- Email: [email protected]
Immunotherapy Trials for Glioblastoma Multiforme: Promise and Pitfalls
Perspectives Commentary on: Adjuvant Immunotherapy with Whole-Cell Lysate Dendritic Cells Vaccine for Glioblastoma Multiforme: A Phase II Clinical Trial by Cho et al. pp. 736-744.
Russell R. Lonser, M.D. Chair, Surgical Neurology Branch National Institute of Neurological Disorders and Stroke National Institutes of Health
Immunotherapy Trials for Glioblastoma Multiforme: Promise and Pitfalls Raymund L. Yong and Russell R. Lonser
A
t less than 2 years, the expected median survival of patients with newly diagnosed glioblastoma multiforme (GBM) is poor with current standard treatment regimens, including surgery, radiation, and chemotherapy (11, 22). More recent advances in immunotherapy for systemic malignancies, in particular, for metastatic melanoma and prostate cancer (14, 20, 21), have generated considerable enthusiasm that similar strategies could be applied successfully in patients with GBM. A potential and significant obstacle to developing effective immunotherapy regimens for the treatment of primary central nervous system (CNS) malignancies is the immune-privileged status of the nervous system, owing in large part to the blood-brain barrier and lack of a lymphatic drainage system. Nevertheless, more recent data show that this separation between the central and systemic immune environments is far from absolute. Antigens within the brain are able to drain via cerebrospinal fluid pathways in the perivascular compartment to reach the cervical lymph nodes through the anterior skull base and nasal mucosa (10). Activated T cells cross the blood-brain barrier and are able to access the same pathways to circulate through the CNS relatively freely (13). In response to active or passive peripheral immunization, globulin levels in the cerebrospinal fluid and brain parenchyma increase (although to levels ⬍ 5% of serum titers) (7, 9, 18). The basic components of cell-mediated and humoral immunity appear to be active within the brain. GBMs express numerous specific tumor-associated antigens, including epidermal growth factor receptor isoform III (1), tenascin (23), and survivin (24), which have the potential to induce effective adaptive immune responses. However, local immunosuppressive mechanisms abrogate these potential adaptive immune initiators via various mechanisms. Gliomas express factors
Key words 䡲 Dendritic cells 䡲 Glioblastoma multiforme 䡲 Immunotherapy 䡲 Overall survival 䡲 Progression-free survival 䡲 Vaccine
636
Abbreviations and Acronyms APC: Antigen-presenting cell CNS: Central nervous system DC: Dendritic cell GBM: Glioblastoma multiforme
www.SCIENCEDIRECT.com
including vascular endothelial growth factor (8), transforming growth factor- (19), interleukin-10, prostaglandin E2 (6), and others that impair T-cell proliferation and function. GBM-infiltrating macrophages and microglia often lack the costimulatory molecules required for T-cell activation and instead produce T-cell anergy (15). Numerous solid tumors, including GBM, have associated high levels of CD4⫹ CD25⫹ Fox P3⫹ regulatory T cells that act both systemically and locally within the tumor microenvironment to inhibit the activation of antigen-presenting cells (APCs) (5). To overcome the myriad barriers that could diminish the effectiveness of immunotherapy for CNS malignancies, investigators have pursued numerous immunotherapeutic strategies, which may broadly be categorized as passive or active. Passive approaches consist of delivering tumor antigen-specific monoclonal antibodies or, alternatively, the adoptive transfer of activated antigen-specific T lymphocytes. Active approaches, which to date have proven less toxic and more effective for GBM, rely on the activation and maturation of APCs, either in vivo or ex vivo. Dendritic cells (DCs) are the most potent known APCs (17) and are present in an immature form at nearly all sites of potential pathogen entry into the body. On exposure to a pathogen, tissue damage, or signs of inflammation, DCs mature and migrate to lymph nodes, carrying phagocytosed antigens that are presented in major histocompatibility complex class I or II molecules on the cell surface, activating CD8⫹ cytotoxic T cells and CD4⫹ helper T cells. Additionally, innate immune responses are triggered via DC interactions with natural killer and natural killer T cells (4). In this way, DCs are capable of coordinating robust and specific responses to target antigens. Using an in vivo immunotherapeutic approach, tumor-specific antigens may be injected intradermally, where they are phagocytosed, processed, and presented by resident local APCs.
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA To whom correspondence should be addressed: Russell R. Lonser, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2012) 77, 5/6:636-638. DOI: 10.1016/j.wneu.2011.10.010
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.10.010
PERSPECTIVES
Advantages of this approach include the ability to detect specific reactivity after immunization and the lack of a requirement to obtain tissue from patients to produce the vaccine. A major disadvantage is the limited number of tumor-specific antigens that can be targeted, ultimately leading to the escape and survival of non–antigen-expressing tumor cells (2). Ex vivo approaches, as used by Cho et al., frequently involve the manipulation of DCs cultured from peripheral blood monocytes. DCs are matured with cytokines, loaded with tumor antigens from surgical specimens, and reintroduced directly into the patient’s lymphatic system. A major advantage of this approach is that its efficacy does not depend on the expression of a particular predetermined tumor antigen profile, which may be lacking in a significant proportion of patients with GBM (3). At the same time, this lack of a predetermined tumor antigen profile presents greater challenges for devising consistent methods of monitoring responses in vaccinated patients because the specific molecular targets are unknown and variable. Cho et al. randomly assigned 34 adult patients with a new diagnosis of GBM with performance status ⱖ 70 to receive either standard therapy or standard therapy plus an autologous DC vaccine. Standard therapy consisted of a ⬎ 74% resection followed by radiation with concomitant and adjuvant temozolomide. In the experimental arm, patients received a radiated whole tumor cell lysate-loaded DC vaccine beginning 1–2 months after standard therapy. Higher concentration inoculations (2–5 ⫻ 107 cells/injection) administered over a longer period (6 months) were used compared with other recent DC vaccine studies. On progression, all patients were eligible for stereotactic radiosurgery or repeat resection. Patients in the experimental arm underwent revaccination using tumor lysates obtained at reoperation. Based on the data provided by the authors, an impressive overall survival advantage of 14 months was achieved in vaccinated patients compared with control arm patients. However, rates of progression-free and overall survival at 12 months were similar in both groups. This finding indicates that much of the difference in outcomes between the control and experimental (vaccine) groups can be attributed to what occurs after first progression. With randomization taking place only on entry into the trial, an important question needs to be answered: To what extent are the benefits seen in the experimental arm accounted for by more aggressive multimodality care at recurrence? Although salvage radiosurgery was used more frequently in vaccinated patients, the authors assert that this was not associ-
REFERENCES 1. Batra SK, Castelino-Prabhu S, Wikstrand CJ, Zhu X, Humphrey PA, Friedman HS, Bigner DD: Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ 6:1251-1259, 1995.
2. Choi BD, Archer GE, Mitchell DA, Heimberger AB, McLendon RE, Bigner DD, Sampson JH: EGFRvIIItargeted vaccination therapy of malignant glioma. Brain Pathol 19:713-723, 2009.
ated with improved survival. They also report that rates of reoperation were similar in both groups. However, it is apparent from the data provided that many patients in the control group received neither reoperation nor reirradiation at first relapse— they received no further treatment at all—whereas patients in the vaccine group nearly always received some form of salvage therapy. Multiple single-arm phase II studies on disparate experimental agents have reported median overall survivals from the time of diagnosis nearing 20 months, suggesting that factors at referral centers unrelated to experimental treatments may be playing a role in improving the outcomes of patients with GBM since the landmark EORTC-NCIC trial (11). If we are to take a survival improvement of 14 months at face value, it is imperative that these putative “level of care” factors be controlled for. Future trials on DC vaccines that randomly assign patients at first relapse to reoperation versus reoperation with vaccination might help address this problem. Despite these methodologic shortcomings, the promising findings of Cho et al. underscore the findings of other more recent trials for DC vaccines in GBM (16, 25, 26) and other malignancies. Two recent phase III vaccine-based immunotherapy trials, one for hormone-refractory prostate cancer (21) and one for metastatic melanoma (14), similarly reported significant overall survival benefit without improvement in median time to progression. In both trials, there was a separation in the freedom from progression curves of the study arms only after the median progression-free survival time was reached. One explanation is that the immune response against malignancy takes time to be shaped and strengthened by vaccines, inhibiting the proliferation of neoplastic cells more gradually and indirectly than conventional cytotoxic therapies. Overall, these findings indicate that rather than emphasizing progression-free survival, future DC vaccine trials need to incorporate validated prognostic methods of monitoring anticancer immunologic activity in vivo as an interim measure of efficacy. Several approaches, such as delayed-type hypersensitivity responses and T-cell cytotoxicity assays, have been used, but none have gained universal acceptance or have evaluated fully the multifaceted immune response DC vaccines invoke (12). Moreover, few approaches adequately account for the baseline immunosuppression of cancer patients. Advances in our basic understanding of neuroimmunology will do much to inform the rational design of future immunotherapy trials for GBM.
3. de Vleeschouwer S, Rapp M, Sorg RV, Steiger HJ, Stummer W, van Gool S, Sabel M: Dendritic cell vaccination in patients with malignant gliomas: current status and future directions. Neurosurgery 59:988-999, 2006.
Dranoff G, Sampson JH: Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 66:3294-3302, 2006.
4. Dhodapkar KM, Cirignano B, Chamian F, Zagzag D, Miller DC, Finlay JL, Steinman RM: Invariant natural killer T cells are preserved in patients with glioma and exhibit antitumor lytic activity following dendritic cell-mediated expansion. Int J Cancer 109: 893-899, 2004.
6. Fontana A, Kristensen F, Dubs R, Gemsa D, Weber E: Production of prostaglandin E and an interleukin-1 like factor by cultured astrocytes and C6 glioma cells. J Immunol 129:2413-2419, 1982.
5. Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, Herndon JE 2nd, Bigner DD,
WORLD NEUROSURGERY 77 [5/6]: 636-638, MAY/JUNE 2012
7. Furr M: Antigen-specific antibodies in cerebrospinal fluid after intramuscular injection of ovalbumin in horses. J Vet Intern Med 16:588-592, 2002.
www.WORLDNEUROSURGERY.org
637
PERSPECTIVES
8. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP: Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92: 4150-4166, 1998. 9. Gigliotti F, Lee D, Insel RA, Scheld WM: IgG penetration into the cerebrospinal fluid in a rabbit model of meningitis. J Infect Dis 156:394-398, 1987. 10. Goldmann J, Kwidzinski E, Brandt C, Mahlo J, Richter D, Bechmann I: T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J Leukoc Biol 80:797-801, 2006. 11. Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M, Fisher J: Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res 16:2443-2449, 2010. 12. Heimberger AB, Sampson JH: Immunotherapy coming of age: what will it take to make it standard of care for glioblastoma? Neuro Oncol 13:3-13, 2011. 13. Hickey WF, Hsu BL, Kimura H: T-lymphocyte entry into the central nervous system. J Neurosci Res 28: 254-260, 1991. 14. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010. 15. Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB: The role of human glioma-infiltrat-
638
www.SCIENCEDIRECT.com
ing microglia/macrophages in mediating antitumor immune responses. Neuro Oncol 8:261-279, 2006. 16. Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, Giovannone AJ, Lin JW, Chute DJ, Mischel PS, Cloughesy TF, Roth MD: Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res 11:5515-5525, 2005. 17. Nouri-Shirazi M, Banchereau J, Bell D, Burkeholder S, Kraus ET, Davoust J, Palucka KA: Dendritic cells capture killed tumor cells and present their antigens to elicit tumor-specific immune responses. J Immunol 165:3797-3803, 2000. 18. Pestalozzi BC, Brignoli S: Trastuzumab in CSF. J Clin Oncol 18:2349-2351, 2000. 19. Platten M, Wick W, Weller M: Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape. Microsc Res Tech 52:401-410, 2001. 20. Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P: gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 364:2119-2127, 2011. 21. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:30893094, 2006.
22. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005. 23. Ventimiglia JB, Wikstrand CJ, Ostrowski LE, Bourdon MA, Lightner VA, Bigner DD: Tenascin expression in human glioma cell lines and normal tissues. J Neuroimmunol 36:41-55, 1992. 24. Yamada Y, Kuroiwa T, Nakagawa T, Kajimoto Y, Dohi T, Azuma H, Tsuji M, Kami K, Miyatake S: Transcriptional expression of survivin and its splice variants in brain tumors in humans. J Neurosurg 99:738-745, 2003. 25. Yamanaka R, Homma J, Yajima N, Tsuchiya N, Sano M, Kobayashi T, Yoshida S, Abe T, Narita M, Takahashi M, Tanaka R: Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin Cancer Res 11:4160-4167, 2005. 26. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ: Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 64:49734979, 2004. Citation: World Neurosurg. (2012) 77, 5/6:636-638. DOI: 10.1016/j.wneu.2011.10.010 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter Published by Elsevier Inc.
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.10.010
Russell R. Lonser, M.D. Chair, Surgical Neurology Branch National Institute of Neurological Disorders and Stroke National Institutes of Health
Immunotherapy Trials for Glioblastoma Multiforme: Promise and Pitfalls Raymund L. Yong and Russell R. Lonser
A
t less than 2 years, the expected median survival of patients with newly diagnosed glioblastoma multiforme (GBM) is poor with current standard treatment regimens, including surgery, radiation, and chemotherapy (11, 22). More recent advances in immunotherapy for systemic malignancies, in particular, for metastatic melanoma and prostate cancer (14, 20, 21), have generated considerable enthusiasm that similar strategies could be applied successfully in patients with GBM. A potential and significant obstacle to developing effective immunotherapy regimens for the treatment of primary central nervous system (CNS) malignancies is the immune-privileged status of the nervous system, owing in large part to the blood-brain barrier and lack of a lymphatic drainage system. Nevertheless, more recent data show that this separation between the central and systemic immune environments is far from absolute. Antigens within the brain are able to drain via cerebrospinal fluid pathways in the perivascular compartment to reach the cervical lymph nodes through the anterior skull base and nasal mucosa (10). Activated T cells cross the blood-brain barrier and are able to access the same pathways to circulate through the CNS relatively freely (13). In response to active or passive peripheral immunization, globulin levels in the cerebrospinal fluid and brain parenchyma increase (although to levels ⬍ 5% of serum titers) (7, 9, 18). The basic components of cell-mediated and humoral immunity appear to be active within the brain. GBMs express numerous specific tumor-associated antigens, including epidermal growth factor receptor isoform III (1), tenascin (23), and survivin (24), which have the potential to induce effective adaptive immune responses. However, local immunosuppressive mechanisms abrogate these potential adaptive immune initiators via various mechanisms. Gliomas express factors
Key words 䡲 Dendritic cells 䡲 Glioblastoma multiforme 䡲 Immunotherapy 䡲 Overall survival 䡲 Progression-free survival 䡲 Vaccine
636
Abbreviations and Acronyms APC: Antigen-presenting cell CNS: Central nervous system DC: Dendritic cell GBM: Glioblastoma multiforme
www.SCIENCEDIRECT.com
including vascular endothelial growth factor (8), transforming growth factor- (19), interleukin-10, prostaglandin E2 (6), and others that impair T-cell proliferation and function. GBM-infiltrating macrophages and microglia often lack the costimulatory molecules required for T-cell activation and instead produce T-cell anergy (15). Numerous solid tumors, including GBM, have associated high levels of CD4⫹ CD25⫹ Fox P3⫹ regulatory T cells that act both systemically and locally within the tumor microenvironment to inhibit the activation of antigen-presenting cells (APCs) (5). To overcome the myriad barriers that could diminish the effectiveness of immunotherapy for CNS malignancies, investigators have pursued numerous immunotherapeutic strategies, which may broadly be categorized as passive or active. Passive approaches consist of delivering tumor antigen-specific monoclonal antibodies or, alternatively, the adoptive transfer of activated antigen-specific T lymphocytes. Active approaches, which to date have proven less toxic and more effective for GBM, rely on the activation and maturation of APCs, either in vivo or ex vivo. Dendritic cells (DCs) are the most potent known APCs (17) and are present in an immature form at nearly all sites of potential pathogen entry into the body. On exposure to a pathogen, tissue damage, or signs of inflammation, DCs mature and migrate to lymph nodes, carrying phagocytosed antigens that are presented in major histocompatibility complex class I or II molecules on the cell surface, activating CD8⫹ cytotoxic T cells and CD4⫹ helper T cells. Additionally, innate immune responses are triggered via DC interactions with natural killer and natural killer T cells (4). In this way, DCs are capable of coordinating robust and specific responses to target antigens. Using an in vivo immunotherapeutic approach, tumor-specific antigens may be injected intradermally, where they are phagocytosed, processed, and presented by resident local APCs.
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA To whom correspondence should be addressed: Russell R. Lonser, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2012) 77, 5/6:636-638. DOI: 10.1016/j.wneu.2011.10.010
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.10.010
PERSPECTIVES
Advantages of this approach include the ability to detect specific reactivity after immunization and the lack of a requirement to obtain tissue from patients to produce the vaccine. A major disadvantage is the limited number of tumor-specific antigens that can be targeted, ultimately leading to the escape and survival of non–antigen-expressing tumor cells (2). Ex vivo approaches, as used by Cho et al., frequently involve the manipulation of DCs cultured from peripheral blood monocytes. DCs are matured with cytokines, loaded with tumor antigens from surgical specimens, and reintroduced directly into the patient’s lymphatic system. A major advantage of this approach is that its efficacy does not depend on the expression of a particular predetermined tumor antigen profile, which may be lacking in a significant proportion of patients with GBM (3). At the same time, this lack of a predetermined tumor antigen profile presents greater challenges for devising consistent methods of monitoring responses in vaccinated patients because the specific molecular targets are unknown and variable. Cho et al. randomly assigned 34 adult patients with a new diagnosis of GBM with performance status ⱖ 70 to receive either standard therapy or standard therapy plus an autologous DC vaccine. Standard therapy consisted of a ⬎ 74% resection followed by radiation with concomitant and adjuvant temozolomide. In the experimental arm, patients received a radiated whole tumor cell lysate-loaded DC vaccine beginning 1–2 months after standard therapy. Higher concentration inoculations (2–5 ⫻ 107 cells/injection) administered over a longer period (6 months) were used compared with other recent DC vaccine studies. On progression, all patients were eligible for stereotactic radiosurgery or repeat resection. Patients in the experimental arm underwent revaccination using tumor lysates obtained at reoperation. Based on the data provided by the authors, an impressive overall survival advantage of 14 months was achieved in vaccinated patients compared with control arm patients. However, rates of progression-free and overall survival at 12 months were similar in both groups. This finding indicates that much of the difference in outcomes between the control and experimental (vaccine) groups can be attributed to what occurs after first progression. With randomization taking place only on entry into the trial, an important question needs to be answered: To what extent are the benefits seen in the experimental arm accounted for by more aggressive multimodality care at recurrence? Although salvage radiosurgery was used more frequently in vaccinated patients, the authors assert that this was not associ-
REFERENCES 1. Batra SK, Castelino-Prabhu S, Wikstrand CJ, Zhu X, Humphrey PA, Friedman HS, Bigner DD: Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ 6:1251-1259, 1995.
2. Choi BD, Archer GE, Mitchell DA, Heimberger AB, McLendon RE, Bigner DD, Sampson JH: EGFRvIIItargeted vaccination therapy of malignant glioma. Brain Pathol 19:713-723, 2009.
ated with improved survival. They also report that rates of reoperation were similar in both groups. However, it is apparent from the data provided that many patients in the control group received neither reoperation nor reirradiation at first relapse— they received no further treatment at all—whereas patients in the vaccine group nearly always received some form of salvage therapy. Multiple single-arm phase II studies on disparate experimental agents have reported median overall survivals from the time of diagnosis nearing 20 months, suggesting that factors at referral centers unrelated to experimental treatments may be playing a role in improving the outcomes of patients with GBM since the landmark EORTC-NCIC trial (11). If we are to take a survival improvement of 14 months at face value, it is imperative that these putative “level of care” factors be controlled for. Future trials on DC vaccines that randomly assign patients at first relapse to reoperation versus reoperation with vaccination might help address this problem. Despite these methodologic shortcomings, the promising findings of Cho et al. underscore the findings of other more recent trials for DC vaccines in GBM (16, 25, 26) and other malignancies. Two recent phase III vaccine-based immunotherapy trials, one for hormone-refractory prostate cancer (21) and one for metastatic melanoma (14), similarly reported significant overall survival benefit without improvement in median time to progression. In both trials, there was a separation in the freedom from progression curves of the study arms only after the median progression-free survival time was reached. One explanation is that the immune response against malignancy takes time to be shaped and strengthened by vaccines, inhibiting the proliferation of neoplastic cells more gradually and indirectly than conventional cytotoxic therapies. Overall, these findings indicate that rather than emphasizing progression-free survival, future DC vaccine trials need to incorporate validated prognostic methods of monitoring anticancer immunologic activity in vivo as an interim measure of efficacy. Several approaches, such as delayed-type hypersensitivity responses and T-cell cytotoxicity assays, have been used, but none have gained universal acceptance or have evaluated fully the multifaceted immune response DC vaccines invoke (12). Moreover, few approaches adequately account for the baseline immunosuppression of cancer patients. Advances in our basic understanding of neuroimmunology will do much to inform the rational design of future immunotherapy trials for GBM.
3. de Vleeschouwer S, Rapp M, Sorg RV, Steiger HJ, Stummer W, van Gool S, Sabel M: Dendritic cell vaccination in patients with malignant gliomas: current status and future directions. Neurosurgery 59:988-999, 2006.
Dranoff G, Sampson JH: Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 66:3294-3302, 2006.
4. Dhodapkar KM, Cirignano B, Chamian F, Zagzag D, Miller DC, Finlay JL, Steinman RM: Invariant natural killer T cells are preserved in patients with glioma and exhibit antitumor lytic activity following dendritic cell-mediated expansion. Int J Cancer 109: 893-899, 2004.
6. Fontana A, Kristensen F, Dubs R, Gemsa D, Weber E: Production of prostaglandin E and an interleukin-1 like factor by cultured astrocytes and C6 glioma cells. J Immunol 129:2413-2419, 1982.
5. Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, Herndon JE 2nd, Bigner DD,
WORLD NEUROSURGERY 77 [5/6]: 636-638, MAY/JUNE 2012
7. Furr M: Antigen-specific antibodies in cerebrospinal fluid after intramuscular injection of ovalbumin in horses. J Vet Intern Med 16:588-592, 2002.
www.WORLDNEUROSURGERY.org
637
PERSPECTIVES
8. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP: Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92: 4150-4166, 1998. 9. Gigliotti F, Lee D, Insel RA, Scheld WM: IgG penetration into the cerebrospinal fluid in a rabbit model of meningitis. J Infect Dis 156:394-398, 1987. 10. Goldmann J, Kwidzinski E, Brandt C, Mahlo J, Richter D, Bechmann I: T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J Leukoc Biol 80:797-801, 2006. 11. Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M, Fisher J: Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res 16:2443-2449, 2010. 12. Heimberger AB, Sampson JH: Immunotherapy coming of age: what will it take to make it standard of care for glioblastoma? Neuro Oncol 13:3-13, 2011. 13. Hickey WF, Hsu BL, Kimura H: T-lymphocyte entry into the central nervous system. J Neurosci Res 28: 254-260, 1991. 14. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010. 15. Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB: The role of human glioma-infiltrat-
638
www.SCIENCEDIRECT.com
ing microglia/macrophages in mediating antitumor immune responses. Neuro Oncol 8:261-279, 2006. 16. Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, Giovannone AJ, Lin JW, Chute DJ, Mischel PS, Cloughesy TF, Roth MD: Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res 11:5515-5525, 2005. 17. Nouri-Shirazi M, Banchereau J, Bell D, Burkeholder S, Kraus ET, Davoust J, Palucka KA: Dendritic cells capture killed tumor cells and present their antigens to elicit tumor-specific immune responses. J Immunol 165:3797-3803, 2000. 18. Pestalozzi BC, Brignoli S: Trastuzumab in CSF. J Clin Oncol 18:2349-2351, 2000. 19. Platten M, Wick W, Weller M: Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape. Microsc Res Tech 52:401-410, 2001. 20. Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P: gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 364:2119-2127, 2011. 21. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:30893094, 2006.
22. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005. 23. Ventimiglia JB, Wikstrand CJ, Ostrowski LE, Bourdon MA, Lightner VA, Bigner DD: Tenascin expression in human glioma cell lines and normal tissues. J Neuroimmunol 36:41-55, 1992. 24. Yamada Y, Kuroiwa T, Nakagawa T, Kajimoto Y, Dohi T, Azuma H, Tsuji M, Kami K, Miyatake S: Transcriptional expression of survivin and its splice variants in brain tumors in humans. J Neurosurg 99:738-745, 2003. 25. Yamanaka R, Homma J, Yajima N, Tsuchiya N, Sano M, Kobayashi T, Yoshida S, Abe T, Narita M, Takahashi M, Tanaka R: Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin Cancer Res 11:4160-4167, 2005. 26. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ: Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 64:49734979, 2004. Citation: World Neurosurg. (2012) 77, 5/6:636-638. DOI: 10.1016/j.wneu.2011.10.010 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter Published by Elsevier Inc.
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.10.010