Ependymomas: Development of immunotherapeutic strategies

Expert Review of Neurotherapeutics

Volumn 13, Issue 10, 2013, Pages 1089-1098

  Pollack, Ian F ^a,b,c   Jakacki, Regina I ^a,b,c   Butterfield, Lisa H ^a,c   Okada, Hideho ^a,c  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^b CHILDREN S HOSPITAL OF PITTSBURGH   (United States)

^c UNIVERSITY OF PITTSBURGH CANCER INSTITUTE   (United States)

Author keywords

brain tumor; ependymoma; immunotherapy; pseudoprogression

Indexed keywords

CANCER VACCINE; CARBOPLATIN; CARBOXYMETHYLCELLULOSE POLYCYTIDYLIC POLYINOSINIC ACID POLYLYSINE; CISPLATIN; DEXAMETHASONE; IMIQUIMOD; PEPTIDE VACCINE; TETANUS TOXOID; TUMOR ANTIGEN;

ASTROCYTOMA; BRAIN; CANCER ADJUVANT THERAPY; CANCER CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CANCER PROGNOSIS; CANCER RADIOTHERAPY; CANCER RECURRENCE; CANCER RISK; CANCER SURGERY; CORTICOSTEROID THERAPY; DISEASE CONTROL; EPENDYMOMA; GLIOBLASTOMA; GLIOMA; HUMAN; LOW DRUG DOSE; MORBIDITY; NONHUMAN; REVIEW; TUMOR GROWTH; TUMOR RECURRENCE; VACCINATION;

BRAIN NEOPLASMS; CANCER VACCINES; EPENDYMOMA; HUMANS; IMMUNOTHERAPY;

EID: 84886903462     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/14737175.2013.840420     Document Type: Review

References (92)

1. Godfraind C, Kaczmarska JM, Kocak M et al. Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas. Acta Neuropathol. 124(2), 247-257 (2012).
2. Johnson RA, Wright KD, Poppleton H et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 466(7306), 632-636 (2010).
3. Gilbert MR, Ruda R, Soffietti R. Ependymomas in adults. Curr. Neurol. Neurosci. Rep. 10(3), 240-247 (2010).
4. Tihan T, Zhou T, Holmes E, Burger PC, Ozuysal S, Rushing EJ. The prognostic value of histological grading of posterior fossa ependymomas in children: a Children's Oncology Group study and a review of prognostic factors. Mod. Pathol. 21(2), 165-177 (2008). (Pubitemid 351172168)
5. Horn B, Heideman R, Geyer R et al. A multi-institutional retrospective study of intracranial ependymoma in children: identification of risk factors. J. Pediatr. Hematol. Oncol. 21(3), 203-211 (1999). (Pubitemid 30306031)
6. Robertson PL, Zeltzer PM, Boyett JM et al. Survival and prognostic factors following radiation therapy and chemotherapy for ependymomas in children: a report of the Children's Cancer Group. J. Neurosurg. 88(4), 695-703 (1998). (Pubitemid 28145213)
7. Merchant TE, Mulhern RK, Krasin MJ et al. Preliminary results from a Phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J. Clin. Oncol. 22(15), 3156-3162 (2004). (Pubitemid 41103730)
8. Merchant TE, Li C, Xiong X, Kun LE, Boop FA, Sanford RA. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol. 10(3), 258-266 (2009).
9. Merchant TE, Zhu Y, Thompson SJ, Sontag MR, Heideman RL, Kun LE. Preliminary results from a Phase II trail of conformal radiation therapy for pediatric patients with localised low-grade astrocytoma and ependymoma. Int. J. Radiat. Oncol. Biol. Phys. 52(2), 325-332 (2002). (Pubitemid 34170841)
10. Merchant TE, Jenkins JJ, Burger PC et al. Influence of tumor grade on time to progression after irradiation for localized ependymoma in children. Int. J. Radiat. Oncol. Biol. Phys. 53(1), 52-57 (2002). (Pubitemid 34465807)
11. Hukin J, Epstein F, Lefton D, Allen J. Treatment of intracranial ependymoma by surgery alone. Pediatr. Neurosurg. 29(1), 40-45 (1998). (Pubitemid 29060798)
12. Duffner PK, Horowitz ME, Krischer JP et al. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N. Engl. J. Med. 328(24), 1725-1731 (1993). (Pubitemid 23170121)
13. Gaynon PS, Ettinger LJ, Baum ES, Siegel SE, Krailo MD, Hammond GD. Carboplatin in childhood brain tumors. A Children's Cancer Study Group Phase II trial. Cancer 66(12), 2465-2469 (1990).
14. Duffner PK, Krischer JP, Sanford RA et al. Prognostic factors in infants and very young children with intracranial ependymomas. Pediatr. Neurosurg. 28(4), 215-222 (1998). (Pubitemid 28402001)
15. Needle MN, Goldwein JW, Grass J et al. Adjuvant chemotherapy for the treatment of intracranial ependymoma of childhood. Cancer 80(2), 341-347 (1997). (Pubitemid 27282329)
16. Ridley L, Rahman R, Brundler MA et al. Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma. Neuro Oncol. 10(5), 675-689 (2008).
17. Tabori U, Ma J, Carter M et al. Human telomere reverse transcriptase expression predicts progression and survival in pediatric intracranial ependymoma. J. Clin. Oncol. 24(10), 1522-1528 (2006). (Pubitemid 46638773)
18. Taylor MD, Poppleton H, Fuller C et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell. 8(4), 323-335 (2005). (Pubitemid 41443417)
19. Evans AE, Anderson JR, Lefkowitz-Boudreaux IB, Finlay JL. Adjuvant chemotherapy of childhood posterior fossa ependymoma: cranio-spinal irradiation with or without adjuvant CCNU, vincristine, and prednisone: a Childrens Cancer Group study. Med. Pediatr. Oncol. 27(1), 8-14 (1996).
20. Mason WP, Goldman S, Yates AJ, Boyett J, Li H, Finlay JL. Survival following intensive chemotherapy with bone marrow reconstitution for children with recurrent intracranial ependymoma-a report of the Children's Cancer Group. J. Neurooncol. 37(2), 135-143 (1998). (Pubitemid 28073586)
21. Fouladi M, Stewart CF, Blaney SM et al. Phase I trial of lapatinib in children with refractory CNS malignancies: a Pediatric Brain Tumor Consortium study. J. Clin. Oncol. 28(27), 4221-4227 (2010).
22. Gururangan S, Fangusaro J, Young Poussaint T et al. Lack of efficacy of bevacizumab + irinotecan in cases of pediatric recurrent ependymoma-a Pediatric Brain Tumor Consortium study. Neuro. Oncol. 14(11), 1404-1412 (2012).
23. Pollack IF, Jakacki RI, Butterfield LH, Okada H. Results of a pilot study to evaluate the effects of vaccinations with HLA-A2 restricted glioma antigen-peptides in combination with poly-ICLC for children with newly diagnosed malignant brainstem gliomas, non-brainstem high-grade gliomas, or recurrent unresectable gliomas. Neuro. Oncol. 13(Suppl. 3), iii34-iii40. (2011).
24. Pollack IF, Jakacki RI, Butterfield LH, Okada H. Peptide vaccine therapy for childhood gliomas. J. Neurosurg. 60(Suppl. 1), 113-119 (2012).
25. Yeung JT, Hamilton RL, Okada H, Jakacki RI, Pollack IF. Increased expression of tumor-associated antigens in pediatric and adult ependymomas: implication for vaccine therapy. J. Neurooncol. 111(2), 103-111 (2013).
26. Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363(5), 411-422 (2010).
27. Rosenberg SA, Sherry RM, Morton KE et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. J. Immunol. 175(9), 6169-6176 (2005). (Pubitemid 41508105)
28. Rosenberg SA, Yang JC, Schwartzentruber DJ et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat. Med. 4(3), 321-327 (1998). (Pubitemid 28144091)
29. Slingluff CL Jr, Petroni GR, Yamshchikov GV et al. Clinical and immunologic results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte-macrophage colony-stimulating factor in adjuvant or pulsed on dendritic cells. J. Clin. Oncol. 21(21), 4016-4026 (2003). (Pubitemid 46606217)
30. Ardon H, De Vleeschouwer S, Van Calenbergh F et al. Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours. Pediatr. Blood Cancer. 54(4), 519-525 (2010).
31. Caruso DA, Orme LM, Neale AM et al. Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. Neuro Oncol, 6(3), 236-246 (2004). (Pubitemid 39136507)
32. De Vleeschouwer S, Fieuws S, Rutkowski S et al. Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin. Cancer Res. 14(10), 3098-3104 (2008).
33. Donson AM, Birks DK, Barton VN et al. Immune gene and cell enrichment is associated with a good prognosis in ependymoma. J. Immunol. 183(11), 7428-7440 (2009).
34. Walker PR, Calzascia T, de Tribolet N, Dietrich PY. T-cell immune responses in the brain and their relevance for cerebral malignancies. Brain Res. Brain Res. Rev. 42(2), 97-122 (2003). (Pubitemid 36549171)
35. Okada H, Kohanbash G, Zhu X et al. Immunotherapeutic approaches for glioma. Crit. Rev. Immunol. 29(1), 1-42 (2009).
36. Engelhardt B. Molecular mechanisms involved in T cell migration across the blood-brain barrier. J. Neural Transm. 113(4), 477-485 (2006).
37. Krakowski ML, Owens T. The central nervous system environment controls effector CD4+ T cell cytokine profile in experimental allergic encephalomyelitis. Eur. J. Immunol. 27(11), 2840-2847 (1997). (Pubitemid 27478352)
38. Albert ML, Darnell JC, Bender A, Francisco LM, Bhardwaj N, Darnell RB. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat. Med. 4(11), 1321-1324 (1998). (Pubitemid 28512116)
39. Okada H, Lieberman FS, Edington HD et al. Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of recurrent glioblastoma: preliminary observations in a patient with a favorable response to therapy. J. Neurooncol. 64(1-2), 13-20 (2003). (Pubitemid 36992456)
40. Okada H, Lieberman FS, Walter KA et al. Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas. J. Transl. Med. 5, 67 (2007).
41. Okada H, Pollack IF. Cytokine gene therapy for malignant glioma. Expert Opin. Biol. Ther. 4(10), 1609-1620 (2004). (Pubitemid 39371756)
42. Okada H, Pollack IF, Lieberman F et al. Gene therapy of malignant gliomas: a pilot study of vaccination with irradiated autologous glioma and dendritic cells admixed with IL-4 transduced fibroblasts to elicit an immune response. Hum. Gene. Ther. 12(5), 575-595 (2001). (Pubitemid 32511078)
43. Okada H, Pollack IF, Lotze MT et al. Gene therapy of malignant gliomas: a phase I study of IL-4-HSV-TK gene-modified autologous tumor to elicit an immune response. Hum. Gene. Ther. 11(4), 637-653 (2000). (Pubitemid 30134307)
44. Kikuchi T, Akasaki Y, Abe T et al. Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12. J. Immunother. 27(6), 452-459 (2004). (Pubitemid 39447353)
45. Liau LM, Prins RM, Kiertscher SM et al. 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(15), 5515-5525 (2005). (Pubitemid 41060828)
46. Wheeler CJ, Black KL, Liu G et al. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res. 68(14), 5955-5964 (2008).
47. Yamanaka R, Abe T, Yajima N et al. Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial. Br. J. Cancer 89(7), 1172-1179 (2003). (Pubitemid 37363398)
48. Yamanaka R, Homma J, Yajima N et al. Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin. Cancer Res. 11(11), 4160-4167 (2005). (Pubitemid 40791581)
49. 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(14), 4973-4979 (2004). (Pubitemid 38924545)
50. Okada H, Kalinski P, Ueda R et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J. Clin. Oncol. 29(3), 330-336 (2011).
51. Okano F, Storkus WJ, Chambers WH, Pollack IF, Okada H. Identification of a novel HLA-A*0201-restricted, cytotoxic T lymphocyte epitope in a human glioma-associated antigen, interleukin 13 receptor alpha2 chain. Clin. Cancer Res. 8(9), 2851-2855 (2002). (Pubitemid 35025729)
52. Eguchi J, Hatano M, Nishimura F et al. Identification of interleukin-13 receptor alpha2 peptide analogues capable of inducing improved antiglioma CTL responses. Cancer Res. 66(11), 5883-5891 (2006). (Pubitemid 43927143)
53. Hatano M, Eguchi J, Tatsumi T et al. EphA2 as a glioma-associated antigen: a novel target for glioma vaccines. Neoplasia 7(8), 717-722 (2005).
54. Debinski W, Gibo DM. Molecular expression analysis of restrictive receptor for interleukin 13, a brain tumor-associated cancer/testis antigen. Mol. Med. 6(5), 440-449 (2000).
55. Debinski W, Gibo DM, Obiri NI, Kealiher A, Puri RK. Novel anti-brain tumor cytotoxins specific for cancer cells. Nat. Biotechnol. 16(5), 449-453 (1998). (Pubitemid 28211197)
56. Debinski W, Gibo DM, Slagle B, Powers SK, Gillespie GY. Receptor for interleukin 13 is abundantly and specifically over-expressed in patients with glioblastoma multiforme. Int. J. Oncol. 15(3), 481-486 (1999).
57. Dodelet VC, Pasquale EB. Eph receptors and ephrin ligands: embryogenesis to tumorigenesis. Oncogene 19(49), 5614-5619 (2000).
58. Kinch MS, Moore MB, Harpole DH Jr. Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival. Clin. Cancer Res. 9(2), 613-618 (2003). (Pubitemid 36182592)
59. Oba SM, Wang YJ, Song JP et al. Genomic structure and loss of heterozygosity of EPHB2 in colorectal cancer. Cancer Lett. 164(1), 97-104 (2001). (Pubitemid 32144995)
60. Liu F, Park PJ, Lai W et al. A genome-wide screen reveals functional gene clusters in the cancer genome and identifies EphA2 as a mitogen in glioblastoma. Cancer Res. 66(22), 10815-10823 (2006). (Pubitemid 44876977)
61. Chakravarti A, Delaney MA, Noll E et al. Prognostic and pathologic significance of quantitative protein expression profiling in human gliomas. Clin. Cancer Res. 7(8), 2387-2395 (2001). (Pubitemid 32751640)
62. Chakravarti A, Noll E, Black PM et al. Quantitatively determined survivin expression levels are of prognostic value in human gliomas. J. Clin. Oncol. 20(4), 1063-1068 (2002). (Pubitemid 34141851)
63. Kogiku M, Ohsawa I, Matsumoto K et al. Prognosis of glioma patients by combined immunostaining for survivin, Ki-67 and epidermal growth factor receptor. J. Clin. Neurosci. 15(11), 1198-1203 (2008).
64. Uematsu M, Ohsawa I, Aokage T et al. Prognostic significance of the immunohistochemical index of survivin in glioma: a comparative study with the MIB-1 index. J. Neurooncol. 72(3), 231-238 (2005). (Pubitemid 40867405)
65. Zhen H-N, Zhang X, Hu P-Z et al. Survivin expression and its relation with proliferation, apoptosis, and angiogenesis in brain gliomas. Cancer 104(12), 2775-2783 (2005). (Pubitemid 41798288)
66. Andersen MH, Pedersen LO, Becker JC, Straten PT. Identification of a cytotoxic T lymphocyte response to the apoptosis inhibitor protein survivin in cancer patients. Cancer Res. 61(3), 869-872 (2001). (Pubitemid 32175146)
67. Andersen MH, Pedersen LO, Capeller B, Brocker EB, Becker JC, Straten P. Spontaneous cytotoxic T-cell responses against survivin-derived MHC class I-restricted T-cell epitopes in situ as well as ex vivo in cancer patients. Cancer Res. 61(16), 5964-5968 (2001). (Pubitemid 32768582)
68. Wobser M, Keikavoussi P, Kunzmann V, Weininger M, Andersen MH, Becker JC. Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin. Cancer Immunol. Immunother. 55(10), 1294-1298 (2005). (Pubitemid 43992055)
69. Zhang JG, Kruse CA, Driggers L et al. Tumor antigen precursor protein profiles of adult and pediatric brain tumors identify potential targets for immunotherapy. J. Neurooncol. 88(1), 65-76 (2008).
70. Okada H, Low KL, Kohanbash G, McDonald HA, Hamilton RL, Pollack IF. Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas. J. Neurooncol. 88(3), 245-250 (2008).
71. Zhang JG, Equchi J, Kruse CA et al. Antigenic profiles of human glioma cells; Implications for patient CTL targeting of tumor associated antigens with allogeneic tumor cell-based vaccine or other immune-cell based therapies. Neuro-oncol. 8, 431 (2007).
72. Yajima N, Yamanaka R, Mine T et al. Immunologic evaluation of personalized peptide vaccination for patients with advanced malignant glioma. Clin. Cancer Res. 11(16), 5900-5911 (2005). (Pubitemid 41170319)
73. Giezeman-Smits KM, Okada H, Brissette-Storkus CS et al. Cytokine gene therapy of gliomas: induction of reactive CD4+ T cells by interleukin-4- transfected 9L gliosarcoma is essential for protective immunity. Cancer Res. 60(9), 2449-2457 (2000). (Pubitemid 30262436)
74. Matsui S, Ahlers JD, Vortmeyer AO et al. A model for CD8+ CTL tumor immunosurveillance and regulation of tumor escape by CD4 T cells through an effect on quality of CTL. J. Immunol. 163(1), 184-193 (1999). (Pubitemid 29295840)
75. Adams M, Navabi H, Croston D et al. The rationale for combined chemo/immunotherapy using a Toll-like receptor 3 (TLR3) agonist and tumour-derived exosomes in advanced ovarian cancer. Vaccine 23(17-18), 2374-2378 (2005). (Pubitemid 40341487)
76. Salem ML, El-Naggar SA, Kadima A, Gillanders WE, Cole DJ. The adjuvant effects of the toll-like receptor 3 ligand polyinosinic-cytidylic acid poly (I:C) on antigen-specific CD8+ T cell responses are partially dependent on NK cells with the induction of a beneficial cytokine milieu. Vaccine 24(24), 5119-5132 (2006). (Pubitemid 43818196)
77. Schulz O, Diebold SS, Chen M et al. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433(7028), 887-892 (2005). (Pubitemid 40314900)
78. Zhu X, Nishimura F, Sasaki K et al. Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models. J. Transl. Med. 5, 10 (2007).
79. Sasaki K, Zhu X, Vasquez C et al. Preferential expression of very late antigen-4 on type 1 CTL cells plays a critical role in trafficking into central nervous system tumors. Cancer Res. 67(13), 6451-6458 (2007). (Pubitemid 47037530)
80. Butowski N, Lamborn KR, Lee BL et al. A North American brain tumor consortium phase II study of poly-ICLC for adult patients with recurrent anaplastic gliomas. J. Neurooncol. 91(2), 183-189 (2009).
81. Salazar AM, Levy HB, Ondra S et al. Long-term treatment of malignant gliomas with intramuscularly administered polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose: an open pilot study. Neurosurgery 38(6), 1096-1103, discussion 1103-1094 (1996).
82. Butowski N, Chang SM, Junck L et al. A phase II clinical trial of poly-ICLC with radiation for adult patients with newly diagnosed supratentorial glioblastoma: a North American Brain Tumor Consortium (NABTC01-05). J. Neurooncol. 91(2), 175-182 (2009).
83. Okada H, Butterfield LH, Hamilton RL et al. A bi-institutional pilot study of peptide-based vaccines in combination with poly ICLC in patients with WHO grade 2 low-grade glioma. Neuro-oncol. 14(Suppl. 6), vi45 (2012).
84. Okada H, Pollack IF. Do we need novel radiologic response criteria for brain tumor immunotherapy? Expert Rev. Neurother. 11(5), 619-622 (2011).
85. Prins RM, Craft N, Bruhn KW et al. The TLR-7 agonist, imiquimod, enhances dendritic cell survival and promotes tumor antigen-specific T cell priming: relation to central nervous system antitumor immunity. J. Immunol. 176(1), 157-164 (2006). (Pubitemid 43023259)
86. Prins RM, Soto H, Konkankit V et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin. Cancer Res. 17(6), 1603-1615 (2011).
87. Hanna D, Hatami A, Powell J et al. A prospective randomized trial comparing the efficacy and adverse effects of four recognized treatments of molluscum contagiosum in children. Pediatr. Dermatol. 23(6), 574-579 (2006). (Pubitemid 44800278)
88. Majewski S, Pniewski T, Malejczyk M, Jablonska S. Imiquimod is highly effective for extensive, hyperproliferative condyloma in children. Pediatr. Dermatol. 20(5), 440-442 (2003). (Pubitemid 37280493)
89. Vrabec M, Van Cauter S, Himmelreich U et al. MR perfusion and diffusion imaging in the follow-up of recurrent glioblastoma treated with dendritic cell immunotherapy: a pilot study. Neuroradiology 53(10), 721-731 (2011).
90. Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363(8), 711-723 (2010).
91. Brahmer JR, Drake CG, Wollner I et al. Phase I study of single-agent antiprogrammed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28(19), 3167-3175 (2010).
92. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12(4), 252-264 (2012).