182
Views
0
CrossRef citations to date
0
Altmetric
Review

Challenges and opportunities in the development of combination immunotherapy with OX40 agonists

Pages 901-912 | Received 18 Jul 2023, Accepted 15 Aug 2023, Published online: 20 Aug 2023

References

  • Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23(1):515–548. doi: 10.1146/annurev.immunol.23.021704.115611
  • Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol. 2001;19(1):225–252. doi: 10.1146/annurev.immunol.19.1.225
  • Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol. 1996;14(1):233–258. doi: 10.1146/annurev.immunol.14.1.233
  • Croft M, Duan W, Choi H, et al. TNF superfamily in inflammatory disease: translating basic insights. Trends Immunol. 2012 Mar;33(3):144–152. doi: 10.1016/j.it.2011.10.004
  • Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol. 2005;23(1):23–68. doi: 10.1146/annurev.immunol.23.021704.115839
  • Redmond WL, Ruby CE, Weinberg AD. The role of OX40-mediated co-stimulation in T-cell activation and survival. Crit Rev Immunol. 2009;29(3):187–201. doi: 10.1615/CritRevImmunol.v29.i3.10
  • Croft M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu Rev Immunol. 2010 Mar;28(1):57–78. doi: 10.1146/annurev-immunol-030409-101243
  • So T, Ishii N. The TNF-TNFR family of co-signal molecules. Adv Exp Med Biol. 2019;1189:53–84.
  • Voo KS, Foglietta M, Percivalle E, et al. Selective targeting of toll-like receptors and OX40 inhibit regulatory T-cell function in follicular lymphoma. Int J Cancer. 2014 Dec 15;135(12):2834–2846.
  • Kitamura N, Murata S, Ueki T, et al. OX40 costimulation can abrogate Foxp3+ regulatory T cell-mediated suppression of antitumor immunity. Int J Cancer. 2009 Aug 1;125(3):630–638.
  • Vu MD, Xiao X, Gao W, et al. OX40 costimulation turns off Foxp3+ Tregs. Blood. 2007 Oct 1;110(7):2501–2510.
  • Bulliard Y, Jolicoeur R, Zhang J, et al. OX40 engagement depletes intratumoral Tregs via activating FcgammaRs, leading to antitumor efficacy. Immunol Cell Biol. 2014 Jul;92(6):475–480. doi: 10.1038/icb.2014.26
  • Marabelle A, Kohrt H, Sagiv-Barfi I, et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest. 2013 Jun;123(6):2447–2463. doi: 10.1172/JCI64859
  • Zhang X, Xiao X, Lan P, et al. OX40 costimulation Inhibits Foxp3 expression and Treg induction via BATF3-dependent and independent mechanisms. Cell Rep. 2018 Jul 17;24(3):607–618.
  • Redmond WL, Linch SN, Kasiewicz MJ. Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity. Cancer Immunol Res. 2014 Feb;2(2):142–153. doi: 10.1158/2326-6066.CIR-13-0031-T
  • Ruby CE, Yates MA, Hirschhorn-Cymerman D, et al. cutting edge: OX40 agonists can drive regulatory T cell expansion if the cytokine milieu is right. J Immunol. 2009 Oct 15;183(8):4853–4857.
  • Polesso F, Sarker M, Weinberg AD, et al. OX40 agonist tumor immunotherapy does not impact regulatory T cell suppressive function. J Immunol. 2019 Oct 1;203(7):2011–2019.
  • Turaj AH, Cox KL, Penfold CA, et al. Augmentation of CD134 (OX40)-dependent NK anti-tumour activity is dependent on antibody cross-linking. Sci Rep. 2018 Feb 2;8(1):2278.
  • Nuebling T, Schumacher CE, Hofmann M, et al. The immune checkpoint modulator OX40 and its ligand OX40L in NK-cell immunosurveillance and acute myeloid leukemia. Cancer Immunol Res. 2018 Feb;6(2):209–221. doi: 10.1158/2326-6066.CIR-17-0212
  • McNamara MJ, Kasiewicz MJ, Linch SN, et al. Common gamma chain (gc) cytokines differentially potentiate TNFR family signaling in antigen-activated CD8 + T cells. J Immunother Cancer. 2014;2(1):28. doi: 10.1186/PREACCEPT-1295181861132210
  • Redmond WL, Triplett T, Floyd K, et al. Dual anti-OX40/IL-2 therapy augments tumor immunotherapy via IL-2R-mediated regulation of OX40 expression. PLoS One. 2012;7(4):e34467. doi: 10.1371/journal.pone.0034467
  • Williams CA, Murray SE, Weinberg AD, et al. OX40-mediated differentiation to effector function requires IL-2 receptor signaling but not CD28, CD40, IL-12Rbeta2, or T-bet. J Immunol. 2007 Jun 15;178(12):7694–7702.
  • Gramaglia I, Weinberg AD, Lemon M, et al. Ox-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T cell responses. J Immunol. 1998 Dec 15;161(12):6510–6517.
  • Verdeil G, Puthier D, Nguyen C, et al. STAT5-mediated signals sustain a TCR-initiated gene expression program toward differentiation of CD8 T cell effectors. J Immunol. 2006 Apr 15;176(8):4834–4842.
  • Rogers PR, Song J, Gramaglia I, et al. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity. 2001 Sep;15(3):445–455. doi: 10.1016/S1074-7613(01)00191-1
  • Toennies HM, Green JM, Arch RH. Expression of CD30 and Ox40 on T lymphocyte subsets is controlled by distinct regulatory mechanisms. J Leukocyte Biol. 2004 Feb;75(2):350–357. doi: 10.1189/jlb.0803401
  • Murray SE, Polesso F, Rowe AM, et al. NF-kappaB-inducing kinase plays an essential T cell-intrinsic role in graft-versus-host disease and lethal autoimmunity in mice. J Clin Invest. 2011 Dec;121(12):4775–4786. doi: 10.1172/JCI44943
  • Song J, So T, Croft M. Activation of NF-kappaB1 by OX40 contributes to antigen-driven T cell expansion and survival. J Immunol. 2008 Jun 1;180(11):7240–7248.
  • Xiao X, Balasubramanian S, Liu W, et al. OX40 signaling favors the induction of T(H)9 cells and airway inflammation. Nat Immunol. 2012 Oct;13(10):981–990. doi: 10.1038/ni.2390
  • Song J, So T, Cheng M, et al. Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion. Immunity. 2005 May;22(5):621–631. doi: 10.1016/j.immuni.2005.03.012
  • So T, Croft M. Regulation of PI-3-Kinase and Akt signaling in T lymphocytes and other cells by TNFR family molecules. Front Immunol. 2013;4:139. doi: 10.3389/fimmu.2013.00139
  • Song J, Salek-Ardakani S, Rogers PR, et al. The costimulation-regulated duration of PKB activation controls T cell longevity. Nat Immunol. 2004 Feb;5(2):150–158. doi: 10.1038/ni1030
  • Huddleston CA, Weinberg AD, Parker DC. OX40 (CD134) engagement drives differentiation of CD4+ T cells to effector cells. Eur J Immunol. 2006 May;36(5):1093–1103. doi: 10.1002/eji.200535637
  • Kuriyama H, Watanabe S, Kjaergaard J, et al. Mechanism of third signals provided by IL-12 and OX-40R ligation in eliciting therapeutic immunity following dendritic-tumor fusion vaccination. Cell Immunol. 2006 Sep;243(1):30–40. doi: 10.1016/j.cellimm.2006.11.002
  • Lathrop SK, Huddleston CA, Dullforce PA, et al. A signal through OX40 (CD134) allows anergic, autoreactive T cells to acquire effector cell functions. J Immunol. 2004 Jun 1;172(11):6735–6743.
  • De Smedt T, Smith J, Baum P, et al. Ox40 costimulation enhances the development of T cell responses induced by dendritic cells in vivo. J Immunol. 2002 Jan 15;168(2):661–670.
  • Redmond WL, Gough MJ, Charbonneau B, et al. Defects in the acquisition of CD8 T cell effector function after priming with tumor or soluble antigen can be overcome by the addition of an OX40 agonist. J Immunol. 2007 Dec 1;179(11):7244–7253.
  • Gough MJ, Killeen N, Weinberg AD. Targeting macrophages in the tumour environment to enhance the efficacy of alphaOX40 therapy. Immunology. 2012 Aug;136(4):437–447. doi: 10.1111/j.1365-2567.2012.03600.x
  • Gough MJ, Ruby CE, Redmond WL, et al. OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor. Cancer Res. 2008 Jul 1;68(13):5206–5215.
  • Redmond WL, Weinberg AD. Targeting OX40 and OX40L for the treatment of autoimmunity and cancer. Crit Rev Immunol. 2007;27(5):415–436. doi: 10.1615/CritRevImmunol.v27.i5.20
  • Andarini S, Kikuchi T, Nukiwa M, et al. Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances antitumor immunity of tumor-bearing hosts. Cancer Res. 2004 May 1;64(9):3281–3287.
  • Kjaergaard J, Tanaka J, Kim JA, et al. Therapeutic efficacy of OX-40 receptor antibody depends on tumor immunogenicity and anatomic site of tumor growth. Cancer Res. 2000 Oct 1;60(19):5514–5521.
  • Weinberg AD, Rivera MM, Prell R, et al. Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol. 2000 Feb 15;164(4):2160–2169.
  • Diab A, Hamid O, Thompson JA, et al. A phase I, open-label, dose-escalation study of the OX40 agonist Ivuxolimab in patients with locally advanced or metastatic cancers. Clin Cancer Res. 2022 Jan 1;28(1):71–83.
  • Yadav R, Redmond WL. Current clinical trial landscape of OX40 agonists. Curr Oncol Rep. 2022 Jul;24(7):951–960. doi: 10.1007/s11912-022-01265-5
  • Curti BD, Kovacsovics-Bankowski M, Morris N, et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 2013 Dec 15;73(24):7189–7198. doi: 10.1158/0008-5472.CAN-12-4174
  • Davis EJ, Martin-Liberal J, Kristeleit R, et al. First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors. J Immunother Cancer. 2022 Oct;10(10):e004235. doi: 10.1136/jitc-2021-004235
  • Gutierrez M, Moreno V, Heinhuis KM, et al. OX40 agonist BMS-986178 alone or in combination with Nivolumab and/or ipilimumab in patients with Advanced solid tumors. Clin Cancer Res. 2021 Jan 15;27(2):460–472. doi: 10.1158/1078-0432.CCR-20-1830
  • Choi Y, Shi Y, Haymaker CL, et al. T-cell agonists in cancer immunotherapy. J Immunother Cancer. 2020 Oct;8(2):e000966. doi: 10.1136/jitc-2020-000966
  • Muller D. Targeting co-stimulatory receptors of the TNF superfamily for Cancer immunotherapy. BioDrugs. 2023 Jan;37(1):21–33. doi: 10.1007/s40259-022-00573-3
  • Redmond WL, Gough MJ, Weinberg AD. Ligation of the OX40 co-stimulatory receptor reverses self-Ag and tumor-induced CD8 T-cell anergy in vivo. Eur J Immunol. 2009 Aug;39(8):2184–2194. doi: 10.1002/eji.200939348
  • Redmond WL, Sherman LA. Peripheral tolerance of CD8 T lymphocytes. Immunity. 2005 Mar;22(3):275–284. doi: 10.1016/j.immuni.2005.01.010
  • Schwartz RH. T cell anergy. Annu Rev Immunol. 2003;21(1):305–334. doi: 10.1146/annurev.immunol.21.120601.141110
  • Wei SC, Levine JH, Cogdill AP, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell. 2017 Sep 7;170(6):1120–1133 e17.
  • Guo Z, Wang X, Cheng D, et al. PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS One. 2014;9(2):e89350. doi: 10.1371/journal.pone.0089350
  • Li W, Zhang X, Zhang C, et al. Biomimetic nanoparticles deliver mRnas encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy. Nat Commun. 2021 Dec 14;12(1):7264.
  • Ma Y, Li J, Wang H, et al. Combination of PD-1 inhibitor and OX40 agonist induces tumor rejection and immune memory in mouse models of pancreatic Cancer. Gastroenterology. 2020 Jul;159(1):306–319 e12. doi: 10.1053/j.gastro.2020.03.018
  • Messenheimer DJ, Jensen SM, Afentoulis ME, et al. Timing of PD-1 blockade is critical to effective combination immunotherapy with anti-OX40. Clin Cancer Res. 2017 Oct 15;23(20):6165–6177. doi: 10.1158/1078-0432.CCR-16-2677
  • Wang R, Gao C, Raymond M, et al. An Integrative approach to Inform optimal administration of OX40 agonist antibodies in patients with Advanced solid tumors. Clin Cancer Res. 2019 Nov 15;25(22):6709–6720.
  • Emerson DA, Rolig AS, Redmond WL. Enhancing the generation of Eomes(hi) CD8(+) T cells augments the efficacy of OX40- and CTLA-4-Targeted immunotherapy. Cancer Immunol Res. 2021 Apr;9(4):430–440. doi: 10.1158/2326-6066.CIR-20-0338
  • Linch SN, Kasiewicz MJ, McNamara MJ, et al. Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice. Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):E319–27.
  • Shrikant P, Khoruts A, Mescher MF. CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism. Immunity. 1999 Oct;11(4):483–493. doi: 10.1016/S1074-7613(00)80123-5
  • Kim TW, Burris HA, de Miguel Luken MJ, et al. First-in-human phase I study of the OX40 agonist MOXR0916 in patients with Advanced solid tumors. Clin Cancer Res. 2022 Aug 15;28(16):3452–3463.
  • Hamid O, Chiappori AA, Thompson JA, et al. First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors. J Immunother Cancer. 2022 Oct;10(10):e005471. doi: 10.1136/jitc-2022-005471
  • Postel-Vinay S, Lam VK, Ros W, et al. First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1). J Immunother Cancer. 2023 Mar;11(3):e005301. doi: 10.1136/jitc-2022-005301
  • Goldman JW, Piha-Paul SA, Curti B, et al. Safety and tolerability of MEDI0562, an OX40 agonist mAb, in combination with Durvalumab or tremelimumab in adult patients with Advanced solid tumors. Clin Cancer Res. 2022 Sep 1;28(17):3709–3719. doi: 10.1158/1078-0432.CCR-21-3016
  • Short NJ, Borthakur G, Pemmaraju N, et al. A multi-arm phase Ib/II study designed for rapid, parallel evaluation of novel immunotherapy combinations in relapsed/refractory acute myeloid leukemia. Leuk Lymphoma. 2022 Sep;63(9):2161–2170. doi: 10.1080/10428194.2022.2062345
  • Shrimali RK, Ahmad S, Verma V, et al. Concurrent PD-1 blockade negates the effects of OX40 agonist antibody in combination immunotherapy through inducing T-cell apoptosis. Cancer Immunol Res. 2017 Sep;5(9):755–766. doi: 10.1158/2326-6066.CIR-17-0292
  • Duhen R, Ballesteros-Merino C, Frye AK, et al. Neoadjuvant anti-OX40 (MEDI6469) therapy in patients with head and neck squamous cell carcinoma activates and expands antigen-specific tumor-infiltrating T cells. Nat Commun. 2021 Feb 16;12(1):1047.
  • Evans DE, Prell RA, Thalhofer CJ, et al. Engagement of OX40 enhances antigen-specific CD4(+) T cell mobilization/memory development and humoral immunity: comparison of alphaOX-40 with alphaCTLA-4. J Immunol. 2001 Dec 15;167(12):6804–6811.
  • Weinberg AD, Thalhofer C, Morris N, et al. Anti-OX40 (CD134) administration to nonhuman primates: immunostimulatory effects and toxicokinetic study. J Immunother. 2006 Nov;29(6):575–585. doi: 10.1097/01.cji.0000211319.00031.fc
  • Oberst MD, Auge C, Morris C, et al. Potent immune modulation by MEDI6383, an engineered human OX40 ligand IgG4P Fc fusion protein. Mol Cancer Ther. 2018 May;17(5):1024–1038. doi: 10.1158/1535-7163.MCT-17-0200
  • Ruby CE, Montler R, Zheng R, et al. IL-12 is required for anti-OX40-mediated CD4 T cell survival. J Immunol. 2008 Feb 15;180(4):2140–2148.
  • Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003 Feb;3(2):133–146. doi: 10.1038/nri1001
  • Ruby CE, Weinberg AD. OX40-enhanced tumor rejection and effector T cell differentiation decreases with age. J Immunol. 2009 Feb 1;182(3):1481–1489.
  • Nanni P, De Giovanni C, Burocchi A, et al. OX40 triggering concomitant to IL12-engineered cell vaccine hampers the immunoprevention of HER2/neu-driven mammary carcinogenesis. Oncoimmunology. 2018;7(8):e1465164. doi: 10.1080/2162402X.2018.1465164
  • Propper DJ, Balkwill FR. Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol. 2022 Apr;19(4):237–253. doi: 10.1038/s41571-021-00588-9
  • Lou Y, Liu C, Lizee G, et al. Antitumor activity mediated by CpG: the route of administration is critical. J Immunother. 2011 Apr;34(3):279–288. doi: 10.1097/CJI.0b013e31820d2a05
  • Weigel BJ, Rodeberg DA, Krieg AM, et al. CpG oligodeoxynucleotides potentiate the antitumor effects of chemotherapy or tumor resection in an orthotopic murine model of rhabdomyosarcoma. Clin Cancer Res. 2003 Aug 1;9(8):3105–3114.
  • Kerkmann M, Rothenfusser S, Hornung V, et al. Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells. J Immunol. 2003 May 1;170(9):4465–4474.
  • Takauji R, Iho S, Takatsuka H, et al. CpG-DNA-induced IFN-alpha production involves p38 MAPK-dependent STAT1 phosphorylation in human plasmacytoid dendritic cell precursors. J Leukocyte Biol. 2002 Nov;72(5):1011–1019. doi: 10.1189/jlb.72.5.1011
  • Sagiv-Barfi I, Czerwinski DK, Levy S, et al. Eradication of spontaneous malignancy by local immunotherapy. Sci Transl Med. 2018 Jan 31;10(426). doi: 10.1126/scitranslmed.aan4488
  • Houot R, Levy R. T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy. Blood. 2009 Apr 9;113(15):3546–3552.
  • Hong WX, Sagiv-Barfi I, Czerwinski DK, et al. Neoadjuvant intratumoral immunotherapy with TLR9 activation and anti-OX40 antibody eradicates metastatic Cancer. Cancer Res. 2022 Apr 1;82(7):1396–1408.
  • Sagiv-Barfi I, Czerwinski DK, Shree T, et al. Intratumoral immunotherapy relies on B and T cell collaboration. Sci Immunol. 2022 May 27;7(71):eabn5859.
  • van der Sluis TC, Beyrend G, van der Gracht ETI, et al. OX40 agonism enhances PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum. Cell Rep Med. 2023 Mar 21;4(3):100939.
  • McLaughlin M, Patin EC, Pedersen M, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer. 2020 Apr;20(4):203–217. doi: 10.1038/s41568-020-0246-1
  • Deng L, Liang H, Xu M, et al. STING-Dependent cytosolic DNA sensing promotes Radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014 Nov 20;41(5):843–852.
  • Gough MJ, Crittenden MR, Sarff M, et al. Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control after surgical or radiation therapy of cancer in mice. J Immunother. 2010 Oct;33(8):798–809. doi: 10.1097/CJI.0b013e3181ee7095
  • Niknam S, Barsoumian HB, Schoenhals JE, et al. Radiation followed by OX40 stimulation drives local and abscopal antitumor effects in an anti-PD1-resistant lung tumor model. Clin Cancer Res. 2018 Nov 15;24(22):5735–5743.
  • Young KH, Baird JR, Savage T, et al. Optimizing timing of immunotherapy improves control of tumors by hypofractionated Radiation therapy. PLoS One. 2016;11(6):e0157164. doi: 10.1371/journal.pone.0157164
  • Tormoen GW, Blair TC, Bambina S, et al. Targeting MerTK enhances adaptive immune responses after Radiation therapy. Int J Radiat Oncol Biol Phys. 2020 Sep 1;108(1):93–103.
  • Pieper AA, Zangl LM, Speigelman DV, et al. Radiation augments the local anti-tumor effect of in situ vaccine with CpG-Oligodeoxynucleotides and anti-OX40 in immunologically cold tumor models. Front Immunol. 2021;12:763888. doi: 10.3389/fimmu.2021.763888
  • Younes AI, Barsoumian HB, Sezen D, et al. Addition of TLR9 agonist immunotherapy to radiation improves systemic antitumor activity. Transl Oncol. 2021 Feb;14(2):100983. doi: 10.1016/j.tranon.2020.100983
  • Frank MJ, Reagan PM, Bartlett NL, et al. In situ vaccination with a TLR9 agonist and local low-dose Radiation induces systemic responses in untreated indolent lymphoma. Cancer Discov. 2018 Oct;8(10):1258–1269. doi: 10.1158/2159-8290.CD-18-0743
  • Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol. 2003 Aug;3(8):609–620. doi: 10.1038/nri1148
  • Melero I, Hirschhorn-Cymerman D, Morales-Kastresana A, et al. Agonist antibodies to TNFR molecules that costimulate T and NK cells. Clin Cancer Res. 2013 Mar 1;19(5):1044–1053.
  • Qui HZ, Hagymasi AT, Bandyopadhyay S, et al. CD134 plus CD137 dual costimulation induces eomesodermin in CD4 T cells to program cytotoxic Th1 differentiation. J Immunol. 2011 Oct 1;187(7):3555–3564.
  • Cuadros C, Dominguez AL, Lollini PL, et al. Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice. Int J Cancer. 2005 Oct 10;116(6):934–943.
  • Van Braeckel-Budimir N, Dolina JS, Wei J, et al. Combinatorial immunotherapy induces tumor-infiltrating CD8 + T cells with distinct functional, migratory, and stem-like properties. J Immunother Cancer. 2021 Dec;9(12):e003614. doi: 10.1136/jitc-2021-003614
  • Gray JC, French RR, James S, et al. Optimising anti-tumour CD8 T-cell responses using combinations of immunomodulatory antibodies. Eur J Immunol. 2008 Sep;38(9):2499–2511. doi: 10.1002/eji.200838208
  • Pan PY, Zang Y, Weber K, et al. OX40 ligation enhances primary and memory cytotoxic T lymphocyte responses in an immunotherapy for hepatic colon metastases. Mol Ther. 2002 Oct;6(4):528–536. doi: 10.1006/mthe.2002.0699
  • Boyman O, Kovar M, Rubinstein MP, et al. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science. 2006 Mar 31;311(5769):1924–1927.
  • Leonard WJ, Lin JX, O’Shea JJ. The gamma(c) family of cytokines: basic biology to therapeutic ramifications. Immunity. 2019 Apr 16;50(4):832–850.
  • Doberstein SK. Bempegaldesleukin (NKTR-214): a CD-122-biased IL-2 receptor agonist for cancer immunotherapy. Expert Opin Biol Ther. 2019 Dec;19(12):1223–1228. doi: 10.1080/14712598.2019.1685489
  • Mitra S, Leonard WJ. Biology of IL-2 and its therapeutic modulation: mechanisms and strategies. J Leukocyte Biol. 2018 Apr;103(4):643–655. doi: 10.1002/JLB.2RI0717-278R
  • Payne R, Glenn L, Hoen H, et al. Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and renal cancer in a community hospital biotherapy program. J Immunother Cancer. 2014;2(1):13. doi: 10.1186/2051-1426-2-13
  • Hewitt SL, Bai A, Bailey D, et al. Durable anticancer immunity from intratumoral administration of IL-23, IL-36gamma, and OX40L mRNAs. Sci Transl Med. 2019 Jan 30;11(477). doi: 10.1126/scitranslmed.aat9143
  • Banerjee A, Gordon SM, Intlekofer AM, et al. Cutting edge: the transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche. J Immunol. 2010 Nov 1;185(9):4988–4992.
  • Zhu Y, Ju S, Chen E, et al. T-bet and eomesodermin are required for T cell-mediated antitumor immune responses. J Immunol. 2010 Sep 15;185(6):3174–3183.
  • Intlekofer AM, Takemoto N, Wherry EJ, et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol. 2005 Dec;6(12):1236–1244. doi: 10.1038/ni1268
  • Pearce EL, Mullen AC, Martins GA, et al. Control of effector CD8+ T cell function by the transcription factor eomesodermin. Science. 2003 Nov 7;302(5647):1041–1043.
  • Nayar R, Schutten E, Jangalwe S, et al. IRF4 regulates the ratio of T-Bet to eomesodermin in CD8+ T cells responding to persistent LCMV Infection. PLoS One. 2015;10(12):e0144826. doi: 10.1371/journal.pone.0144826
  • Nayar R, Enos M, Prince A, et al. TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation. Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):E2794–802.
  • Zhang Y, Chung SF, Tam SY, et al. Arginine deprivation as a strategy for cancer therapy: an insight into drug design and drug combination. Cancer Lett. 2021 Apr 1;502:58–70.
  • Badeaux MD, Rolig AS, Agnello G, et al. Arginase therapy combines effectively with immune checkpoint blockade or agonist anti-OX40 immunotherapy to Control tumor growth. Cancer Immunol Res. 2021 Apr;9(4):415–429. doi: 10.1158/2326-6066.CIR-20-0317
  • Werner A, Koschke M, Leuchtner N, et al. Reconstitution of T cell proliferation under arginine limitation: activated human T cells take up citrulline via l-type amino acid transporter 1 and use it to regenerate arginine after induction of argininosuccinate synthase expression. Front Immunol. 2017;8:864. doi: 10.3389/fimmu.2017.00864
  • Henderson NC, Sethi T. The regulation of inflammation by galectin-3. Immunol Rev. 2009 Jul;230(1):160–171. doi: 10.1111/j.1600-065X.2009.00794.x
  • Nangia-Makker P, Balan V, Raz A. Regulation of tumor progression by extracellular galectin-3. Cancer Microenviron. 2008 Dec;1(1):43–51. doi: 10.1007/s12307-008-0003-6
  • Krzeslak A, Lipinska A. Galectin-3 as a multifunctional protein. Cell Mol Biol Lett. 2004;9(2):305–328.
  • Farhad M, Rolig AS, Redmond WL. The role of galectin-3 in modulating tumor growth and immunosuppression within the tumor microenvironment. Oncoimmunology. 2018;7(6):e1434467. doi: 10.1080/2162402X.2018.1434467
  • Gordon-Alonso M, Hirsch T, Wildmann C, et al. Galectin-3 captures interferon-gamma in the tumor matrix reducing chemokine gradient production and T-cell tumor infiltration. Nat Commun. 2017 Oct 6;8(1):793.
  • Jia W, Kidoya H, Yamakawa D, et al. Galectin-3 accelerates M2 macrophage infiltration and angiogenesis in tumors. Am J Pathol. 2013 May;182(5):1821–1831. doi: 10.1016/j.ajpath.2013.01.017
  • Braeuer RR, Zigler M, Kamiya T, et al. Galectin-3 contributes to melanoma growth and metastasis via regulation of NFAT1 and autotaxin. Cancer Res. 2012 Nov 15;72(22):5757–5766.
  • Song S, Ji B, Ramachandran V, et al. Overexpressed galectin-3 in pancreatic cancer induces cell proliferation and invasion by binding Ras and activating Ras signaling. PLoS One. 2012;7(8):e42699. doi: 10.1371/journal.pone.0042699
  • Wang YG, Kim SJ, Baek JH, et al. Galectin-3 increases the motility of mouse melanoma cells by regulating matrix metalloproteinase-1 expression. Exp Mol Med. 2012 Jun 30;44(6):387–393.
  • Chen HY, Fermin A, Vardhana S, et al. Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14496–14501.
  • Hsu DK, Chen HY, Liu FT. Galectin-3 regulates T-cell functions. Immunol Rev. 2009 Jul;230(1):114–127. doi: 10.1111/j.1600-065X.2009.00798.x
  • Compagno D, Laderach DJ, Gentilini L, et al. Delineating the “galectin signature” of the tumor microenvironment. Oncoimmunology. 2013 Apr 01;2(4):e23565.
  • Rabinovich GA, Toscano MA. Turning ‘sweet’ on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nat Rev Immunol. 2009 May;9(5):338–352. doi: 10.1038/nri2536
  • MacKinnon AC, Farnworth SL, Hodkinson PS, et al. Regulation of alternative macrophage activation by galectin-3. J Immunol. 2008 Feb 15;180(4):2650–2658.
  • Curti BD, Koguchi Y, Leidner RS, et al. Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor. J Immunother Cancer. 2021 Apr;9(4):e002371. doi: 10.1136/jitc-2021-002371
  • Sturgill ER, Rolig AS, Linch SN, et al. Galectin-3 inhibition with belapectin combined with anti-OX40 therapy reprograms the tumor microenvironment to favor anti-tumor immunity. Oncoimmunology. 2021 Mar 1;10(1):1892265.
  • Vuong L, Kouverianou E, Rooney CM, et al. An orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and augments response to PD-L1 blockade. Cancer Res. 2019 Apr 1;79(7):1480–1492.
  • Berrong Z, Mkrtichyan M, Ahmad S, et al. Antigen-specific antitumor responses induced by OX40 agonist are enhanced by the IDO inhibitor Indoximod. Cancer Immunol Res. 2018 Feb;6(2):201–208. doi: 10.1158/2326-6066.CIR-17-0223
  • Murphy KA, Erickson JR, Johnson CS, et al. CD8+ T cell-independent tumor regression induced by Fc-OX40L and therapeutic vaccination in a mouse model of glioma. J Immunol. 2014 Jan 01;192(1):224–233.
  • Biagi E, Dotti G, Yvon E, et al. Molecular transfer of CD40 and OX40 ligands to leukemic human B cells induces expansion of autologous tumor-reactive cytotoxic T lymphocytes. Blood. 2005 Mar 15;105(6):2436–2442.
  • Ali SA, Ahmad M, Lynam J, et al. Anti-tumour therapeutic efficacy of OX40L in murine tumour model. Vaccine. 2004 Sep 9;22(27–28):3585–3594.
  • Gri G, Gallo E, Di Carlo E, et al. OX40 ligand-transduced tumor cell vaccine synergizes with GM-CSF and requires CD40-Apc signaling to boost the host T cell antitumor response. J Immunol. 2003 Jan 1;170(1):99–106.
  • Kinkead HL, Hopkins A, Lutz E, et al. Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer. JCI Insight. 2018 Oct 18;3(20): doi: 10.1172/jci.insight.122857
  • Foote JB, Kok M, Leatherman JM, et al. A STING agonist given with OX40 receptor and PD-L1 modulators primes immunity and reduces tumor growth in tolerized mice. Cancer Immunol Res. 2017 Jun;5(6):468–479. doi: 10.1158/2326-6066.CIR-16-0284
  • Yu G, Li Y, Cui Z, et al. Combinational immunotherapy with Allo-DRibble vaccines and anti-OX40 co-stimulation leads to generation of cross-reactive effector T cells and tumor regression. Sci Rep. 2016 Nov 22;6(1):37558.
  • Rojas LA, Sethna Z, Soares KC, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 2023 Jun;618(7963):144–150. doi: 10.1038/s41586-023-06063-y
  • Awad MM, Govindan R, Balogh KN, et al. Personalized neoantigen vaccine NEO-PV-01 with chemotherapy and anti-PD-1 as first-line treatment for non-squamous non-small cell lung cancer. Cancer Cell. 2022 Sep 12;40(9):1010–1026 e11.
  • Palmer CD, Rappaport AR, Davis MJ, et al. Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results. Nat Med. 2022 Aug;28(8):1619–1629. doi: 10.1038/s41591-022-01937-6
  • Duhen T, Duhen R, Montler R, et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat Commun. 2018 Jul 13;9(1):2724.
  • Fabian KP, Padget MR, Fujii R, et al. Differential combination immunotherapy requirements for inflamed (warm) tumors versus T cell excluded (cool) tumors: engage, expand, enable, and evolve. J Immunother Cancer. 2021 Feb;9(2):e001691. doi: 10.1136/jitc-2020-001691

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.