Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists

Expert Review of Anticancer Therapy

Volumn 17, Issue 2, 2017, Pages 175-186

  Beatty, Gregory L ^a   Li, Yan ^a   Long, Kristen B ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

cancer; CD40 agonists; chemotherapy; clinical trials; macrophages; T cells

Indexed keywords

ADC 1013; ADENOVIRUS VECTOR; APX 005; CARBOPLATIN; CD40 AGONIST; CD40 LIGAND; CHILOB 7 4; CISPLATIN; CP 870893; CYCLOPHOSPHAMIDE; DACETUZUMAB; FC RECEPTOR; GEMCITABINE; LUCATUMUMAB; MONOCLONAL ANTIBODY; PACLITAXEL; PEMETREXED; PEPTIDE VACCINE; RECOMBINANT HUMAN CD40 LIGAND; SEA CD40; TICILIMUMAB; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; CD40 ANTIGEN; TUMOR MARKER;

ADAPTIVE IMMUNITY; ADOPTIVE TRANSFER; ADVANCED CANCER; ANEMIA; ANTIGEN EXPRESSION; ANTIGEN SPECIFICITY; ANTINEOPLASTIC ACTIVITY; AUTOIMMUNE DISEASE; BLADDER CANCER; BLADDER CARCINOMA; CANCER IMMUNOTHERAPY; CANCER RESISTANCE; CELLULAR IMMUNITY; CHILL; CLINICAL TRIAL (TOPIC); COLITIS; CYTOKINE RELEASE SYNDROME; DERMATITIS; DRUG DESIGN; DRUG EFFICACY; DRUG MONITORING; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; EYE INFLAMMATION; FEVER; HODGKIN DISEASE; HUMAN; HYPERTRANSAMINASEMIA; HYPOPHYSITIS; IMMUNOMODULATION; IMMUNOSTIMULATION; IMMUNOSURVEILLANCE; IN VIVO STUDY; INFUSION RELATED REACTION; INNATE IMMUNITY; LIVER TOXICITY; LOW DRUG DOSE; MELANOMA; MESOTHELIOMA; METASTATIC MELANOMA; NONHODGKIN LYMPHOMA; NONHUMAN; OUTCOME ASSESSMENT; PANCREAS CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PLEURA EFFUSION; PLEURA MESOTHELIOMA; PROTEIN MODIFICATION; REVIEW; RIGOR; RISK BENEFIT ANALYSIS; SINGLE DRUG DOSE; SOLID TUMOR; THROMBOCYTOPENIA; THROMBOEMBOLISM; THYROIDITIS; TREATMENT RESPONSE; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; VIRAL GENE DELIVERY SYSTEM; VIRAL GENE THERAPY; AGONISTS; ANIMAL; IMMUNOLOGY; IMMUNOTHERAPY; METABOLISM; NEOPLASMS; PATHOLOGY; PROCEDURES;

ADAPTIVE IMMUNITY; ANIMALS; ANTIGENS, CD40; ANTINEOPLASTIC AGENTS; BIOMARKERS, TUMOR; DRUG DESIGN; HUMANS; IMMUNITY, INNATE; IMMUNOTHERAPY; NEOPLASMS; RECEPTORS, FC;

EID: 85010917048     PISSN: 14737140     EISSN: 17448328     Source Type: Journal    
DOI: 10.1080/14737140.2017.1270208     Document Type: Review

References (95)

1. 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.
2. 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.
3. Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res. 2015;21(4):687–692.
4. 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.
5. 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.
6. Hess S, Engelmann H. A novel function of CD40:induction of cell death in transformed cells. J Exp Med. 1996;183(1):159–167.
7. + cytolytic T cell responses.
8. 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.•• This paper showed that signaling through CD40 on antigen presenting cells was critical for providing T cell help in the stimulation of antigen-specific cytotoxic T cells.
9. 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.•• This study revealed that dendritic cells activated via CD40 signaling or viral infection could stimulate the generation of cytolytic T cells without the need for CD4 T cell help.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. Lanzavecchia A. Immunology. Licence to kill. Nature. 1998;393(6684):413–414.
17. 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.•• This paper demonstrated that CD40 agonists could be used to overcome T cell tolerance against tumor-derived antigens.
18. 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.•• This study demonstrated that an agonist CD40 mAb could induce T cell-dependent eradication of large established lymphomas in mice without the need for CD4 T cell help.
19. 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.•• This paper revealed a role for CD40-CD40 ligand interactions in defining T cell tolerance versus priming to tumor antigens.
20. 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.
21. Armitage RJ, Fanslow WC, Strockbine L, et al. Molecular and biological characterization of a murine ligand for CD40. Nature. 1992;357(6373):80–82.
22. 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.
23. 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.
24. 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.•• The first clinical study of an agonistic CD40 antibody conducted in patients with advanced solid malignancies showed safety and promising clinical activity.
25. 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.•• This paper demonstrated in humans and mice that CD40 agonists could invoke productive immunosurveillance in cancer that was dependent on macrophages.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. Li F, Ravetch JV. Inhibitory Fcgamma receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science. 2011;333(6045):1030–1034.
33. 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.
34. 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.
35. 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.
36. 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.•• This paper describes a novel humanized mouse model for evaluating CD40 agonists and demonstrates a role for the Fc region of an agonist CD40 mAb in defining its T cell stimulatory capacity.
37. Smith KG, Clatworthy MR. FcgammaRIIB in autoimmunity and infection:evolutionary and therapeutic implications. Nat Rev Immunol. 2010;10(5):328–343.
38. 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.•• This paper demonstrates that crosslinking of CD40 antibodies by either activatory or inhibitory FcRs is critical for its in vivo potency and shows that alternative strategies using chemical crosslinking can produce activity that is Fc independent.
39. Bedian V, Gladue RP, Corvalan J, et al. Methods of treating cancer and enhancing immune responses with antibodies that bind CD40. US7338660. 2008.
40. Zhang Y, Yu G, Zhu W, Anti-cd40 antibodies and methods of use. WO2014070934. 2014.
41. 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.
42. 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.•• This paper demonstrates that preexisting activation of the CD40 pathway and DNA damage are critical determinants of the direct cytotoxic effects of CD40 antibodies in B cell lymphomas.
43. 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.
44. 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.
45. 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.
46. 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.
47. 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.
48. 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.
49. 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.
50. 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.
51. 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.
52. 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.
53. 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.
54. 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.
55. 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.
56. 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.
57. 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.
58. 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.
59. 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.
60. 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.
61. Cho HI, Celis E. Optimized peptide vaccines eliciting extensive CD8 T-cell responses with therapeutic antitumor effects. Cancer Res. 2009;69(23):9012–9019.
62. 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.
63. 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.
64. 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.
65. 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.
66. 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.
67. 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.
68. 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.
69. 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.
70. 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.
71. 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.
72. Gruss HJ, Dower SK. Tumor necrosis factor ligand superfamily:involvement in the pathology of malignant lymphomas. Blood. 1995;85(12):3378–3404.
73. Young LS, Eliopoulos AG, Gallagher NJ, et al. CD40 and epithelial cells:across the great divide. Immunol Today. 1998;19(11):502–506.
74. 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.
75. 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.
76. 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.
77. 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.
78. 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.
79. 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.
80. 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.
81. Obeid M, Tesniere A, Ghiringhelli F, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13(1):54–61.
82. 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.
83. 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.
84. 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.
85. 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.
86. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825.
87. 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.
88. Byrne KT, Vonderheide RH. CD40 stimulation obviates innate sensors and drives T cell immunity in cancer. Cell Rep. 2016;15(12):2719–2732.
89. 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.
90. 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.
91. 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.
92. 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.
93. 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.
94. 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.
95. 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.