Cancer immunotherapy in mice and humans: personal observations
Abstract
An experiment involving active immunotherapy of leukemia in mice and its extension to human patients with
chronic lymphocytic leukemia is described. First, anticancer activation of the immune system, how it is achieved,
and observations of the central blockade of the immune system in leukemia are discussed. Clinical results of
antileukemia immune activation are then presented, along with a description of new attempts to remove the
immune checkpoint blockade. Personal observations are presented on possible further steps to achieving more
effective active immunotherapy of cancer.
Keywords: apoptosisL1210 leukemia cellsDBA/2 micethymushuman B-CLLvaccination with apoptotic CLL lymphocytesclinical trial
References
- Geran RI, Greenberg NH, Macdonald MM, et al. Modified protocol for the testing of new synthetics in the L1210 lymphoid leukemia murine model in the DR&D program, DCT, NCI. Natl Cancer Inst Monogr. 1977(45): 151–153.
- Kawiak J, Skórski T, Ciechanowicz A, et al. Cytochemical characterization of mouse L1210 leukemia. Immunol Invest. 1988; 17(6-7): 543–550.
- Fabisiewicz A, Pacholewicz K, Paszkiewicz-Kozik E, et al. Polymorphisms of DNA repair and oxidative stress genes in B-cell lymphoma patients. Biomed Rep. 2013; 1(1): 151–155.
- Verdegaal EME, de Miranda NF, Visser M, et al. Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature. 2016; 536(7614): 91–95.
- Lennerz V, Fatho M, Gentilini C, et al. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci U S A. 2005; 102(44): 16013–16018.
- Eil R, Vodnala SK, Clever D, et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature. 2016; 537(7621): 539–543.
- Meyn RE, Stephens LC, Hunter NR, et al. Induction of apoptosis in murine tumors by cyclophosphamide. Cancer Chemother Pharmacol. 1994; 33(5): 410–414.
- Tabarkiewicz J, Kawiak J. Start of apoptosis process observed in human irradiated B-CLL cells of peripheral blood. 1 × 107 MNC of the patient were suspended in 1 ml of 0.9% NaCl, irradiated with 1000 Gy of -irradiation (137Cs) using Gamma Cell 1000 Elite apparatus (Nordion International Inc. Canada), and start of apoptosis within cells was observed over the six following days. ; 2003: unpublished observations.
- Davidoff AN, Mendelow BV. Cell-cycle disruptions and apoptosis induced by the cyclophosphamide derivative mafosfamide. Exp Hematol. 1993; 21(7): 922–927.
- Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972; 26(4): 239–257.
- Koopman G, Reutelingsperger CP, Kuijten GA, et al. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood. 1994; 84(5): 1415–1420.
- Kawalec M, Jakóbisiak M, Skórski T, et al. Immunogenicity of cyclophosphamide-treated leukaemia cells. Folia Biol (Praha). 1982; 28(5): 334–343.
- Kawalec M, Skórski T, Kawiak J. Successful chemoimmunotherapy of murine L1210 lymphatic leukemia with cyclophosphamide and mafosfamide-treated leukemia cells. Invest New Drugs. 1988; 6(3): 169–172.
- Kawalec M, Hoser G, Skórski T, et al. Immunogenic and nondividing mafosfamide-treated L 1210 cells--comparison of lines resistant and nonresistant to cyclophosphamide. Folia Histochem Cytobiol. 1993; 31(2): 63–66.
- Kawiak J, Kawalec M. Leukemia L 1210 cells induce depletion of Lyt 2+ thymocytes. Folia Histochem Cytobiol. 1990; 28(1-2): 15–17.
- Kawiak J, Kawalec M, Hoser G, et al. Changes of thymocyte subpopulations induced by activities diffusing from leukemia L1210 cells. Thymus. 1991; 18(3): 185–192.
- Gaczynska M, Rock KL, Goldberg AL. Gamma-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature. 1993; 365(6443): 264–267.
- Aki M, Shimbara N, Takashina M, et al. Interferon-gamma induces different subunit organizations and functional diversity of proteasomes. J Biochem. 1994; 115(2): 257–269.
- Rock KL, Gramm C, Rothstein L, et al. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell. 1994; 78(5): 761–771.
- Wójcik C, Stoklosa T, Giermasz A, et al. Apoptosis induced in L1210 leukaemia cells by an inhibitor of the chymotrypsin-like activity of the proteasome. Apoptosis. 1997; 2(5): 455–462.
- Kawiak J, Vensel W, Komender J, et al. Non-pancreatic proteases of the chymotrypsin family I. A chymotrypsin-like protease from rat mast cells. Biochimica et Biophysica Acta (BBA) - Enzymology. 1971; 235(1): 172–187.
- Kimura H, Caturegli P, Takahashi M, et al. New Insights into the Function of the Immunoproteasome in Immune and Nonimmune Cells. J Immunol Res. 2015; 2015: 541984.
- Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature. 1998; 392(6671): 86–89.
- Brossart P, Bevan MJ. Presentation of exogenous protein antigens on major histocompatibility complex class I molecules by dendritic cells: Pathway of presentation and regulation by cytokines. Blood 1997 Aug 15;90(4):1594–9. PMID. : 9269778.
- Lappin MB, Weiss JM, Delattre V, et al. Analysis of mouse dendritic cell migration in vivo upon subcutaneous and intravenous injection. Immunology. 1999; 98(2): 181–188.
- MartIn-Fontecha A, Sebastiani S, Höpken UE, et al. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med. 2003; 198(4): 615–621.
- Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995; 333(16): 1052–1057.
- Poplawska-Szczyglowska L, Walewski J, Pienkowska-Grela B, et al. Chronic lymphocytic leukaemia presenting with central nervous system involvement. Med Oncol. 1999; 16(1): 65–68.
- Rawstron AC, Villamor N, Ritgen M, et al. International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia. 2007; 21(5): 956–964.
- Plosker GL, Figgitt DP. Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Drugs. 2003; 63(8): 803–843.
- Robak T, Smolewski P, Cebula B, et al. Rituximab plus cladribine with or without cyclophosphamide in patients with relapsed or refractory chronic lymphocytic leukemia. European Journal of Haematology. 2007; 79(2): 107–113.
- Tam CS, O'Brien S, Plunkett W, et al. Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood. 2014; 124(20): 3059–3064.
- Robak T, Dmoszynska A, Solal-Céligny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2010; 28(10): 1756–1765.
- Bologna L, Gotti E, Da Roit F, et al. Ofatumumab is more efficient than rituximab in lysing B chronic lymphocytic leukemia cells in whole blood and in combination with chemotherapy. J Immunol. 2013; 190(1): 231–239.
- Kawiak J, Rolinski J, Hus I, et al. Analysis of peripheral blood lymphocyte count in patients with B-cell chronic lymphocytic leukemia (B-cell CLL) treated (vaccinated) with own irradiated mononuclear cells. The case report. Acta Haematologica Pol. 2003; 34(suppl.1): 129.
- Kawiak J, Hus I, Rolinski J, et al. Immunotherapy od B-CLL patients with autologous irradiated leukemic cells and BCG. Polish J. Environmental Studies. 2005; 14(suppl. II): 187–191.
- Hus I, Kawiak J, Tabarkiewicz J, et al. Immunotherapy with irradiated autologous leukemic cells in patients with B-CLL in early stages. Oncol Rep. 2008; 20(2): 443–451.
- Kosmaczewska A, Ciszak L, Boćko D, et al. Expression and functional significance of CTLA-4, a negative regulator of T cell activation. Arch Immunol Ther Exp (Warsz). 2001; 49(1): 39–46.
- Ciszak L, Frydecka I, Wolowiec D, et al. Patients with chronic lymphocytic leukaemia (CLL) differ in the pattern of CTLA-4 expression on CLL cells: the possible implications for immunotherapy with CTLA-4 blocking antibody. Tumour Biol. 2016; 37(3): 4143–4157.
- Ren Z, Guo J, Liao J, et al. CTLA-4 Limits Anti-CD20-Mediated Tumor Regression. Clin Cancer Res. 2017; 23(1): 193–203.
- Grzywnowicz M, Karabon L, Karczmarczyk A, et al. The function of a novel immunophenotype candidate molecule PD-1 in chronic lymphocytic leukemia. Leuk Lymphoma. 2015; 56(10): 2908–2913.
- Larkin J, Hatswell AJ, Nathan P, et al. The Predicted Impact of Ipilimumab Usage on Survival in Previously Treated Advanced or Metastatic Melanoma in the UK. PLoS One. 2015; 10(12): e0145524.
- Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015; 372(21): 2006–2017.
- Kaszubowska L, Piotrowska A, Siedlecka-Kroplewska K, et al. cells as a connecting element between innate and adaptive immunity. Adv Cell Biol 2013(4). ; 40: 697–724.
- Brennan PJ, Tatituri RVV, Heiss C, et al. Activation of iNKT cells by a distinct constituent of the endogenous glucosylceramide fraction. Proc Natl Acad Sci U S A. 2014; 111(37): 13433–13438.
- Ferguson LR, Chen H, Collins AR, et al. Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Semin Cancer Biol. 2015; 35 Suppl: S5–SS24.
- Rauch J, Gumperz J, Robinson C, et al. Structural features of the acyl chain determine self-phospholipid antigen recognition by a CD1d-restricted invariant NKT (iNKT) cell. J Biol Chem. 2003; 278(48): 47508–47515.
- Murphy RA, Mourtzakis M, Chu QSC, et al. Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with nonsmall cell lung cancer receiving chemotherapy. Cancer. 2011; 117(8): 1775–1782.
- Murphy RA, Mourtzakis M, Mazurak VC. n-3 polyunsaturated fatty acids: the potential role for supplementation in cancer. Curr Opin Clin Nutr Metab Care. 2012; 15(3): 246–251.
- Pappalardo G, Almeida A, Ravasco P. Eicosapentaenoic acid in cancer improves body composition and modulates metabolism. Nutrition. 2015; 31(4): 549–555.
- Vermorken JB, Claessen AM, van Tinteren H, et al. Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet. 1999; 353(9150): 345–350.
- Harris JE, Ryan L, Hoover HC, et al. Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin Oncol. 2000; 18(1): 148–157.
- Uyl-de Groot CA, Vermorken JB, Hanna MG, et al. Immunotherapy with autologous tumor cell-BCG vaccine in patients with colon cancer: a prospective study of medical and economic benefits. Vaccine. 2005; 23(17-18): 2379–2387.
- Sathyanarayanan V, Neelapu SS. Cancer immunotherapy: Strategies for personalization and combinatorial approaches. Mol Oncol. 2015; 9(10): 2043–2053.
- Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol. 2015; 33(13): 1430–1437.
- Sul J, Blumenthal GM, Jiang X, et al. FDA Approval Summary: Pembrolizumab for the Treatment of Patients With Metastatic Non-Small Cell Lung Cancer Whose Tumors Express Programmed Death-Ligand 1. Oncologist. 2016; 21(5): 643–650.
- Wang Yi, Wu L, Tian C, et al. PD-1-PD-L1 immune-checkpoint blockade in malignant lymphomas. Annals of Hematology. 2017; 97(2): 229–237.
- Grzywnowicz M, Karczmarczyk A, Skorka K, et al. Expression of Programmed Death 1 Ligand in Different Compartments of Chronic Lymphocytic Leukemia. Acta Haematol. 2015; 134(4): 255–262.
- Kawiak J, Hoser G, Domagała-Kulawik J. Problems of Cancer Treatment. Part 2. Treatment Based on Modification of Anticancer Immunological Responses in Therapy. Advances in Cell Biology. 2017; 5(1).
- Xu-Monette ZY, Zhou J, Young KH. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood. 2018; 131(1): 68–83.
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