The advent of immune checkpoint inhibition (ICI) using antibodies against PD1 and its ligand PDL1 has prompted substantial efforts to develop complementary drugs. Although many of these are antibodies directed against additional checkpoint proteins, there is an increasing interest in small-molecule immuno-oncology drugs that address intracellular pathways, some of which have recently entered clinical trials. In parallel, small molecules that target pro-tumorigenic pathways in cancer cells and the tumour microenvironment have been found to have immunostimulatory effects that synergize with the action of ICI antibodies, leading to the approval of an increasing number of regimens that combine such drugs. Combinations with small molecules targeting cancer metabolism, cytokine/chemokine and innate immune pathways, and T cell checkpoints are now under investigation. This Review discusses the recent milestones and hurdles encountered in this area of drug development, as well as our views on the best path forward.
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Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).
Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).
Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).
Goebeler, M. E. & Bargou, R. C. T cell-engaging therapies — BiTEs and beyond. Nat. Rev. Clin. Oncol. 17, 418–434 (2020).
Sanmamed, M. F. et al. Agonists of co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin. Oncol. 42, 640–655 (2015).
Vonderheide, R. H. & Glennie, M. J. Agonistic CD40 antibodies and cancer therapy. Clin. Cancer Res. 19, 1035–1043 (2013).
Haanen, J. B. A. G. et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 28, iv119–iv142 (2017).
Ramos-Casals, M. et al. Immune-related adverse events of checkpoint inhibitors. Nat. Rev. Dis. Prim. 6, 38 (2020).
Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).
Galluzzi, L. et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J. Immunother. Cancer 8, e000337 (2020).
Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).
Ménétrier-Caux, C., Ray-Coquard, I., Blay, J.-Y. & Caux, C. Lymphopenia in cancer patients and its effects on response to immunotherapy: an opportunity for combination with cytokines? J. Immunother. Cancer 7, 85 (2019).
Lito, P., Rosen, N. & Solit, D. B. Tumor adaptation and resistance to RAF inhibitors. Nat. Med. 19, 1401–1409 (2013).
Caunt, C. J., Sale, M. J., Smith, P. D. & Cook, S. J. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat. Rev. Cancer 15, 577–592 (2015).
Ribas, A. et al. Extended 5-year follow-up results of a phase Ib study (BRIM7) of vemurafenib and cobimetinib in BRAF-mutant melanoma. Clin. Cancer Res. 26, 46 (2020).
Robert, C. et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N. Engl. J. Med. 381, 626–636 (2019).
Garbe, C. et al. European consensus-based interdisciplinary guideline for melanoma. Part 2: treatment–update 2019. Eur. J. Cancer 126, 159–177 (2020).
Ribas, A. et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat. Med. 25, 936–940 (2019).
Sullivan, R. J. et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat. Med. 25, 929–935 (2019).
Hu-Lieskovan, S. et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma. Sci. Transl. Med. 7, 279ra241 (2015). First preclinical evidence of the pro-immunogenic impact of MEK inhibitors.
Ebert, P. J. R. et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44, 609–621 (2016).
Dushyanthen, S. et al. Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer. Nat. Commun. 8, 606 (2017).
Baumann, D. et al. Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy. Nat. Commun. 11, 2176 (2020).
Baumann, D. et al. p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition. J. Immunother. Cancer 9, e002319 (2021).
Dörrie, J. et al. BRAF and MEK inhibitors influence the function of reprogrammed T cells: consequences for adoptive T-cell therapy. Int. J. Mol. Sci. 19, 289 (2018).
Ferrucci, P. F. et al. KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma. J. Immunother. Cancer 8, e001806 (2020).
Gutzmer, R. et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 395, 1835–1844 (2020). Clinical trial that fulfilled the concept of synergy between MEK/BRAF inhibition and ICI, resulting in FDA approval of this triple regimen for BRAF-mutated melanoma.
Dummer, R. et al. Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. Nat. Med. 26, 1557–1563 (2020).
Dummer, R. et al. Randomized phase III trial evaluating spartalizumab plus dabrafenib and trametinib for BRAF V600-mutant unresectable or metastatic melanoma. J. Clin. Oncol. 40, 1428–1438 (2022).
Canon, J. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019). First preclinical evidence for synergy of a mutant-KRAS-specific drug with ICI.
Briere, D. M. et al. The KRAS(G12C) inhibitor MRTX849 reconditions the tumor immune microenvironment and sensitizes tumors to checkpoint inhibitor therapy. Mol. Cancer Ther. 20, 975–985 (2021).
Łuksza, M. et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 551, 517–520 (2017).
Eng, C. et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 20, 849–861 (2019).
Haigis, K. M. KRAS alleles: the devil is in the detail. Trends Cancer 3, 686–697 (2017).
Hack, S. P., Zhu, A. X. & Wang, Y. Augmenting anticancer immunity through combined targeting of angiogenic and PD-1/PD-L1 pathways: challenges and opportunities. Front. Immunol. 11, 598877 (2020).
Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018). The clinical study presented in this paper is the first to show clinical benefit of combining a drug that inhibits the VEGF/VEGFR pathway with ICI. Although this study provided proof of concept for the VEGF-blocking Ab bevacizumab, the two publications below demonstrate that this synergy could also be achieved by using small-molecule VEGFR inhibitor axitinib.
Motzer, R. J. et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1103–1115 (2019).
Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).
Choueiri, T. K. et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 384, 829–841 (2021).
Motzer, R. et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N. Engl. J. Med. 384, 1289–1300 (2021).
Briukhovetska, D. et al. Interleukins in cancer: from biology to therapy. Nat. Rev. Cancer 21, 481–499 (2021).
Conlon, K. C., Miljkovic, M. D. & Waldmann, T. A. Cytokines in the treatment of cancer. J. Interferon Cytokine Res. 39, 6–21 (2019).
Hu, X., Li, J., Fu, M., Zhao, X. & Wang, W. The JAK/STAT signaling pathway: from bench to clinic. Signal. Transduct. Target. Ther. 6, 402 (2021).
Setrerrahmane, S. & Xu, H. Tumor-related interleukins: old validated targets for new anti-cancer drug development. Mol. Cancer 16, 153 (2017).
Derynck, R., Turley, S. J. & Akhurst, R. J. TGFβ biology in cancer progression and immunotherapy. Nat. Rev. Clin. Oncol. 18, 9–34 (2021).
Ouyang, W. & O’Garra, A. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. Immunity 50, 871–891 (2019).
Cannarile, M. A. et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J. Immunother. Cancer 5, 53 (2017).
Osipov, A., Saung, M. T., Zheng, L. & Murphy, A. G. Small molecule immunomodulation: the tumor microenvironment and overcoming immune escape. J. Immunother. Cancer 7, 224 (2019).
Harb, W. A. et al. A phase 1b/2 study of ARRY-382, an oral inhibitor of colony stimulating factor 1 receptor (CSF1R), in combination with pembrolizumab (Pembro) for the treatment of patients (Pts) with advanced solid tumors. J. Clin. Oncol. 35, TPS3110 (2017).
Pfizer. A study of ARRY-382 in combination with pembrolizumab for the treatment of patients with advanced solid tumors: https://www.pfizer.com/study-arry-382-combination-pembrolizumab-treatment-patients-advanced-solid-tumors, (2022).
Smith, B. D. et al. Vimseltinib: a precision CSF1R therapy for tenosynovial giant cell tumors and diseases promoted by macrophages. Mol. Cancer Ther. 20, 2098–2109 (2021).
Gelderblom, H. et al. Safety and preliminary efficacy of vimseltinib in tenosynovial giant cell tumor (TGCT). Ann. Oncol. 32, S1233–S1234 (2021). EMSO Congress 2021, Abstr. 1821P.
Strachan, D. C. et al. CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells. Oncoimmunology 2, e26968 (2013).
Lin, C.-C. et al. Phase I study of BLZ945 alone and with spartalizumab (PDR001) in patients (pts) with advanced solid tumors. J. Clin. Oncol. 80 (Suppl. 16), CT171 (2020).
Balkwill, F. Cancer and the chemokine network. Nat. Rev. Cancer 4, 540–550 (2004).
Keeley, E. C., Mehrad, B. & Strieter, R. M. CXC chemokines in cancer angiogenesis and metastases. Adv. Cancer Res. 106, 91–111 (2010).
Miao, M., De Clercq, E. & Li, G. Clinical significance of chemokine receptor antagonists. Expert. Opin. Drug Metab. Toxicol. 16, 11–30 (2020).
Poeta, V. M., Massara, M., Capucetti, A. & Bonecchi, R. Chemokines and chemokine receptors: new targets for cancer immunotherapy. Front. Immunol. 10, 379 (2019).
Bader, J. E., Voss, K. & Rathmell, J. C. Targeting metabolism to improve the tumor microenvironment for cancer immunotherapy. Mol. Cell 78, 1019–1033 (2020).
Oh, M.-H. et al. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J. Clin. Invest. 130, 3865–3884 (2020).
O’Sullivan, D., Sanin, D. E., Pearce, E. J. & Pearce, E. L. Metabolic interventions in the immune response to cancer. Nat. Rev. Immunol. 19, 324–335 (2019).
Emberley, E. et al. The glutaminase inhibitor telaglenastat enhances the antitumor activity of signal transduction inhibitors everolimus and cabozantinib in models of renal cell carcinoma. PLoS ONE 16, e0259241 (2021).
Varghese, S. et al. The glutaminase inhibitor CB-839 (Telaglenastat) enhances the antimelanoma activity of T-cell–mediated immunotherapies. Mol. Cancer Ther. 20, 500 (2021).
Miret, J. J. et al. Suppression of myeloid cell arginase activity leads to therapeutic response in a NSCLC mouse model by activating anti-tumor immunity. J. Immunother. Cancer 7, 32 (2019).
Pham, T. N., Liagre, B., Girard-Thernier, C. & Demougeot, C. Research of novel anticancer agents targeting arginase inhibition. Drug Discov. Today 23, 871–878 (2018).
Steggerda, S. M. et al. Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. J. Immunother. Cancer 5, 101–112 (2017).
Koyama, T. et al. Phase 1 study of retifanlimab (anti-PD-1) and INCB001158 (arginase inhibitor), alone or in combination, in solid tumors. Ann. Oncol. 32, S302 (2021). Conference abstract MO310-306 JSMO2021 Virtual Congress 2021 the Japanese Society of Medical Oncology Annual Meeting.
Naing, A. Phase I study of the arginase inhibitor INCB001158 (1158) alone and in combination with pembrolizumab (PEM) in patients (Pts) with advanced/metastatic (adv/met) solid tumours [Abstr. 1621]. Ann. Oncol. 30 (Suppl. 5), v160 (2019).
Lu, M. et al. Structure-based discovery of proline-derived arginase inhibitors with improved oral bioavailability for immuno-oncology. ACS Med. Chem. Lett. 12, 1380–1388 (2021).
Allard, B., Allard, D., Buisseret, L. & Stagg, J. The adenosine pathway in immuno-oncology. Nat. Rev. Clin. Oncol. 17, 611–629 (2020).
Thompson, E. A. & Powell, J. D. Inhibition of the adenosine pathway to potentiate cancer immunotherapy: potential for combinatorial approaches. Annu. Rev. Med. 72, 331–348 (2021).
Kötzner, L., Huck, B., Garg, S. & Urbahns, K. Small molecules — giant leaps for immuno-oncology. Prog. Med. Chem. 59, 1–62 (2020).
Seitz, L. et al. Safety, tolerability, and pharmacology of AB928, a novel dual adenosine receptor antagonist, in a randomized, phase 1 study in healthy volunteers. Invest. New Drugs 37, 711–721 (2019). The potency of this dual A2aR/A2bR inhibitor in combination with the well-tolerated properties in patients provide a perspective for clinical benefit in combination with ICI.
Subudhi, S. K. et al. ARC-6: a phase 1b/2, open-label, randomized platform study to evaluate efficacy and safety of etrumadenant (AB928)-based treatment combinations in patients with metastatic castrate-resistant prostate cancer (mCRPC). J. Clin. Oncol. 39, 5039–5039 (2021).
Cecchini, M. et al. ARC-3: updated results of etrumadenant (AB928)+modified FOLFOX-6 (mFOLFOX-6) in metastatic colorectal cancer (mCRC) patients. Cancer Res. 81 (Suppl. 13), CT129 (2021).
Han, H., Zhao, L., Yao, W. & Wang, X. Triazolopyrimidines as A2a/A2b inhibitors. International Patent Application WO/2021/041360 (2021).
Fan, P. et al. TT-702, a selective and potent A2B receptor antagonist for the treatment of cancer. Cancer Res. 81 (Suppl. 13), Abstr. 55 (2021).
Liu, J. & Elzein, E. Adenosine receptor antagonists and uses thereof. International Patent Application WO/2019/173380 (2019).
Du, X. et al. Orally bioavailable small-molecule CD73 inhibitor (OP-5244) reverses immunosuppression through blockade of adenosine production. J. Med. Chem. 63, 10433–10459 (2020).
Lawson, K. V. et al. Discovery of AB680: a potent and selective inhibitor of CD73. J. Med. Chem. 63, 11448 (2020).
Sutimantanapi, D. et al. Blocking adenosine production with ORIC-533, a CD73 inhibitor with best-in-class properties, reverses immunosuppression in high-AMP environments. Cancer Res. 81 (Suppl. 13), Abstr. LB163 (2021).
Manji, G. A. et al. ARC-8: phase I/Ib study to evaluate safety and tolerability of AB680+chemotherapy+zimberelimab (AB122) in patients with treatment-naive metastatic pancreatic adenocarcinoma (mPDAC). J. Clin. Oncol. 39(Suppl. 3), Abstr. 404 (2021).
Boison, D. & Yegutkin, G. G. Adenosine metabolism: emerging concepts for cancer therapy. Cancer Cell 36, 582–596 (2019).
Opitz, C. A. et al. The therapeutic potential of targeting tryptophan catabolism in cancer. Br. J. Cancer 122, 30–44 (2020).
Muller, A. J., Manfredi, M. G., Zakharia, Y. & Prendergast, G. C. Inhibiting IDO pathways to treat cancer: lessons from the ECHO-301 trial and beyond. Semin. Immunopathol. 41, 41–48 (2019).
Van den Eynde, B. J., van Baren, N. & Baurain, J.-F. Is there a clinical future for IDO1 inhibitors after the failure of epacadostat in melanoma? Annu. Rev. Cancer Biol. 4, 241–256 (2020).
Poncelet, L., Ait-Belkacem, R., Marillier, R., Gomes, B. & Stauber, J. Target exposure and pharmacodynamics study of the indoleamine 2,3-dioxygenase-1 (IDO-1) inhibitor epacadostat in the CT26 mouse tumor model. J. Pharm. Biomed. Anal. 170, 220–227 (2019).
Balog, A. et al. Preclinical characterization of linrodostat mesylate, a novel, potent, and selective oral indoleamine 2,3-dioxygenase 1 inhibitor. Mol. Cancer Ther. 20, 467 (2021). The ongoing phase III study with linrodostat will show whether the lack of success with its predecessor epacadostat was a matter of potency and/or dosage or conceptual issues. Its outcome is likely to have tremendous impact on the entire effort concerning the targeting of metabolic pathways.
Sadik, A. et al. IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression. Cell 182, 1252–1270.e1234 (2020).
Gyulveszi, G. et al. RG70099: a novel, highly potent dual IDO1/TDO inhibitor to reverse metabolic suppression of immune cells in the tumor micro-environment. Cancer Res. 76 (Suppl. 14), Abstr. LB-085 (2016).
Naing, A. et al. Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors. J. Immunother. Cancer 8, e000870 (2020).
Schmees, N. et al. Identification of BAY-218, a potent and selective small-molecule AhR inhibitor, as a new modality to counteract tumor immunosuppression. Cancer Res. 79 (Suppl. 13), Abstr. 4454 (2019).
Castro, A. et al. AHR inhibitors and uses thereof. International Patent Application WO/2019/036657 (2017).
Palm, N. W. & Medzhitov, R. Pattern recognition receptors and control of adaptive immunity. Immunol. Rev. 227, 221–233 (2009).
Smith, M. et al. Trial Watch: Toll-like receptor agonists in cancer immunotherapy. OncoImmunology 7, e1526250 (2018).
Kaczanowska, S., Joseph, A. M. & Davila, E. TLR agonists: our best frenemy in cancer immunotherapy. J. Leukoc. Biol. 93, 847–863 (2013). This review article explains the reasons underlying the difficulties of translating promising data with TLR agonists obtained in preclinical mouse models into a therapeutic window for cancer patients.
Adams, S. Toll-like receptor agonists in cancer therapy. Immunotherapy 1, 949–964 (2009).
Rehli, M. Of mice and men: species variations of Toll-like receptor expression. Trends Immunol. 23, 375–378 (2002).
Anwar, M. A., Shah, M., Kim, J. & Choi, S. Recent clinical trends in Toll-like receptor targeting therapeutics. Med. Res. Rev. 39, 1053–1090 (2019).
Deane, J. A. et al. Identifıcation and characterization of LHC165, a TLR7 agonist designed for localized intratumoral therapies. Cancer Res. 81 (Suppl. 13), Abstr. 4128 (2019).
Curigliano, G. et al. Phase I study of LHC165±spartalizumab (PDR001) in patients (pts) with advanced solid tumors. Cancer Res 81 (Suppl. 13), Abstr. CT103 (2021).
Klempner, S. et al. A phase 1/2 study of SBT6050 combined with trastuzumab deruxtecan (T-DXd) or trastuzumab and tucatinib with or without capecitabine in patients with HER2-expressing or HER2-amplified cancers. J. Immunother. Cancer 9 (Suppl. 2), A426 (2021). Abstr. 393.
Fucikova, J. et al. Detection of immunogenic cell death and its relevance for cancer therapy. Cell Death Dis. 11, 1013 (2020).
Flood, B. A., Higgs, E. F., Li, S., Luke, J. J. & Gajewski, T. F. STING pathway agonism as a cancer therapeutic. Immunol. Rev. 290, 24–38 (2019).
Ding, C., Song, Z., Shen, A., Chen, T. & Zhang, A. Small molecules targeting the innate immune cGAS–STING–TBK1 signaling pathway. Acta Pharm. Sin. B 10, 2272–2298 (2020).
Motedayen Aval, L., Pease, J. E., Sharma, R. & Pinato, D. J. Challenges and opportunities in the clinical development of STING agonists for cancer immunotherapy. J. Clin. Med. 9, 3323 (2020).
Bratulic, A. Novartis drops Aduro’s STING agonist ADU-S100 from portfolio, https://www.firstwordpharma.com/node/1688694?tsid=17 (2019).
Le Naour, J., Zitvogel, L., Galluzzi, L., Vacchelli, E. & Kroemer, G. Trial watch: STING agonists in cancer therapy. OncoImmunology 9, 1777624 (2020).
Luke, J. J. et al. 598TiP A phase I/Ib dose-escalation study of intravenously administered SB 11285 alone and in combination with nivolumab in patients with advanced solid tumours. Ann. Oncol. 31, S500 (2020).
Ramanjulu, J. M. et al. Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature 564, 439–443 (2018).
Zhang, R., Kang, R. & Tang, D. The STING1 network regulates autophagy and cell death. Signal. Transduct. Target. Ther. 6, 208 (2021).
Amouzegar, A., Chelvanambi, M., Filderman, J. N., Storkus, W. J. & Luke, J. J. STING agonists as cancer therapeutics. Cancer 13, 2695 (2021).
Larkin, B. et al. Cutting edge: activation of STING in T cells induces type I IFN responses and cell death. J. Immunol. 199, 397 (2017).
Onyedibe, K. I., Wang, M. & Sintim, H. O. ENPP1, an old enzyme with new functions, and small molecule inhibitors — a STING in the tale of ENPP1. Molecules 24, 4192 (2019).
Motwani, M., Pesiridis, S. & Fitzgerald, K. A. DNA sensing by the cGAS–STING pathway in health and disease. Nat. Rev. Genet. 20, 657–674 (2019).
Baird, J. MV-626, a potent and selective inhibitor of ENPP1 enhances STING activation and augments T-cell mediated anti-tumor activity in vivo. Society for Immunotherapy of Cancer 2018 Annual Meeting P410 (2018).
Weston, A. et al. Preclinical studies of SR-8314, a highly selective ENPP1 inhibitor and an activator of STING pathway. Cancer Res. 79 (Suppl. 13), Abstr. 3077 (2019).
Weston, A. S. et al. SR8541A is a potent inhibitor of ENPP1 and exhibits dendritic cell mediated antitumor activity. Cancer Res. 80 (suppl. 16), Abstr. LB-118 (2020).
Decout, A., Katz, J. D., Venkatraman, S. & Ablasser, A. The cGAS–STING pathway as a therapeutic target in inflammatory diseases. Nat. Rev. Immunol. 21, 548–569 (2021).
Hemphill, W. O. et al. TREX1 as a novel immunotherapeutic target. Front. Immunol. 12, 660184 (2021).
Hopp, A.-K. & Hottiger, M. O. Uncovering the invisible: mono-ADP-ribosylation moved into the spotlight. Cells 10, 680 (2021).
Gozgit, J. M. et al. RBN-2397: a potent and selective small molecule inhibitor of PARP7 that induces tumor-derived antitumor immunity dependent on CD8 T cells. Cancer Res. 81 (Suppl. 13), Abstr. 48 (2021).
Mérida, I., Andrada, E., Gharbi, S. I. & Ávila-Flores, A. Redundant and specialized roles for diacylglycerol kinases α and ζ in the control of T cell functions. Sci. Signal. 8, re6 (2015).
Shui, J.-W. et al. Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell–mediated immune responses. Nat. Immunol. 8, 84–91 (2007).
Stromnes, I. M. et al. Abrogation of Src homology region 2 domain-containing phosphatase 1 in tumor-specific T cells improves efficacy of adoptive immunotherapy by enhancing the effector function and accumulation of short-lived effector T cells in vivo. J. Immunol. 189, 1812 (2012).
Brownlie, R. J., Wright, D., Zamoyska, R. & Salmond, R. J. Deletion of PTPN22 improves effector and memory CD8+ T cell responses to tumors. JCI Insight 5, e127847 (2019).
Cubas, R. et al. Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy. J. Immunother. Cancer 8, e001439 (2020).
Loeser, S. et al. Spontaneous tumor rejection by CBL-B–deficient CD8+ T cells. J. Exp. Med. 204, 879–891 (2007). This publication provides the first preclinical proof of concept for targeting CBL-B in the context of cancer immunotherapy.
Chuang, H.-C., Wang, X. & Tan, T.-H. Chapter seven – MAP4K family kinases in immunity and inflammation. Adv. Immunol. 129, 277–314 (2016).
Magiera-Mularz, K. et al. Human and mouse PD-L1: similar molecular structure, but different druggability profiles. iScience 24, 101960 (2021).
Ramachandra, M. et al. Small molecule immune checkpoint antagonists for cancer therapy. EFMC-ISMC 2018–2025th EFMC International Symposium on Medicinal Chemistry, Abstr. LE005 (2018).
Radhakrishnan, V. et al. Excellent CBR and prolonged PFS in non-squamous NSCLC with oral CA-170, an inhibitor of VISTA and PD-L1 [Abstr. 1209P]. Ann. Oncol. 30 (Suppl. 5), v494 (2019).
Sasikumar, P. G. et al. PD-1 derived CA-170 is an oral immune checkpoint inhibitor that exhibits preclinical anti-tumor efficacy. Commun. Biol. 4, 699 (2021).
ElTanbouly, M. A., Croteau, W., Noelle, R. J. & Lines, J. L. VISTA: a novel immunotherapy target for normalizing innate and adaptive immunity. Semin. Immunol. 42, 101308 (2019).
Park, J.-J. et al. Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1. Nat. Commun. 12, 1222 (2021).
Wu, L. Discovery of INCB86550: a potent, orally bioavailable small molecule inhibitor of PDL1 for the treatment of cancer. Cancer Res. 81 (Suppl. 13), Abstr. ND01 (2021).
Boomer, J. S. & Tan, T.-H. Functional interactions of HPK1 with adaptor proteins. J. Cell. Biochem. 95, 34–44 (2005).
Bartolo, V. D. et al. A novel pathway down-modulating T cell activation involves HPK-1–dependent recruitment of 14-3-3 proteins on SLP-76. J. Exp. Med. 204, 681–691 (2007).
Alzabin, S. et al. Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2-mediated suppression of the anti-tumor immune response. Cancer Immunol. Immunother. 59, 419 (2009). This is the preclinical study that eventually helped put MAP4K1 inhibition on the IO agenda.
Sawasdikosol, S., Pyarajan, S., Alzabin, S., Matejovic, G. & Burakoff, S. J. Prostaglandin E2 activates HPK1 kinase activity via a PKA-dependent pathway. J. Biol. Chem. 282, 34693–34699 (2007).
Hernandez, S. et al. The kinase activity of hematopoietic progenitor kinase 1 is essential for the regulation of T cell function. Cell Rep. 25, 80–94 (2018).
Linney, I. D. & Kaila, N. Inhibitors of immuno-oncology target HPK1–a patent review (2016 to 2020). Expert Opin. Ther. Pat. 31, 893–910 (2021).
Si, J. et al. Hematopoietic progenitor kinase1 (HPK1) mediates T cell dysfunction and is a druggable target for T cell-based immunotherapies. Cancer Cell 38, 551–566.e511 (2020).
Jin, J. et al. Heterobifunctional compounds as degraders of HPK1. International Patent Application WO/2020/227325A1 (2019).
You, D. et al. Enhanced antitumor immunity by a novel small molecule HPK1 inhibitor. J. Immunother. Cancer 9, e001402 (2021).
Leder, G. et al. Enhancement of anti-tumor T-cell immunity by means of an oral small molecule targeting the intracellular immune checkpoint MAP4K1. Cancer Res. 81 (Suppl. 13), Abstr. 1722 (2021).
Vara, B. A. et al. Discovery of diaminopyrimidine carboxamide HPK1 inhibitors as preclinical immunotherapy tool compounds. ACS Med. Chem. Lett. 12, 653–661 (2021).
Degnan, A. P. et al. Discovery of orally active isofuranones as potent, selective inhibitors of hematopoetic progenitor kinase 1. ACS Med. Chem. Lett. 12, 443–450 (2021).
Yu, E. C. et al. Identification of potent reverse indazole inhibitors for HPK1. ACS Med. Chem. Lett. 12, 459–466 (2021).
Ciccone, D. et al. A highly selective and potent HPK1 inhibitor enhances immune cell activation and induces robust tumor growth inhibition in a murine syngeneic tumor model. Eur. J. Cancer 138, S20 (2020).
Ciccone, D. et al. A highly selective and potent HPK1 inhibitor induces robust tumor growth inhibition as a single agent and in combination with anti-PD1 in multiple syngeneic tumor models. AACR Annual Meeting 2021 Poster https://www.nimbustx.com/wp-content/uploads/AACR-2021-POSTER.pdf (2021).
Ishisaka, M. & Hara, H. The roles of diacylglycerol kinases in the central nervous system: review of genetic studies in mice. J. Pharmacol. Sci. 124, 336–343 (2014).
Arranz-Nicolás, J. et al. Diacylglycerol kinase α inhibition cooperates with PD-1-targeted therapies to restore the T cell activation program. Cancer Immunol. Immunother. 70, 3277–3289 (2021).
Chauveau, A., Le Floc’h, A., Bantilan, N. S., Koretzky, G. A. & Huse, M. Diacylglycerol kinase α establishes T cell polarity by shaping diacylglycerol accumulation at the immunological synapse. Sci. Signal. 7, ra82 (2014).
de Chaffoy de Courcelles, D. et al. The role of endogenously formed diacylglycerol in the propagation and termination of platelet activation: a biochemical and functional analysis using the novel diacylglycerol kinase inhibitor, R 59 949. J. Biol. Chem. 264, 3274–3285 (1989).
de Chaffoy de Courcelles, D. C., Roevens, P. & Van Belle, H. R 59 022, a diacylglycerol kinase inhibitor. Its effect on diacylglycerol and thrombin-induced C kinase activation in the intact platelet. J. Biol. Chem. 260, 15762–15770 (1985).
Baldanzi, G. et al. SAP-mediated inhibition of diacylglycerol kinase α regulates TCR-induced diacylglycerol signaling. J. Immunol. 187, 1002476 (2011).
Prinz, P. U. et al. High DGK-α and disabled MAPK pathways cause dysfunction of human tumor-infiltrating CD8+ T cells that is reversible by pharmacologic intervention. J. Immunol. 206, 1103028 (2012). Early proof of concept for pharmacological DGK inhibition towards enhancement of anti-tumour T cell immunity.
Moon, E. K. et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor–transduced human T cells in solid tumors. Clin. Cancer Res. 20, 4262 (2014).
Liu, K. et al. A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response. J. Lipid Res. 57, 368–379 (2016).
Arranz-Nicolás, J. et al. Diacylglycerol kinase α inactivation is an integral component of the costimulatory pathway that amplifies TCR signals. Cancer Immunol. Immunother. 67, 965–980 (2018).
Dominguez, C. L. et al. Diacylglycerol kinase α is a critical signaling node and novel therapeutic target in glioblastoma and other cancers. Cancer Discov. 3, 782–797 (2013).
Fu, L. et al. DGKA mediates resistance to PD-1 blockade. Cancer Immunol. Res. 9, 371 (2021).
Velaparthi, U. et al. Substituted naphthyridinone compounds useful as T cell activators. International Patent Application WO/2020/006018 (2020).
Velnati, S. et al. Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors. J. Enzym. Inhib. Med. Chem. 35, 96–108 (2020).
Bachmaier, K. et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403, 211–216 (2000).
Chiang, Y. J. et al. Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403, 216–220 (2000).
Li, D. et al. Cutting edge: Cbl-b: one of the key molecules tuning CD28- and CTLA-4-mediated T cell costimulation. J. Immunol. 173, 7135 (2004).
Karwacz, K. et al. PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells. EMBO Mol. Med. 3, 581–592 (2011).
Chiang, J. Y., Jang, I. K., Hodes, R. & Gu, H. Ablation of Cbl-b provides protection against transplanted and spontaneous tumors. J. Clin. Invest. 117, 1029–1036 (2007).
Wirnsberger, G. et al. Inhibition of CBLB protects from lethal Candida albicans sepsis. Nat. Med. 22, 915–923 (2016).
Hinterleitner, R. et al. Adoptive transfer of siRNA Cblb-silenced CD8+ T lymphocytes augments tumor vaccine efficacy in a B16 melanoma model. PLoS ONE 7, e44295 (2012).
Jajour, J., Havens, K. & Krostag, A. R. Cblb endonuclease variants, compositions, and methods of use. International Patent Application WO/2020/072059 (2020).
Sather, B. D. et al. Efficient modification of CCR5 in primary human hematopoietic cells using a megaTAL nuclease and AAV donor template. Sci. Transl. Med. 7, 307ra156 (2015).
Chirino, L. M. et al. TAM receptors attenuate murine NK-cell responses via E3 ubiquitin ligase Cbl-b. Eur. J. Immunol. 50, 48–55 (2020).
Rountree, R. et al. Small molecule inhibition of the ubiquitin ligase CBL-B results in potent T and NK cell mediated anti-tumor response. Cancer Res. 81 (Suppl. 13), Abstr. 1595 (2021). The preclinical data on the CBL-B inhibitor developed by Nurix demonstrates that this is a very powerful small-molecule ICI. The unanswered question, given its capacity to inhibit both CBL-B and C-CBL, is whether it will show a therapeutic window in patients.
Naramura, M. et al. c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat. Immunol. 3, 1192–1199 (2002).
Xu, F. et al. Ablation of Cbl-b and c-Cbl in dendritic cells causes spontaneous liver cirrhosis via altering multiple properties of CD103+ cDC1s. Cell Death Discov. 8, 142 (2022).
Lorenz, U. SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol. Rev. 228, 342–359 (2009).
Chen, Y.-N. P. et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 535, 148–152 (2016). A pioneering example of a potent and selective phosphatase inhibitor, raising hope that the same can also be achieved for the more immune-specific phosphatases SHP1 and PTPN22.
LaMarche, M. J. et al. Identification of TNO155, an allosteric SHP2 inhibitor for the treatment of cancer. J. Med. Chem. 63, 13578–13594 (2020).
Liu, C. et al. Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling. Clin. Cancer Res. 27, 342 (2021).
Quintana, E. et al. Allosteric inhibition of SHP2 stimulates antitumor immunity by transforming the immunosuppressive environment. Cancer Res. 80, 2889 (2020).
Mullard, A. Phosphatases start shedding their stigma of undruggability. Nat. Rev. Drug Discov. 17, 847–849 (2018).
Tawbi, H. A. et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N. Engl. J. Med. 386, 24–34 (2022).
Mullard, A. LAG3 pushes immuno-oncology’s leading edge. Nat. Rev. Drug Discov. 21, 167–169 (2022). This recent commentary provides a vivid account of the dilemmas, hopes and fears faced by all biotech and pharma companies investing in IO drug development.
Woo, S. R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).
Chau, C. H., Steeg, P. S. & Figg, W. D. Antibody–drug conjugates for cancer. Lancet 394, 793–804 (2019).
Patel Ravi, B. et al. Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade. Sci. Transl. Med. 13, eabb3631 (2021).
Pende, D. et al. Killer Ig-Like receptors (KIRs): their role in NK cell modulation and developments leading to their clinical exploitation. Front. Immunol. 10, 1179 (2019).
van Hall, T. et al. Monalizumab: inhibiting the novel immune checkpoint NKG2A. J. Immunother. Cancer 7, 263 (2019).
R.O. receives funding from the K. H. Bauerstiftung. The authors gratefully acknowledge A. Unzue-Lopez, Merck Healthcare KGaA, Darmstadt, Germany, who helped to proofread the manuscript and to kindly double-check the accuracy of chemical structures in this article. The authors also gratefully acknowledge T. Johnson, EMD Serono, Billerica, MA, USA, who created the picture of the co-crystal structure of compound 24 in HPK1 from the Protein Data Bank.
R.O. is a recipient of research funding through the DKFZ–Bayer strategic research alliance. L.K., K.U. are employees of Merck Healthcare KGaA and B.H. is an employee at EMD Serono, respectively, and declare no competing interests.
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- Immune checkpoint inhibitor
(ICI). A compound, often an antibody, that blocks the functionality of immune checkpoint proteins.
Anti-cytotoxic lymphocytic protein 4 (CTLA4) antibody, marketed under the brand name Yervoy, developed by Bristol-Myers Squibb, that obtained its first FDA approval in March 2011.
Anti-PD1 antibody, marketed under the name Keytruda, developed by Merck & Co., that obtained its first FDA approval in September 2014.
Anti-PD1 antibody, marketed under the name Opdivo, developed by Bristol-Myers Squibb, that obtained its first FDA approval in December 2014.
- Tumour microenvironment
(TME). The environment around a tumour, including the surrounding blood vessels, immune cells, fibroblasts, signalling molecules and the extracellular matrix.
- Immunogenic cell death
(ICD). Cell death resulting from the disruption of cell integrity and/or stress factors, including cytostatic drugs, that cause the release of intracellular components into the extracellular environment and pro-inflammatory signals that initiate an immune response. These downstream events are avoided in the context of apoptotic cell death.
- Myeloid-derived suppressor cells
(MDSCs). A diverse population of immature myeloid cells with potent immunosuppressive activity that is often enriched in the tumour microenvironment.
Anti-PDL1 antibody, marketed under the name Tecentriq, developed by Genentech/Roche that obtained its first FDA approval in May 2016.
Anti-PD1 antibody developed by Novartis that is under investigation in multiple clinical trials.
Anti-PDL1 antibody, marketed under the name Bavencio, developed by Merck KGaA and Pfizer that obtained its first FDA approval in March 2017.
Anti-PD1 antibody developed by Arcus Biosciences that is under investigation in multiple clinical trials.
A chemotherapy regimen consisting of folinic acid, 5-fluorouracil, irinotecan and oxaliplatin.
A tolerance mechanism in which the lymphocyte is functionally inactivated but remains alive in a hyporesponsive state.
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Offringa, R., Kötzner, L., Huck, B. et al. The expanding role for small molecules in immuno-oncology. Nat Rev Drug Discov 21, 821–840 (2022). https://doi.org/10.1038/s41573-022-00538-9
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