Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists

References

• Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8(328):328rv324.
   Web of Science ®Google Scholar
• Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from Phase II and Phase III trials of Ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33(17):1889–1894.
   PubMed Web of Science ®Google Scholar
• Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res. 2015;21(4):687–692.
   PubMed Web of Science ®Google Scholar
• Posner MR, Cavacini LA, Upton MP, et al. Surface membrane-expressed CD40 is present on tumor cells from squamous cell cancer of the head and neck in vitro and in vivo and regulates cell growth in tumor cell lines. Clin Cancer Res. 1999;5(8):2261–2270.
   PubMed Web of Science ®Google Scholar
• Weiss JM, Gregory Alvord W, Quinones OA, et al. CD40 expression in renal cell carcinoma is associated with tumor apoptosis, CD8(+) T cell frequency and patient survival. Hum Immunol. 2014;75(7):614–620.
   PubMed Web of Science ®Google Scholar
• Hess S, Engelmann H. A novel function of CD40: induction of cell death in transformed cells. J Exp Med. 1996;183(1):159–167.
   PubMed Web of Science ®Google Scholar
• Schoenberger SP, Toes RE, Van Der Voort EI, et al. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature. 1998;393(6684):480–483.
   PubMed Web of Science ®Google Scholar
• Bennett SR, Carbone FR, Karamalis F, et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature. 1998;393(6684):478–480.
   PubMed Web of Science ®Google Scholar
• Ridge JP, Di Rosa F, Matzinger P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature. 1998;393(6684):474–478.
   PubMed Web of Science ®Google Scholar
• Grammer AC, Bergman MC, Miura Y, et al. The CD40 ligand expressed by human B cells costimulates B cell responses. J Immunol. 1995;154(10):4996–5010.
   PubMed Web of Science ®Google Scholar
• Frentsch M, Stark R, Matzmohr N, et al. CD40L expression permits CD8+ T cells to execute immunologic helper functions. Blood. 2013;122(3):405–412.
   PubMed Web of Science ®Google Scholar
• Carbone E, Ruggiero G, Terrazzano G, et al. A new mechanism of NK cell cytotoxicity activation: the CD40-CD40 ligand interaction. J Exp Med. 1997;185(12):2053–2060.
   PubMed Web of Science ®Google Scholar
• Gauchat JF, Henchoz S, Mazzei G, et al. Induction of human IgE synthesis in B cells by mast cells and basophils. Nature. 1993;365(6444):340–343.
   PubMed Web of Science ®Google Scholar
• Mach F, Schonbeck U, Sukhova GK, et al. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci U S A. 1997;94(5):1931–1936.
   PubMed Web of Science ®Google Scholar
• Henn V, Slupsky JR, Grafe M, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998;391(6667):591–594.
   PubMed Web of Science ®Google Scholar
• Lanzavecchia A. Immunology. Licence to kill. Nature. 1998;393(6684):413–414.
   PubMed Web of Science ®Google Scholar
• French RR, Chan HT, Tutt AL, et al. CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat Med. 1999;5(5):548–553.
   PubMed Web of Science ®Google Scholar
• Sotomayor EM, Borrello I, Tubb E, et al. Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nat Med. 1999;5(7):780–787.
   PubMed Web of Science ®Google Scholar
• Diehl L, Den Boer AT, Schoenberger SP, et al. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med. 1999;5(7):774–779.
   PubMed Web of Science ®Google Scholar
• Clark EA, Ledbetter JA. Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Proc Natl Acad Sci U S A. 1986;83(12):4494–4498.
   PubMed Web of Science ®Google Scholar
• Armitage RJ, Fanslow WC, Strockbine L, et al. Molecular and biological characterization of a murine ligand for CD40. Nature. 1992;357(6373):80–82.
   PubMed Web of Science ®Google Scholar
• Noelle RJ, Roy M, Shepherd DM, et al. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci U S A. 1992;89(14):6550–6554.
   PubMed Web of Science ®Google Scholar
• Nowak AK, Robinson BW, Lake RA. Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res. 2003;63(15):4490–4496.
   PubMed Web of Science ®Google Scholar
• Vonderheide RH, Flaherty KT, Khalil M, et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol. 2007;25(7):876–883.
   PubMed Web of Science ®Google Scholar
• Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331(6024):1612–1616.
   PubMed Web of Science ®Google Scholar
• Zippelius A, Schreiner J, Herzig P, et al. Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer Immunol Res. 2015;3(3):236–244.
   PubMed Web of Science ®Google Scholar
• Long KB, Gladney WL, Tooker GM, et al. IFNgamma and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma. Cancer Discov. 2016;6(4):400–413.
   PubMed Web of Science ®Google Scholar
• Vonderheide RH, Dutcher JP, Anderson JE, et al. Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol. 2001;19(13):3280–3287.
   PubMed Web of Science ®Google Scholar
• Malmstrom PU, Loskog AS, Lindqvist CA, et al. AdCD40L immunogene therapy for bladder carcinoma–the first phase I/IIa trial. Clin Cancer Res. 2010;16(12):3279–3287.
   PubMed Web of Science ®Google Scholar
• Loskog A, Maleka A, Mangsbo S, et al. Immunostimulatory AdCD40L gene therapy combined with low-dose cyclophosphamide in metastatic melanoma patients. Br J Cancer. 2016;114(8):872–880.
   PubMed Web of Science ®Google Scholar
• Medina-Echeverz J, Ma C, Duffy AG, et al. Systemic agonistic anti-CD40 treatment of tumor-bearing mice modulates hepatic myeloid-suppressive cells and causes immune-mediated liver damage. Cancer Immunol Res. 2015;3(5):557–566.
   PubMed Web of Science ®Google Scholar
• Li F, Ravetch JV. Inhibitory Fcgamma receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science. 2011;333(6045):1030–1034.
   PubMed Web of Science ®Google Scholar
• White AL, Chan HT, Roghanian A, et al. Interaction with FcgammaRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody. J Immunol. 2011;187(4):1754–1763.
   PubMed Web of Science ®Google Scholar
• White AL, Chan HT, French RR, et al. Conformation of the human immunoglobulin G2 hinge imparts superagonistic properties to immunostimulatory anticancer antibodies. Cancer Cell. 2015;27(1):138–148.
   PubMed Web of Science ®Google Scholar
• Richman LP, Vonderheide RH. Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer. Cancer Immunol Res. 2014;2(1):19–26.
   PubMed Web of Science ®Google Scholar
• Dahan R, Barnhart BC, Li F, et al. Therapeutic activity of agonistic, human anti-CD40 monoclonal antibodies requires selective fcgammar engagement. Cancer Cell. 2016;29(6):820–831.
   PubMed Web of Science ®Google Scholar
• Smith KG, Clatworthy MR. FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat Rev Immunol. 2010;10(5):328–343.
   PubMed Web of Science ®Google Scholar
• White AL, Dou L, Chan HT, et al. Fcgamma receptor dependency of agonistic CD40 antibody in lymphoma therapy can be overcome through antibody multimerization. J Immunol. 2014;193(4):1828–1835.
   PubMed Web of Science ®Google Scholar
• Bedian V, Gladue RP, Corvalan J et al. Methods of treating cancer and enhancing immune responses with antibodies that bind CD40. US7338660. 2008.
   Google Scholar
• Zhang Y, Yu G, Zhu W Anti-cd40 antibodies and methods of use. WO2014070934. 2014.
   Google Scholar
• Mangsbo SM, Broos S, Fletcher E, et al. The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T-cell-dependent tumor immunity. Clin Cancer Res. 2014;21(5):1115–1126.
   PubMed Web of Science ®Google Scholar
• Burington B, Yue P, Shi X, et al. CD40 pathway activation status predicts response to CD40 therapy in diffuse large B cell lymphoma. Sci Transl Med. 2011;3(74):74ra22.
   PubMed Web of Science ®Google Scholar
• Francisco JA, Donaldson KL, Chace D, et al. Agonistic properties and in vivo antitumor activity of the anti-CD40 antibody SGN-14. Cancer Res. 2000;60(12):3225–3231.
   PubMed Web of Science ®Google Scholar
• Gardai SJ, Epp A, Linares G, et al. Abstract 2472: SEA-CD40, a sugar engineered non-fucosylated anti-CD40 antibody with improved immune activating capabilities. Cancer Res. 2015;75(15 Suppl):Abstract 2472.
   Web of Science ®Google Scholar
• Gardai SJ, Epp A, Linares G, et al. A sugar engineered non-fucosylated anti-CD40 antibody, SEA-CD40, with enhanced immune stimulatory activity alone and in combination with immune checkpoint inhibitors. J Clin Oncol. 2015;33(suppl):Abstract 3074.
   Google Scholar
• Johnson PW, Steven NM, Chowdhury F, et al. A Cancer Research UK phase I study evaluating safety, tolerability, and biological effects of chimeric anti-CD40 monoclonal antibody (MAb), Chi Lob 7/4. J Clin Oncol. 2010;28(15s):Abstract 2507.
   Google Scholar
• Chowdhury F, Johnson PW, Glennie MJ, et al. Ex vivo assays of dendritic cell activation and cytokine profiles as predictors of in vivo effects in an anti-human CD40 monoclonal antibody ChiLob 7/4 phase I trial. Cancer Immunol Res. 2013;2(3):229–240.
   PubMed Web of Science ®Google Scholar
• Byrd JC, Kipps TJ, Flinn IW, et al. Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53(11):2136–2142.
   PubMed Web of Science ®Google Scholar
• Bouchlaka MN, Sckisel GD, Chen M, et al. Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. J Exp Med. 2013;210(11):2223–2237.
   PubMed Web of Science ®Google Scholar
• Advani R, Forero-Torres A, Furman RR, et al. Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27(26):4371–4377.
   PubMed Web of Science ®Google Scholar
• Nowak AK, Cook AM, McDonnell AM, et al. A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma. Ann Oncol. 2015;26(12):2483–2490.
   PubMed Web of Science ®Google Scholar
• Johnson P, Challis R, Chowdhury F, et al. Clinical and biological effects of an agonist anti-CD40 antibody: a Cancer Research UK phase I study. Clin Cancer Res. 2015;21(6):1321–1328.
   PubMed Web of Science ®Google Scholar
• Beatty GL, Torigian DA, Chiorean EG, et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res. 2013;19(22):6286–6295.
   PubMed Web of Science ®Google Scholar
• Sandin LC, Orlova A, Gustafsson E, et al. Locally delivered CD40 agonist antibody accumulates in secondary lymphoid organs and eradicates experimental disseminated bladder cancer. Cancer Immunol Res. 2014;2(1):80–90.
   PubMed Web of Science ®Google Scholar
• Fransen MF, Sluijter M, Morreau H, et al. Local activation of CD8 T cells and systemic tumor eradication without toxicity via slow release and local delivery of agonistic CD40 antibody. Clin Cancer Res. 2011;17(8):2270–2280.
   PubMed Web of Science ®Google Scholar
• Kusam S, Munugalavadla V, Sawant D, et al. BCL6 cooperates with CD40 stimulation and loss of p53 function to rapidly transform primary B cells. Int J Cancer. 2009;125(4):977–981.
   PubMed Web of Science ®Google Scholar
• Homig-Holzel C, Hojer C, Rastelli J, et al. Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis. J Exp Med. 2008;205(6):1317–1329.
   PubMed Web of Science ®Google Scholar
• Ahonen CL, Doxsee CL, McGurran SM, et al. Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN. J Exp Med. 2004;199(6):775–784.
   PubMed Web of Science ®Google Scholar
• Ahonen CL, Wasiuk A, Fuse S, et al. Enhanced efficacy and reduced toxicity of multifactorial adjuvants compared with unitary adjuvants as cancer vaccines. Blood. 2008;111(6):3116–3125.
   PubMed Web of Science ®Google Scholar
• Assudani D, Cho HI, DeVito N, et al. In vivo expansion, persistence, and function of peptide vaccine-induced CD8 T cells occur independently of CD4 T cells. Cancer Res. 2008;68(23):9892–9899.
   PubMed Web of Science ®Google Scholar
• Cho HI, Celis E. Optimized peptide vaccines eliciting extensive CD8 T-cell responses with therapeutic antitumor effects. Cancer Res. 2009;69(23):9012–9019.
   PubMed Web of Science ®Google Scholar
• Thompson EA, Liang F, Lindgren G, et al. Human anti-CD40 antibody and poly IC:LC adjuvant combination induces potent T cell responses in the lung of nonhuman primates. J Immunol. 2015;195(3):1015–1024.
   PubMed Web of Science ®Google Scholar
• Sanchez PJ, McWilliams JA, Haluszczak C, et al. Combined TLR/CD40 stimulation mediates potent cellular immunity by regulating dendritic cell expression of CD70 in vivo. J Immunol. 2007;178(3):1564–1572.
   PubMed Web of Science ®Google Scholar
• Bullock TN, Yagita H. Induction of CD70 on dendritic cells through CD40 or TLR stimulation contributes to the development of CD8+ T cell responses in the absence of CD4+ T cells. J Immunol. 2005;174(2):710–717.
   PubMed Web of Science ®Google Scholar
• McWilliams JA, Sanchez PJ, Haluszczak C, et al. Multiple innate signaling pathways cooperate with CD40 to induce potent, CD70-dependent cellular immunity. Vaccine. 2010;28(6):1468–1476.
   PubMed Web of Science ®Google Scholar
• Murphy WJ, Welniak L, Back T, et al. Synergistic anti-tumor responses after administration of agonistic antibodies to CD40 and IL-2: coordination of dendritic and CD8+ cell responses. J Immunol. 2003;170(5):2727–2733.
   PubMed Web of Science ®Google Scholar
• Weiss JM, Back TC, Scarzello AJ, et al. Successful immunotherapy with IL-2/anti-CD40 induces the chemokine-mediated mitigation of an immunosuppressive tumor microenvironment. Proc Natl Acad Sci U S A. 2009;106(46):19455–19460.
   PubMed Web of Science ®Google Scholar
• Weiss JM, Subleski JJ, Back T, et al. Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/alphaCD40 therapy. J Immunol. 2014;192(12):5821–5829.
   PubMed Web of Science ®Google Scholar
• Liu C, Lewis CM, Lou Y, et al. Agonistic antibody to CD40 boosts the antitumor activity of adoptively transferred T cells in vivo. J Immunother. 2012;35(3):276–282.
   PubMed Web of Science ®Google Scholar
• Tietze JK, Wilkins DE, Sckisel GD, et al. Delineation of antigen-specific and antigen-nonspecific CD8(+) memory T-cell responses after cytokine-based cancer immunotherapy. Blood. 2012;119(13):3073–3083.
   PubMed Web of Science ®Google Scholar
• Pellat-Deceunynck C, Bataille R, Robillard N, et al. Expression of CD28 and CD40 in human myeloma cells: a comparative study with normal plasma cells. Blood. 1994;84(8):2597–2603.
   PubMed Web of Science ®Google Scholar
• Gruss HJ, Dower SK. Tumor necrosis factor ligand superfamily: involvement in the pathology of malignant lymphomas. Blood. 1995;85(12):3378–3404.
   PubMed Web of Science ®Google Scholar
• Young LS, Eliopoulos AG, Gallagher NJ, et al. CD40 and epithelial cells: across the great divide. Immunol Today. 1998;19(11):502–506.
   PubMedGoogle Scholar
• Elmetwali T, Searle PF, McNeish I, et al. CD40 ligand induced cytotoxicity in carcinoma cells is enhanced by inhibition of metalloproteinase cleavage and delivery via a conditionally-replicating adenovirus. Mol Cancer. 2010;9:52.
   PubMed Web of Science ®Google Scholar
• Law CL, Gordon KA, Collier J, et al. Preclinical antilymphoma activity of a humanized anti-CD40 monoclonal antibody, SGN-40. Cancer Res. 2005;65(18):8331–8338.
   PubMed Web of Science ®Google Scholar
• Szocinski JL, Khaled AR, Hixon J, et al. Activation-induced cell death of aggressive histology lymphomas by CD40 stimulation: induction of bax. Blood. 2002;100(1):217–223.
   PubMed Web of Science ®Google Scholar
• Fanale M, Assouline S, Kuruvilla J, et al. Phase IA/II, multicentre, open-label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non-Hodgkin or Hodgkin lymphoma. Br J Haematol. 2014;164(2):258–265.
   PubMed Web of Science ®Google Scholar
• Oflazoglu E, Stone IJ, Brown L, et al. Macrophages and Fc-receptor interactions contribute to the antitumour activities of the anti-CD40 antibody SGN-40. Br J Cancer. 2009;100(1):113–117.
   PubMed Web of Science ®Google Scholar
• Horton HM, Bernett MJ, Peipp M, et al. Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies. Blood. 2010;116(16):3004–3012.
   PubMed Web of Science ®Google Scholar
• Von Leoprechting A, Van Der Bruggen P, Pahl HL, et al. Stimulation of CD40 on immunogenic human malignant melanomas augments their cytotoxic T lymphocyte-mediated lysis and induces apoptosis. Cancer Res. 1999;59(6):1287–1294.
   PubMed Web of Science ®Google Scholar
• Obeid M, Tesniere A, Ghiringhelli F, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13(1):54–61.
   PubMed Web of Science ®Google Scholar
• Beatty GL, Winograd R, Evans RA, et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6C(low) F4/80(+) extratumoral macrophages. Gastroenterology. 2015;149(1):201–210.
   PubMed Web of Science ®Google Scholar
• Vonderheide RH, Burg JM, Mick R, et al. Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors. Oncoimmunology. 2013;2(1):e23033.
   PubMed Web of Science ®Google Scholar
• Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636–2644.
   PubMed Web of Science ®Google Scholar
• Burris HA III, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403–2413.
   PubMed Web of Science ®Google Scholar
• Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825.
   PubMed Web of Science ®Google Scholar
• Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–1703.
   PubMed Web of Science ®Google Scholar
• Byrne KT, Vonderheide RH. CD40 stimulation obviates innate sensors and drives T cell immunity in cancer. Cell Rep. 2016;15(12):2719–2732.
   PubMed Web of Science ®Google Scholar
• Bajor DL, Mick R, Riese MJ, et al. Abstract CT137: Combination of agonistic CD40 monoclonal antibody CP-870,893 and anti-CTLA-4 antibody tremelimumab in patients with metastatic melanoma. Cancer Res. 2015;75(15 Suppl):Abstract CT137.
   Web of Science ®Google Scholar
• Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31(5):616–622.
   PubMed Web of Science ®Google Scholar
• Winograd R, Byrne KT, Evans RA, et al. Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol Res. 2015;3(4):399–411.
   PubMed Web of Science ®Google Scholar
• Lum HD, Buhtoiarov IN, Schmidt BE, et al. In vivo CD40 ligation can induce T-cell-independent antitumor effects that involve macrophages. J Leukoc Biol. 2006;79(6):1181–1192.
   PubMed Web of Science ®Google Scholar
• Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–1461.
   PubMed Web of Science ®Google Scholar
• Provenzano PP, Cuevas C, Chang AE, et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(3):418–429.
   PubMed Web of Science ®Google Scholar
• Byrne KT, Leisenring NH, Bajor DL, et al. CSF-1R-dependent lethal hepatotoxicity when agonistic CD40 antibody is given before but not after chemotherapy. J Immunol. 2016;197(1):179–187.
   PubMed Web of Science ®Google Scholar