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Originally published as JCO Early Release 10.1200/JCO.2004.09.038 on September 27 2004 © 2004 American Society of Clinical Oncology. Antitumor Vaccination of Patients With Glioblastoma Multiforme: A Pilot Study to Assess Feasibility, Safety, and Clinical BenefitFrom the Departments of Neurosurgery, Head and Neck Surgery, Neuropathology, and Neuroanaesthetics, University of Heidelberg; and Division of Cellular Immunology, German Cancer Research Center, Heidelberg, Germany Address reprint requests to Hans Herbert Steiner, MD, Department of Neurosurgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; e-mail: hsteiner{at}med.uni-heidelberg.de
PURPOSE: Prognosis of patients with glioblastoma is poor. Therefore, in glioblastoma patients, we analyzed whether antitumor vaccination with a virus-modified autologous tumor cell vaccine is feasible and safe. Also, we determined the influence on progression-free survival and overall survival and on vaccination-induced antitumor reactivity. PATIENTS AND METHODS: In a nonrandomized study, 23 patients were vaccinated and compared with nonvaccinated controls (n = 87). Vaccine was prepared from patient's tumor cell cultures by infection of the cells with Newcastle Disease Virus, followed by gamma-irradiation, and applied up to eight times. Antitumor immune reactivity was determined in skin, blood, and relapsed tumor by delayed-type hypersensitivity skin reaction, ELISPOT assay, and immunohistochemistry, respectively.
RESULTS: Establishment of tumor cell cultures was successful in approximately 90% of patients. After vaccination, we observed no severe side effects. The median progression-free survival of vaccinated patients was 40 weeks (v 26 weeks in controls; log-rank test, P = .024), and the median overall survival of vaccinated patients was 100 weeks (v 49 weeks in controls; log-rank test, P < .001). Forty-five percent of the controls survived 1 year, 11% survived 2 years, and there were no long-term survivors ( CONCLUSION: Postoperative vaccination with virus-modified autologous tumor cells seems to be feasible and safe and to improve the prognosis of patients with glioblastomas. This could be substantiated by the observed antitumor immune response.
Glioblastoma multiforme is one of the most devastating types of cancer. Despite progress in surgical techniques and an improved application of radiotherapy and chemotherapy, the prognosis remains poor, with a median survival time of less than 1 year.1,2 Glioblastomas are characterized by their infiltrating nature3 and by their ability to induce changes in the microenvironment4 as well as in the host's immune system, leading to reduced T-cell–mediated antitumor immunity.5 It is well documented that glioblastomas release substances that cause immunosuppression, such as transforming growth factor beta, prostaglandin E2, and interleukin (IL)-10.5-7 Nevertheless, immunotherapy of glioblastoma multiforme is very appealing because it offers the potential for tumor specificity with low side effects.8-10 Certain proteins are selectively overexpressed in glioblastomas, and recent studies have shown that T lymphocytes and major histocompatibility complex (MHC) antigens are detectable in the brain during an illness like encephalitis and in tumors despite the blood-brain barrier.11 In animal models, it was shown that subcutaneous vaccination with irradiated, cytokine-producing tumor cells12 or with dendritic cells (DCs) pulsed with tumor extract13 stimulated CD8 T-cell–mediated immunity against tumors located in the immunologically privileged CNS.8 Furthermore, adoptively transfused antiglioma immune T cells were shown to cross the blood-brain barrier and to infiltrate rat gliomas, leading to tumor regression.14 For optimal efficacy, tumor cell vaccines require the addition of danger signals15 by adjuvants. For this purpose, we used Newcastle Disease Virus (NDV),16 an avian paramyxovirus that selectively replicates in tumor cells and exhibits pleiotropic immune modulatory properties.17 In the infected cells, it induces danger signals, such as double-stranded RNA, interferons (IFNs), and chemokines.18 The present pilot study was undertaken to evaluate a NDV-modified autologous tumor vaccine (ATV-NDV) in glioblastoma patients. The primary aims were to determine the feasibility of this approach and to assess possible side effects, vaccine-induced immune effects, and a potential clinical benefit.
Patients From December 1995 to April 2001, antitumor vaccination was offered to 35 patients with a pathologically confirmed glioblastoma. Eligibility criteria included a Karnofsky performance score of 60 or greater and normal baseline hematologic parameters (hemoglobin, total granulocyte count, platelet count, creatinine, transaminases, and thromboplastin time) 2 weeks before the first vaccination, a patient age over 18 years, and written informed consent. Exclusion criteria were pregnancy, severe pulmonary, cardiac, or other systemic disease associated with an unacceptable operative risk, and presence of an acute infection, autoimmune disorders, or other malignancies. All patients were operated on at the Department of Neurosurgery, University of Heidelberg (Heidelberg, Germany). Pathologic grading of tumors was performed according to the classification of WHO.3 Vaccination therapy was offered to all patients fulfilling inclusion and exclusion criteria and attended by the first author (H.H.S.) preoperatively. Three of 35 patients had to be excluded from the study because of insufficient in vitro growth. Seven of 35 patients refused the treatment, mostly because of unknown clinical efficacy and possible side effects. After a histologic re-evaluation by a second neuropathologist, two of 35 patients were excluded because of oligodendroglial components representing a rare glioblastoma multiforme subtype associated with a better prognosis. Thus, the final treatment group consisted of 23 patients. After maximal surgical resection, every patient received radiotherapy using either a hyperfractionated or fractionated irradiation protocol (1.9 Gy in a single dose twice a day or 3.8 Gy once a day, with 57 Gy total dose; linear accelerator with 6-MV photons; Table 1). During radiation therapy, in 19 of 23 patients, a standard corticosteroid medication of dexamethasone 6 mg/d was applied. The remaining four patients received higher doses of up to 12 mg/d. Dexamethasone application was terminated immediately after radiation therapy and was applied again after tumor relapse. Vaccination therapy was started after completion of radiotherapy. After tumor relapse, 15 of 23 patients received chemotherapy consisting of two to nine cycles of carmustine (Table 1).
For comparison of progression-free survival (PFS) and overall survival (OS), a control group was established. Eighty-seven nonselected control patients were chosen from all the patients of the department who were operated on within the study period (n = 155) and who received postoperative radiation therapy and presented preoperatively with a Karnofsky performance score of 60 or greater. All patients, including controls, were closely evaluated during follow-up, which included magnetic resonance image (MRI) scan (every 90 days), to determine tumor relapse and progression or regression of residual tumor. The study was approved by the institutional review board in accordance with the Helsinki Declaration of 1975, as revised in 1983. Patients were numbered 1 to 23 for the vaccination group and 24 to 110 for the control group. Data of the vaccination group and the control group were both analyzed after a median follow-up period of 59 months.
Autologous Tumor Cell Culture and Characterization
Preparation of ATV-NDV
Vaccination Procedure and DTH Test
RNA Isolation and Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) Analysis for Tumor Antigens
Generation of DCs and T Lymphocytes
IFN-
Immunohistochemistry
Statistical Analysis
Patients and Study Design The preparation and characterization of the autologous, virus-modified tumor vaccine for 23 patients are illustrated in Figure 1. Clinical data of these patients are listed in detail in Table 1. Vaccinated patients were compared to a group of 87 nonselected controls who received the same type of standard therapy, consisting of maximal surgical resection and radiation therapy. A comparison of vaccinated patients and controls regarding prognostic parameters, therapy, and outcome is summarized in Table 2. In both groups, MRI-controlled surgical removal of the tumor was followed by radiotherapy. Afterward, patients of the verum group received up to eight vaccinations in 3- to 4-week intervals. Six of 23 patients were vaccinated with a reduced number of five to seven applications because of tumor relapse or insufficient tumor cell growth in vitro. After tumor relapse, chemotherapy was offered to all patients of the verum and the control groups, but not all patients agreed to receive a cytostatic treatment (Table 2).
Characterization of Autologous Tumor Vaccine, Feasibility, and Safety of Application To obtain vaccine in sufficient quantity and quality, ATV-NDV was prepared for each patient from autologous glioblastoma cell cultures. Establishment of primary glioblastoma cultures was possible in almost 90% of the tumor samples (23 of 26 samples). As shown in Figure 1A, glioblastoma cells showed homogenous expression of the astrocytic marker GFAP (23 of 23 samples) and no staining for markers of other cell types that were present in the original glioma tissue such as neuronal (NFPI and -II) and endothelial cells (PECAM-1). All cultured tumor cells expressed MHC class I molecules (23 of 23 samples), which are important for presentation of tumor-associated antigens. In addition, in 14 glioblastoma cultures, we also observed, by immunohistochemistry, expression of a deletion variant of the EGFR (EGFRvIII) that is known to be a possible tumor antigen of glioblastomas.21 Cell cultures from 21 vaccinated patients were analyzed by RT-PCR to determine mRNA expression of common tumor antigens.19,22 All tested glioblastoma cells expressed mage-1, 16 of them expressed gp100, and two expressed trp-2 (Fig 1B). Altogether, two cell cultures expressed mRNA of all three tumor antigens analyzed, 14 were positive for two tumor antigens, and six demonstrated expression of at least mage-1. The housekeeping gene gapdh served as positive control. Six months after surgery, during vaccination therapy, patient 16 presented in T2-weighted MRI scans with distinct signal-intensive fields, which were not seen in the following MRI scan 3 months later. This may be interpreted as a possible immune reaction because concomitant T1-weighted images did not give any evidence for tumor relapse. After vaccination, we did not observe any serious adverse events, and there was no evidence of autoimmune phenomena such as vasculitis, rheumatoid arthritis, or lymphatic disorders. One patient developed a mild fever 3 days after the third vaccination that lasted for 2 days, and another patient presented with a transient cholestasis for 1 month evidenced by a slight elevation of transaminases. In the verum group, mild fatigues and palpable indurations at the vaccination site were reported frequently, but no hematologic toxicities were observed.
Clinical Benefit
For the verum group, percentages of PFS after diagnosis were 21% at 1 year and 4% at 2 years, and percentages of OS were 91% at 1 year, 39% at 2 years, and 4% at 3 years. In the control group, percentages of PFS were 8% at 1 year and 1% at 2 years, and percentages of OS were 45% at 1 year, 11% at 2 years, and 0% at 3 years (Table 2). Differences in PFS and OS were significant (P = .024 and P < .001, respectively). The markedly improved PFS and OS in the verum group and the fact that, in a nonrandomized study design, a selection bias cannot be excluded prompted us to compare the best clinical course in nonvaccinated patients of our control group that could be achieved in our department after standard therapy to our verum group. Comparison of 23 patients of the former control group (n = 87) presenting with the best survival revealed a similar median PFS (42 weeks) and a minor median OS (88 weeks) compared with the verum group, who had a median PFS of 40 weeks and a median OS of 100 weeks (Table 2, Fig 2B). Although these 23 best controls were highly selected, clinical outcome was not superior to the verum group (P = .620 and P = .582 for PFS and OS, respectively), and none of these patients survived more than 2 years in contrast to the verum group. In addition, we obtained evidence by MRI scans of objective tumor remissions in one patient of the vaccinated group. Figure 3 illustrates this case. In the controls, no tumor remissions were observed.
Effects of Vaccination Demonstrated by Immune Monitoring in the Skin, Peripheral Blood, and at the Site of Relapsed Tumor In 15 patients, observation of DTH skin reaction to the virus-modified vaccine as well as to a challenge with unmodified irradiated tumor cells was obtained. Figure 4A shows means of the indurations before the vaccinations started and before the last vaccination (n = 15). Both reactivities were significantly increased after vaccination. Of particular relevance is the increased reactivity to unmodified tumor cells (challenge test, black columns), indicating systemic reactivity to autologous tumor cells as they may have remained in the patient. Highest reactivities to unmodified tumor cells were observed in patient 23 (2.6 cm2), patient 2 (2.2 cm2), and patient 4 (2.6 cm2). Interestingly, patient 23 presented with the highest PFS, and patient 4 presented with a tumor remission after vaccination shown in Figure 3.
In several vaccinated and nonvaccinated patients, we also investigated antitumor memory T-cell reactivity because activated memory T cells from cancer patients were shown to confer antitumor immunity.20 This analysis was performed retrospectively in one long-term surviving patient (patient 8, Table 1 lists clinical data), one patient from the verum group who survived 138 weeks (patient 16), and one patient who is still disease-free after 108 weeks (patient 23). Median PFS of controls was 36 weeks (range, 12 to 39 weeks), and median OS was 48 weeks (range, 13 to 76 weeks). The IFN-  ELISPOT assay, which was used to quantify antitumor memory T-cell reactivity, was entirely autologous and used DCs as antigen-presenting cells.20 T cells from PBMC of vaccinated patients showed elevated tumor-specific memory T-cell frequencies compared with the majority of tested nonvaccinated patients (Fig 4B). Remarkably, the T-cell levels of patient 8 were obtained 3.5 years after the last vaccination. We also analyzed whether antitumor vaccination leads to an increase of tumor-infiltrating lymphocytes (TILs). For this purpose, using immunohistochemistry, we compared frozen sections from all available primary and relapsed tumors that had been removed from either vaccinated patients (n = 7) or controls (n = 4; median time interval between first and second surgery: verum group, 42 weeks; control group, 32 weeks). Figure 4C shows mean numbers of CD8+ cytotoxic TILs/mm2 tumor tissue in primary tumors and relapsed tumors. Numbers of CD8+ T cells from at least three cryostat sections were used for calculation of mean values from each specimen. Whereas in individual primary and relapsed tumors from the nonvaccinated controls, numbers of CD8+ TILs were always very low (Fig 5A and 5B); in the relapsed tumors from the cases, we saw a significant six-fold increase of CD8+ TILs (Fig 5C and 5D).
In this pilot study, we demonstrate that postoperative antitumor vaccination of 23 glioblastoma patients with an autologous virus-modified tumor vaccine is feasible and safe and increases OS and PFS compared with a nonselected control group. Vaccination apparently affected the number of tumor-reactive memory T cells and of CD8+ tumor-infiltrating T cells in secondary tumors. We decided to use individual intact tumor cells from patients as the source of tumor antigens and were able to establish tumor cell cultures in approximately 90% of the cases (23 of 26 samples). This allowed us to produce vaccines with a standardized high number of tumor cells. The high number of 10 million autologous viable tumor cells per vaccine might include individually unique tumor antigens derived from mutations or other genetic alterations and might also be representative of the heterogeneity of tumor antigens in a single tumor. In support of this hypothesis, most of the tested tumor cultures showed expression of multiple common tumor antigens. The use of whole tumor cells is feasible and eliminates the need to first identify the respective tumor antigens, which would require sophisticated techniques. Because even multiple applications of the vaccine did not induce autoimmune disease, this approach can be considered to be safe. Regarding the number of vaccine cells, it was shown in a breast cancer study, using tumor cells obtained by enzymatic digestion of the resected tumor tissue, that a clinical benefit was only seen when patients received at least 1.5 x 106 ATV-NDV cells per vaccine.23 In the present study, we were able to use an even higher cell number for each patient by establishing individual tumor cell cultures. Also, the purity of the tumor cells seems to be improved because of the absence of stroma-derived cells.
As adjuvant in the tumor vaccine, we used NDV strain Ulster based on good experiences in various animal tumor models24 and because infection of glioblastoma cells proved to be an efficient and safe way to produce such a tumor vaccine.17 Recently, interest in the use of tumor-selective replication-competent viruses, such as NDV, which has already been safely applied to many cancer patients in Europe and the United States, is reviving.16 NDV exerts antineoplastic, oncolytic, and immune-stimulatory properties.16,17 In tumor cells, it induces T-cell costimulatory activity,25 upregulates MHC and adhesion molecules, and induces IFN- Regarding the clinical outcome of the vaccinated patients, we observed a clear-cut shift in the survival curves of the verum group, equivalent to approximately 100% prolongation of the mean PFS and OS. The observed 39% 2-year OS rate in the verum group is high and has not been reported by any other type of treatment. Thus, we could confirm preliminary results of this study obtained after a mean follow-up of approximately 1.5 years that already indicate a survival advantage for vaccinated patients.24 Interestingly, clinical benefit within the verum group could also be supported by MRI imaging showing a complete disappearance of the residual tumor mass that was not seen in any of the controls. An unwanted bias caused by the additional cytostatic therapy in a subgroup of vaccinated patients seems to be unlikely, because a randomized trial of 137 glioblastoma patients receiving carmustine treatment after maximal surgical resection and external-beam radiotherapy showed a median survival of only 58.8 weeks.27 Also, the 100-week median OS observed in our study compares favorably with the reported 65-week median OS after vaccination with a peptide-pulsed DC vaccine19 and with the 46-week median OS reported as a preliminary result after immunization with a modified tumor cell vaccine.28 As mentioned before, one important factor for these differences may be the quality of the vaccine, which depends on the source of tumor-associated antigens, on the number and viability of vaccine cells,23 and on the specific adjuvant that we used.
We are aware of the fact that this pilot study has limitations regarding its patient number and the nonrandomized study design. However, the results are remarkable because the treatment is well tolerated, has no major side effects, and therefore does not negatively affect the quality of life of the patients. Altogether, the present study provides evidence in favor of a new concept of tumor vaccine combining multiple tumor antigens with NDV-induced danger signals,15 allowing thereby to mount polyclonal immune responses and to establish a specific antitumor memory20 across the blood-brain barrier. The clinical results reported here encourage a further validation in a randomized trial to exclude unknown confounders. Furthermore, the investigation of an antitumor memory by IFN-
The authors indicated no potential conflicts of interest.
We thank Gitta Schlehofer, MD, for fruitful and valuable discussions and Renate Steinle, Annette Buttler, Heike Westphal, Ilka Hearn, Hilde Discher, and Melanie Bobko for their excellent technical assistance.
Presented in part at the following conferences: European Association of Neuro-Oncology, Florence, Italy, September 7-10, 2002; Deutsche Gesellschaft für Neurologie, Mannheim, Germany, September 25-29, 2002; Deutsche Gesellschaft für Neurochinurgie, Saarbrücken, Germany, May 25-28, 2003; and the 15th International Conference on Brain Tumor Research and Therapy, Sorrento, Italy, May 24-27, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Davies FG, Freels S, Grutsch J, et al: Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: An analysis based on Surveillance, Epidemiology, and End Results (SEER) data, 1973-1991. J Neurosurg 88:1-10, 1998[Medline] 2. Stewart LA: Chemotherapy in adult high-grade glioma: A systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011-1018, 2002[CrossRef][Medline] 3. Kleihues P, Louis DN, Scheithauer BW, et al: The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61:215-225, 2002[Medline] 4. Herold-Mende C, Mueller MM, Bonsanto MM, et al: Clinical impact and functional aspects of tenascin expression during glioma progression. Int J Cancer 98:362-369, 2002[CrossRef][Medline]
5. Castelli MG, Chiabrando C, Fanelli R, et al: Prostaglandin and thromboxane synthesis by human intracranial tumors. Cancer Res 49:1505-1508, 1989 6. Maxwell M, Galanopoulos T, Neville-Golden J, et al: Effect of the expression of transforming growth factor-beta 2 in primary human glioblastomas on immunosuppression and loss of immune surveillance. J Neurosurg 76:799-804, 1992[Medline] 7. Huettner C, Paulu W, Roggendorf W: Messenger RNA expression of the immunosuppressive cytokine IL-10 in human gliomas. Am J Pathol 146:317-322, 1995[Abstract] 8. Pollack IF, Okada H, Chambers WH: Exploitation of immune mechanisms in the treatment of central nervous system cancers. Semin Pediatr Neurol 7:131-143, 2000[CrossRef][Medline]
9. Fakhrai H, Dorigo O, Shawler DL, et al: Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy. Proc Natl Acad Sci U S A 93:2909-2914, 1996 10. Leach DR, Krummel MF, Allison JP: Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734-1736, 1996[Abstract] 11. Kurpad SN, Wikstrand CJ, Bigner DD: Immunobiology of malignant astrocytomas. Semin Oncol 21:149-161, 1994[Medline]
12. Sampson JH, Archer GE, Ashley DM, et al: Subcutaneous vaccination with irradiated cytokine-producing tumor cells stimulates CD8+ cell-mediated immunity against tumors located in the "immunologically privileged" central nervous system. Proc Natl Acad Sci U S A 93:10399-10404, 1996 13. Ni HT, Spellman SR, Jean WC, et al: Immunization with dendritic cells pulsed with tumor extract increases survival of mice bearing intracranial gliomas. J Neurooncol 51:1-9, 2001[CrossRef][Medline] 14. Naujocks G, Serwe M, Bayer TA, et al: Adoptive transfer via immune T-lymphocytes of effective anti-tumor immunity against a malignant rat glioma in the brain. Int J Oncol 11:249-254, 1997
15. Matzinger P: The danger model: A renewed sense of self. Science 296:301-305, 2002
16. Nelson NJ: Scientific interest in Newcastle disease virus is reviving. J Natl Cancer Inst 91:1708-1710, 1999 17. Schirrmacher V, Haas C, Bonifer R, et al: Human tumor cell modification by virus infection: An efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6:63-73, 1999[CrossRef][Medline] 18. Washburn B, Schirrmacher V: Human tumor cell infection by Newcastle Disease Virus leads to upregulation of HLA and cell adhesion molecules and to induction of interferons, chemokines and finally apoptosis. Int J Oncol 21:85-93, 2002[Medline]
19. Yu JS, Wheeler CJ, Zeltzer PM, et al: Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res 61:842-847, 2001 20. Feuerer M, Beckhove P, Bai L, et al: Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T-cells from bone marrow. Nat Med 7:452-458, 2001[CrossRef][Medline] 21. Wikstrand CJ, Reist CJ, Archer GE, et al: The class III variant of the epidermal growth factor receptor (EGFRvIII): Characterization and utilization as an immunotherapeutic target. J Neurovirol 4:148-158, 1998[Medline] 22. Chi DD, Merchant RE, Rand R, et al: Molecular detection of tumor-associated antigens shared by human cutaneous melanomas and gliomas. Am J Pathol 150:2143-2152, 1997[Abstract]
23. Ahlert T, Sauerbrei W, Bastert G, et al: Tumor-cell number and viability as quality and efficacy parameters of autologous virus-modified cancer vaccines in patients with breast or ovarian cancer. J Clin Oncol 15:1354-1366, 1997 24. Schirrmacher V, Ahlert T, Pröbstle T, et al: Immunization with virus-modified tumor cells. Semin Oncol 25:677-696, 1998[Medline] 25. Termeer CC, Schirrmacher V, Bröcker EB, et al: Newcastle disease virus infection induces a B7-1/B7-2-independent T-cell costimulatory activity in human melanoma cells. Cancer Gene Ther 7:316-323, 2000[CrossRef][Medline] 26. von Hoegen P, Zawatzky R, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus: III. Potentiation of tumor-specific cytolytic T cell activity via induction of interferon alpha/beta. Cell Immunol 126:80-90, 1990[CrossRef][Medline] 27. Selker RG, Shapiro WR, Burger P, et al: The Brain Tumor Cooperative Group NIH Trial 87-01: A randomized comparison of surgery, external radiotherapy, and carmustine versus surgery, interstitial radiotherapy boost, external beam radiation therapy, and carmustine. Neurosurgery 51:343-355, 2002[Medline] 28. Schneider T, Gerhards R, Kirches E, et al: Preliminary results of active specific immunization with modified tumor cell vaccine in glioblastoma multiforme. J Neurooncol 53:39-46, 2001[CrossRef][Medline] Submitted September 9, 2003; accepted August 1, 2004. Related Editorial
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3 years). Ninety-one percent of vaccinated patients survived 1 year, 39% survived 2 years, and 4% were long-term survivors. In the vaccinated group, immune monitoring revealed significant increases of delayed-type hypersensitivity reactivity, numbers of tumor-reactive memory T cells, and numbers of CD8+ tumor-infiltrating T-lymphocytes in secondary tumors. 
) Significant difference between primary and relapsed tumors from vaccinated patients. NDV, Newcastle Disease Virus; IFN-
and -ß and the chemokines regulated on activation, normal T-cells expressed and secreted, and inducible protein 10.
