Disease-Free Remission Exceeding 37 Years in Patients Treated as Children for Acute Leukemia (AL) with Immunotherapy Using Viable (Cryopreserved) Allogeneic Leukemic Cells Pages 254-26
Keywords:Acute leukemia, Immunotherapy, Cryopreserved leukemic cells, Prolongation of remission, Immunological indices.
At present time in spite of great achievements in modern chemotherapy of acute leukemia (AL) the issue of eradication of residual leukemic cells (MRD) is still relevant. Since 1971 we included specific immunotherapy in the treatment of children with acute lymphoblastic leukemia in remission using viable cryopreserved allogeneic leukemic cells. 67 children in remission were divided into 2 groups: 27 constituted the control group (only continued standard-for-that-time chemotherapy) and 40 children - the treatment which received immunotherapy in addition to standard chemotherapy. In 3 years all children in the control group relapsed. The median length of remission was 15 months. In the treatment group we observed stabilization of remission only in children over 7 years of age when immunization was initiated after 6 or more months of remission and in children younger than 7 if it was initiated after 1-1,5 years of remission. The median length of remission was 60 months which significantly exceeded (4 times) that parameter in the control group of children. Cytotoxic antibodies against leukemic cells appeared in the serum of effectively immunized children at a higher titer than against donor lymphocytes. Intrathecal administration of this hyperimmune serum to patients with neuroleukemia resistant to chemotherapy led to a sharp decrease in the amount of leukemic cells in the spinal fluid. After 5 years of remission (and 3-5 years of immunotherapy) all treatment in these patients was stopped. Out of 19 patients who received immunotherapy on time, 8 patients (42%) have been in event-free remission for 37 to 41 years (median - 38 years) through the present time and enjoy high quality of life. Our results indicate that immunotherapy initiated during remission period of AL can lead to creation of anti-leukemic immunity with subsequent eradication of MRD and complete recovery.
Coustan–Smith E, Sancho J, Hancock ML, et al. Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. Blood 2000; 96(8): 2691-9.
Van den Ancker W, van Luijn MM, Westers TM, et al. Recent advances in antigen-loaded dendritic cell-based strategies for treatment of minimal residual disease in acute myeloid leukemia. Immunotherapy 2010; 2(1): 69-83. http://dx.doi.org/10.2217/imt.09.85
Pinkel D. Treatment of childhood acute lymphocytic leukemia. J Pediatr 1970; 77: 1089-91. http://dx.doi.org/10.1016/S0022-3476(70)80101-9
Kislyak NS, Mahonova LA, Ivanovskaja TE. Clinical trend and treatment of acute leukemia in children. Moscow. Medgiz 1972 (in Russian).
Harris R. Leukemia antigens and immunity in man. Nature (London) 1973; 241: 95-103. http://dx.doi.org/10.1038/241095a0
Dore JF, Kourilsky FM. Human leukemia-associated antigens and immune reactions. In: Present Probl. in Hematol. Excer Med Amsterdam-Prague 1974; 59-77.
Skurkovich SV, Kislyak NS, Machonova LA, Begunenko SA. Active immunization of children suffering from acute leukemia in acute phase with “live” allogeneic leukaemic cells. Nature 1969; 223: 509-11. http://dx.doi.org/10.1038/223509a0
Skurkovich SV, Bulycheva TI, Kovaleva LI, Isaev VG. Active immunization of patients with ALL with live allogeneic leukemic cells in combination with antileukemic chemotherapy. Probl Hematol 1970; 5: 32-5 (in Russian).
Bulycheva TI, Leontovich BA, Abesgauz HH, Skurkovich SV. A method of long term storage of leukemic cells at ultralow temperatures. Probl Hematol Blood Trans 1972; 6: 47-9 (in Russian).
Bulycheva TI, Leontovich BA, Abezgauz HH, et al. A bank of blast cells designed for immunological research and immunotherapy of patients with leukemia. Probl Hematol 1977; 2: 32-5 (in Russian).
Miterev GY, Samoilova RS, Bulycheva TI, et al. Cell’s indication of immunity from leukemia’s patients in remission. Probl Hematol 1979; 1: 28-34 (in Russian).
Bulycheva TI. Immunological status and new principles of immunotherapy of acute leukemia’s patients. Thesis, (Doct. of Med. Sci. Dissertation) Moscow 1979; (in Russian).
Skurkovich SV, Kisliak NS, Bulycheva TI, et al. Results of immunotherapy of acute leukemia in children and attempts in stimulation antileukemia immunity in experiments. XI. Intern Cancer Congr Abstr 1974; Florence; 4.
Skurkovich SV, Kisliak NS, Bulycheva TI, et al. Active immunization of children suffering from acute leukemia in remission with “living” mixed leukoblast vaccine and means of enhancement of antileukimic immunity. Annal N-Y Acad Sci 1976; 277: 384-95.
Skurkovich SV, Kislyak NC, Bulycheva TI, et al. Active immunization of children of various ages during the period of remission of acute leukemia with live allogeneic leukemic cells. Probl Hematol 1976; 10: 16-21 (in Russian).
Skurkovich SV, Bulycheva TI, Majakova SV, et al. Effect of immunotheralpy with viable cryopreserved allogeneic leukemia cells on the cours of remission in childhood leukemia. Indices of immunological examination. In: Topics in Hematol Amsterdam Exerpta Med 1977; 758-60.
Skurkovich SV, Bulycheva TI. Regarding immunotherapy of acute leukemia. Sov Med 1978; 8: 26-31.
Bulycheva TI. Leukemia cells used for Ca therapy. Med World News 1979 Sept. 17; 28-30.
Majakova SA, Bulycheva TI, Kislyak NS, Machnova LA. Continuous remissions (exceeding 7 years) in children with acute leukemia. Pediatria 1979; 12: 27-32 (in Russian).
Bulycheva TI, Leontovich BA, Kisliak NS, Mahonova LA, Majakova SV. Immunotherapy of children suffering from acute leukemia during remission with cryopreserved (vi able) allogeneic leukemic cells. Practical recommendations. Moscow 1979; (in Russian).
Danilevich SV, Kalinina IA, Bulycheva TI. Experimental model for the detection of leukemia-specific antigens in acute human leukemias. Bull Exp Biol Med 1983; 95: 87-8 (in Russian). http://dx.doi.org/10.1007/BF00831242
Paczesny S, Beranger S, Salzmann JL, Klatzmann D, Colombo BM. Protection of mice against leukemia after vaccination with bone marrow-derived dendritic cells loaded with apoptotic leukemia cells. Cancer Res 2001; 61(6): 2386-9.
Heslop H, Stevenson F, Molldrem J. Immunotherapy of hematologic malignancy Hematology. Am Soc Нematol 2005; 331-46.
Smits EL, Berneman ZN, Van Tendeloo VF. Immunotherapy of acute myeloid leukemia: current approaches. Oncologist 2009; 14(3): 240-52. http://dx.doi.org/10.1634/theoncologist.2008-0165
Van Tendeloo VF, Van de Velde A, Van Driessche A, et al. Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination. Proc Natl Acad Sci USA 2010; 107(31): 13824-9. http://dx.doi.org/10.1073/pnas.1008051107
Barrett AJ, Le Blanc K. Immunotherapy prospects for acute myeloid leukaemia. Clin Exp Immunol 2010; 161(2): 223-32.
Barrett DM, Zhao Y, Liu X, et al. Treatment of advanced leukemia in mice with mRNA engineered T cells. Hum Gene Ther 2011; 22(12): 1575-86. http://dx.doi.org/10.1089/hum.2011.070
Li XL, Sun LR, Wang Z, Sun XF. The preparation of leukemia cell vaccine expressing BCG heat shock protein 70 and anti-leukemia effect in vitro. Int Immunopharmacol 2012; 14(3): 235-42. http://dx.doi.org/10.1016/j.intimp.2012.07.022
Greiner J, Bullinger L, Guinn BA, Dohner H, Smitt M. Leukemia- associated antigens are critical for proliferation of acute myeloid leukemia cell. Clin Cancer Res 2008; 14(22): 7161-6. http://dx.doi.org/10.1158/1078-0432.CCR-08-1102
Greiner J, Ringhoffer M, Taniguchi M, Schmitt A, Kirchner D, Krahn G. Receptor for hyaluronan acid-mediated motility (RHAMM) is a new immunogenic leukemia-associated antigen in acute and chronic myeloid leukemia. Exp Hematol 2002; 30(9): 1029-35. http://dx.doi.org/10.1016/S0301-472X(02)00874-3
Schendel DJ. Is it time to abandon RHAMM/HMMR as a candidate antigen for immunotherapy of acute myeloid leukemia? Haematologica 2012; 97(10): 1454-5. http://dx.doi.org/10.3324/haematol.2012.077099
Snauwaert S, Vanhee S, Goetgeluk G, et al. RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia. Hematologica 2012; 97(10): 1539-47. http://dx.doi.org/10.3324/haematol.2012.065581
Metzgar RS, Mohanakumar T, Miller DS. Antigens specific for human lymphocytic and myeloid leukemia cells: detection by nonhuman primate antiserums. Science 1972; (178): 986-8. http://dx.doi.org/10.1126/science.178.4064.986
Hollinschead AC. Cell membrane antigens associated with human adult acute leukemia. Blood Cells 1976; (2): 257-65.
Greaves MF. Recent progress in the immunological characterization of leukemia cells. Blut 1977; (34): 349-56. http://dx.doi.org/10.1007/BF00996074
Boczkowski D, Nair SK, Snyder D, Gilboa E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J Exp Med 1996; 184(2): 465-72. http://dx.doi.org/10.1084/jem.184.2.465
Nestle FO, Alijagic S, Gilliet M, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 1998; 4(3): 328-32. http://dx.doi.org/10.1038/nm0398-328
Thurner B, Haendle I, Röder C, et al. Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 1999; 190(11): 1669-8. http://dx.doi.org/10.1084/jem.190.11.1669
Shaif-Muthana M, McIntyre C, Sisley K, Rennie I, Murray A. Dead or alive: immunogenicity of human melanoma cells when presented by dendritic cells. Cancer Res 2000; 60(22): 6441-7.
Banchereau J, Palucka AK, Dhodapkar M, et al. Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res 2001; 61(17): 6451-8.
Goldszmid RS, Idoyaga J, Bravo AI, Steinman R, Mordoh J, Wainstok R. Dendritic cells charged with apoptotic tumor cells induce long-lived protective CD4+ and CD8+ T cell immunity against B16 melanoma. J Immunol 2003; 171(11): 5940-7.
Schmitt M, Casalegno-Garduño R, Xu X, Schmitt A. Peptide vaccines for patients with acute myeloid leukemia. Expert Rev Vaccines 2009; 8(10): 1415-25. http://dx.doi.org/10.1586/erv.09.90
Greiner J, Schmitt A, Giannopoulos K, et al. High-dose RHAMM-R3 peptide vaccination for patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma. Haematologica 2010; 95(7): 1191-7. http://dx.doi.org/10.3324/haematol.2009.014704
Anguille S, Lion E, Smits E, Berneman ZN, van Tendeloo VFI. Dendritic cell vaccine therapy for acute myeloid leukemia: questions and answers. Hum Vaccin 2011; 7(5): 579-84. http://dx.doi.org/10.4161/hv.7.5.14652
Dong M, Liang D, Li Y, et al. Autologous dendritic cells combined with cytokine-induced killer cells synergize low-dose chemotherapy in elderly patients with acute myeloid leukaemia. J Int Med Res 2012; 40(4): 1265-74. http://dx.doi.org/10.1177/147323001204000405
Gutterman JU, Hersch EM, Freireich EJ. Cell-midiated and humoral immune response to acute leukemia cells and soluble leukemia antigen. Relationship to immunocompetence and prognosis. Natl Canc Inst Monograph 1973; (37): 153-67.
Powles R. Immunotherapy for acute myelogenous leukemia using irradiated and untreated leukemia cells. Cancer 1974; (34): 1558-62. http://dx.doi.org/10.1002/1097-0142(197410)34:8+<1558::AID-CNCR2820340830>3.0.CO;2-H
Skurkovich SV, Kalinina EA, Eremkina EI, Bulycheva TI, et al. Augmentation of the immune response during immunization with cells L-1210 that were pretreated with interferon. Bull Exp Biol Med 1976; (6): 706-7 (in Russian).
Skurkovich SV, Kalinina IA, Eremkina EI, Bulycheva TI, et al. Increased sensitivity of leukemic cells treated with interferon to cytotoxic activity of leukemic serums. Bull Exp Biol Med 1976; (12): 1459-61 (in Russian).
Holland JF, Bekesi JG. Immunotherapy of human leukemia with neuraminidase-modified cells. Med Clin N Am 1976; (60): 539-49.
Bekesi JG, Roboz JP, Holland JF. Theraputic effectiveness of neuraminidase-treated tumor cells as an immunogen in men and experimental animals with leukemia. Ann NY Acad Sci 1976; (277): 313-32. http://dx.doi.org/10.1111/j.1749-6632.1976.tb41710.x
Mahonova LA, Gavrilova IE, Kuznetsov VP, et al. Preliminary results of application of leukocytic interferon during treatment of acute leukemia in children. Hematol Transf 1983; 12: 8-11 (in Russian).
Leventhal BG, Herberman RB, Rosenberg EB. In vitro and in vivo immunological reactivity against autochtonous leukemia cells. Cancer Res 1972; 329: 1820-25.
Hersch EM, Guttermn JU, Mavligit GM. Effect of haematological malignancies and their treatment on host defense factors. Clin Haematol 1976; 5: 425-48 (in Russian).
Krepler P, Pawlowski J, Kummer M. Immunological follow up of acute lymphoblastic leukemia. Haematologia 1976; 10: 11-12.
Mathe G. The strategy of treatment of acute lymphoblastic leukaemia. Combination of chemotherapy and immunotherapy: pursuit of remission from 1-2 years after stopping chemotherapy. Therapeutique 1969; 45: 154-5.
Borella L, Webster RY. The immunosuppressive effects of longterm combination chemotherapy in children with acute leukemia in remission. Cancer Res 1971; 31: 420-26.
Gutterman JU, Hersch EM, McCredie KB. Lymphocyte blastogenesis to human leukemia cells and their relationship to serum factors, immunocompetence and prognosis. Cancer Res 1972; 32: 2524-31.
Powles RL, Lister TA, Oliver RTD. Safe method of collecting leukemia cells from patients with acute leukemia for use as immunotherapy. Med J 1974; (4): 375-9.
Kawashima K. Leukapheresis of patients with acute leukemia and chronic myelogenous leukemia. Rinsho Ketsueki 1977; 18: 620-6.
Burchenal I. Hematologic Neoplams In: Cancer Medicine 1973; 1167-73.
Mahonova LA, Majakova SA. Modern approaches to treatment of acute lymphoblastic leukemia in children. Pediatria 1980; 5: 22-6 (in Russian).
Reiter AL, Schrappe M, Ludwig WD, et al. Chemotherapy in 998 unselected childhood from acute lymphoblastic leukemia patients. Results and conclusion of the multicenter trial ALL-BF M86. Blood 1994; 84: 3122-33.
Hann J, Vora A, Richards S. Benefit of intensified treatment for all children with acute lymphoblastic leukemia: Results from MRCUCALL XL and MRCALL 97 randomized trials. Leukemia 2000; 14: 356. http://dx.doi.org/10.1038/sj.leu.2401704
Schrappe M, Reiter A, Zimmermann M. Long term results of four consecutive trials in childhood all. All performed by the All-BFM study group from 1982 to 1995. Leukemia 2000; 14: 2205-22. http://dx.doi.org/10.1038/sj.leu.2401973
Mentkevich JL, Majakova SA. In leukemias in children. Practical medicine, Moscow 2009; 247-8 (in Russian).
Rosenthal SR, Crispen RG, Thorue M. BCG vaccination and leukemia mortality. Am Med Assoc 1972; 222: 1543-4. http://dx.doi.org/10.1001/jama.1972.03210120041010
Children’s Cancer Study Group A. BCG in the treatment of acute lymphoblastic leukemia. Proc Am Ass Cancer Res 1973; 14: 45.
Heyn RM, Jee P, Karon M. BCG in the treatment of acute lymphocytic leukemia. Blood 1975; 46: 431-42.
Vogler WR, Bartolucci AA. The effect of BCG on remission duration and survivas in acute myeloblastic leukemia. Proc Am Ass Cancer Res 1976; 17: 109.
Mathe G, de Vassal F, Delgade M. 1975 Current results of the first 100 cytologically typed acute lymphoid leukemia submitted to BCG active immunotherapy. Cancer Immunol Immunopath 1976; 1: 77-86.
Nystrom J, Bateman J, Linman J. Corynebacterium parvum maintanence immunotherapy for acute non lymphocytic leukemia: preliminary report. Pros Am Ass Cancer Res 1977; 18: 102.
Omura GA, Vogler WR, Lynn MJ. A controlled clinical trial of chemotherapy vs BCG immunotherapy vs. no further therapy in remission maintenance of acute myelogenous leukemia. Pros Am Soc Clin Oncol 1977; 18: 272.
Whittaker JA, Slater AJ. The immunotherapy of acute myelogenous leukemia using intravenous BCG. Br J Haematol 1977; 35: 263-74. http://dx.doi.org/10.1111/j.1365-2141.1977.tb00583.x
Powles RL, Risssel J, Lister TA. Immunotherapy in a controlled clinical study2 ½ years after entry of the last patients. Br J Cancer 1977; (35): 265-72. http://dx.doi.org/10.1038/bjc.1977.38
Hersh E, Ezaki K, McCredie K. Active specific immunization in acute leukemia. Proc Am Ass Cancer Res 1977; 18: 242.
Holland JV, Bekesi JG, Cuttner J, Glidewell O. Chemoimmunotherapy in acute leukemias. Israel J Med Sci 1977; 13: 694-700.
Medical Research Council (M.R.C.). Treatment of acute lymphoblastic leukemia. Br Med J 1971; 4(1): 189-94.
Strychkmans PA, Otten J. Immunotherapy in acute lymphoblastic leukemia. Proc Am Ass Cancer Res 1976; 17: 217.
Whiteside MG, Cauchi MV, Paton C. Chemoimmunotherapy for maintenance in acute myeloblastic leukemia Cancer (Phil.) 1976; 38: 1581-6.
Lister TA, Whitehaus JMA, Oliver RTD, et al. Chemotherapy and immunotherapy for acute myelogenius leukemia. Cancer 1980; 46(6): 2142-8. http://dx.doi.org/10.1002/1097-0142(19801115)46:10<2142::AID-CNCR2820461005>3.0.CO;2-J
Whittaker JA, Bailey-Wood R, Hutchins S. Active immunotherapy for treatment of acute myelogenous leukemia: Report of two controlled trials. Br J Hematol 1980; 45(2): 389-400. http://dx.doi.org/10.1111/j.1365-2141.1980.tb07159.x
Baker MA, Taub RN, Carter WH. Immunotherapy for remission maintenance in acute myeloblastic leukemia. Сancer Immunol Immunother 1982; 13(1): 85-8.
Paton CM, Bishop JF, Mathews JP, Whiteside MG. Immunotherapy maintenance in acute nonlymphocytic leukemia Austr. NL J Med 1982; 12(4): 583-9.
Zuhrie SR, Harris R, Freeman SB. Immunotherapy alone vs no maintenance treatment in acute myelogenous leukemia. Br I Cancer 1980; 41(2): 372-7. http://dx.doi.org/10.1038/bjc.1980.60
Freeman CB, Harris R, Geary CG. Active immunotherapy used alone for maintenance of patients with acute myeloid leukemia. Br Med J 1973; 4: 571-4. http://dx.doi.org/10.1136/bmj.4.5892.571
Baker MA, Falk JA, Taub RN. Immunotherapy of human acute leukemia: antibody response to leukemia-associated antigens. Blood 1978; 52: 469-80.