CD8+ t cells in Patiens w Melanoma,, J immunol, 175 (2005), 6175.

[26]

J. Schlom, P. M. Arlen, J. L. Gulley, Cancer vaccines: Moving beyond current paradigms,, Clinical Cancer Research, 13 (2007), 3776. doi: 10.1158/1078-0432.CCR-07-0588.

[27]

J. Schlom, J. L. Gulley, P. M. Arlen, Paradigm shifts in cancer vaccine therapy,, Experimental Biology and Medicine, 233 (2008), 522. doi: 10.3181/0708-MR-226.

[28]

, "Smoking and Health,'', Report of the Advisory Committee to the Surgeon General of the Public Health Service, (1103).

[29]

M. Susser, What is a cause and how do we know one? A grammar for pragmatic epidemiology,, Am. J. of Epidemiology, 133 (1991), 635.

[30]

P. Tieri, S. Valensin, V. Latora, G. C. Castellani, M. Marchiori, D. Remondini and C. Franceschi, Quantifying the relevance of different mediators in the human immune cell network,, Bioinformatics, 21 (2005), 1639. doi: 10.1093/bioinformatics/bti239.

[31]

E. Wang, A. Monaco, V. MonsurrÃ, M. Sabatino, Z. Pos, L. Uccellini, J. Wang, A. Worschech, D. F. Stroncek and F. M. Marincola, Antitumor vaccines, immunotherapy and the immunological constant of rejection,, Idrugs, 12 (2009), 297.

[32]

E. Wang, A. Worschech and F. M. Marincola, The immunologic constant of rejection,, Trends in Immunology, 29 (2008), 256. doi: 10.1016/j.it.2008.03.002.

[33]

T. L. Whiteside, Anti-tumor vaccines in head and neck cancer: Targeting immune responses to the tumor,, Current Cancer Drug Targets, 7 (2007), 633. doi: 10.2174/156800907782418310.

[34]

C. Wiseman, R. Cailleau, M. Olivé, G. R. Blumenschein and J. M. Bowen, Autologous and homologous immunofluorescent antibody to established breast cancer cell lines,, In Vitro, 16 (1980), 629. doi: 10.1007/BF02618388.

[35]

C. Wiseman, C. Presant, R. Rao and J. Smith, Clinical responses to intralymphatic whole-cell melanoma vaccine augmented by in vitro incubation with alpha-interferon,, Ann. N.Y. Acad. Sci., 690 (1993), 388. doi: 10.1111/j.1749-6632.1993.tb44040.x.

[36]

C. L. Wiseman and A. Kharazi, Objective clinical regression of metastatic breast cancer in disparate sites after use of whole-cell vaccine genetically modified to release sargramostim,, Breast Journal, 12 (2006), 475. doi: 10.1111/j.1075-122X.2006.00319.x.

[37]

J. D. Wolchok and P. B. Chapman, How can we tell when cancer vaccines vaccinate,, J. Clin. Oncol., 21 (2003), 586. doi: 10.1200/JCO.2003.12.065.

[38]

J. D. Wolchok, A. Hoos, S. O'Day, J. S. Weber, O. Hamid, C. Lebbé, M. Maio, M. Binder, O. Bohnsack, G. Nichol, R. Humphrey and F. S. Hodi, Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria,, Clinical Cancer Research, 15 (2009), 7412. doi: 10.1158/1078-0432.CCR-09-1624.

[39]

A. Worschech, M. Kmieciak, K. L. Knutson, H. D. Bear, A. A. Szalay, E. Wang, F. M. Marincola and M. H. Manjili, Signatures associated with rejection or recurrence in HER-2/neu-positive mammary tumors,, Cancer Res., 68 (2008), 2436. doi: 10.1158/0008-5472.CAN-07-6822.

[40]

L. Zaritskaya, K. A. Shafer-Weaver, M. K. Gregory, S. L. Strobl, M. Baseler and A. Malyguine, Application of a flow cytometric cytotoxicity assay for monitoring cancer vaccine trials,, Journal of Immunotherapy, 32 (2009), 186. doi: 10.1097/CJI.0b013e318197b1b2.

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