The Next Generation of Immunotherapy for Cancer: Small Molecules Could Make Big Waves

Calreticulin exposure dictates the immunogenicity of cancer cell death

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Car t cell immunotherapy for human cancer

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Immunogenic cell death in cancer and infectious disease

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Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression

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Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase

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Direct Regulation of the Akt Proto-Oncogene Product by Phosphatidylinositol-3,4-bisphosphate

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The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer

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PI3Kγ is a molecular switch that controls immune suppression

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Targeting STING with covalent small-molecule inhibitors

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The Combined Effects of Tryptophan Starvation and Tryptophan Catabolites Down-Regulate T Cell Receptor ζ-Chain and Induce a Regulatory Phenotype in Naive T Cells

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TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression

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Targeting Toll-like receptors: emerging therapeutics?

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Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes

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STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade

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CONTRIBUTION TO THE KNOWLEDGE OF SARCOMA

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The secret ally: immunostimulation by anticancer drugs

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Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells

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Innate Immune Recognition of Cancer

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Tumor-repopulating cells induce PD-1 expression in CD8(+) T cells by transferring kynurenine and AhR activation

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Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer

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Big opportunities for small molecules in immuno-oncology

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Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC)

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Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK

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Managing Immune Checkpoint-Blocking Antibody Side Effects

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The development and immunosuppressive functions of CD4+ CD25+ FoxP3+ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway

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Ibrutinib treatment improves T cell number and function in CLL patients

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Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade

Holmgaard, R. B., Schaer, D. A., Li, Y., Castaneda, S. P., Murphy, M. Y., Xu, X., Inigo, I., Dobkin, J., Manro, J. R., Iversen, P. W., et al. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0356-4 · Cited by 356 · see citing works

Small-molecule inhibitors of PD-1/PD-L1 immune checkpoint alleviate the PD-L1-induced exhaustion of T-cells

Skalniak, Ł., Żak, K. M., Guzik, K., Magiera‐Mularz, K., Musielak, B., Pachota, M., Szelążek, B., Kocik-Krol, J., Grudnik, P., Tomala, M. D., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.20050 · Cited by 308 · see citing works

Cutting Edge: The Phosphoinositide 3-Kinase p110δ Is Critical for the Function of CD4+CD25+Foxp3+ Regulatory T Cells

Patton, D. T., Garden, O. A., Pearce, W. P., Clough, L. E., Monk, C. R., Leung, E. Y., Rowan, W. C., Sancho, S., Walker, L. S. K., Vanhaesebroeck, B., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.10.6598 · Cited by 303 · see citing works

Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination

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Idelalisib: First-in-Class PI3K Delta Inhibitor for the Treatment of Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia, and Follicular Lymphoma

Yang, Q., Modi, P., Newcomb, T. G., Quéva, C., & Gandhi, V. V. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2034 · Cited by 226 · see citing works

Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma

Rook, A. H., Gelfand, J. M., Wysocka, M., Troxel, A. B., Benoit, B. M., Surber, C., Elenitsas, R., Buchanan, M., Leahy, D. S., Watanabe, R., et al. (2015) · Blood · doi:10.1182/blood-2015-02-630335 · Cited by 223 · see citing works

Chimeric Antigen Receptor T Cell Therapy: Challenges to Bench-to-Bedside Efficacy

Srivastava, S., & Riddell, S. R. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701155 · Cited by 219 · see citing works

Immune Checkpoint Blockade in Cancer Therapy

Allison, J. P. (2015) · JAMA · doi:10.1001/jama.2015.11929 · Cited by 213 · see citing works

Inhibition of the adenosine A2a receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models

Leone, R. D., Sun, I.-M., Oh, M. H., Sun, I., Wen, J., Englert, J. M., & Powell, J. D. (2018) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-018-2186-0 · Cited by 191 · see citing works

Preclinical assessment of galunisertib (LY2157299 monohydrate), a first‐in‐class transforming growth factor‐β receptor type I inhibitor

Yingling, J. M., McMillen, W. T., Yan, L., Huang, H., Sawyer, J. S., Graff, J., Clawson, D. K., Britt, K. S., Anderson, B. D., Beight, D. W., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.23795 · Cited by 187 · see citing works

Rationale, progress and development of vaccines utilizing STING-activating cyclic dinucleotide adjuvants

Dubensky, T. W., Kanne, D. B., & Leong, M. L. L. (2013) · Therapeutic Advances in Vaccines · doi:10.1177/2051013613501988 · Cited by 175 · see citing works

First in Human Phase I Trial of 852A, a Novel Systemic Toll-like Receptor 7 Agonist, to Activate Innate Immune Responses in Patients with Advanced Cancer

Dudek, A. Z., Yunis, C., Harrison, L. I., Kumar, S., Hawkinson, R. W., Cooley, S., Vasilakos, J. P., Gorski, K. S., & Miller, J. S. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1443 · Cited by 169 · see citing works

Phosphatidylinositol (3,4,5)P3 Is Essential but Not Sufficient for Protein Kinase B (PKB) Activation; Phosphatidylinositol (3,4)P2 Is Required for PKB Phosphorylation at Ser-473

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Small Molecules Drive Big Improvements in Immuno‐Oncology Therapies

Huck, B. R., Kötzner, L., & Urbahns, K. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201707816 · Cited by 149 · see citing works

GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)

Romero, F. A., Murray, J. M., Lai, K. W., Tsui, V., Albrecht, B. K., An, L., Beresini, M. H., Boenig, G. D. L., Bronner, S. M., Chan, E. W., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00796 · Cited by 146 · see citing works

SHIP1 Inhibition Increases Immunoregulatory Capacity and Triggers Apoptosis of Hematopoietic Cancer Cells

Brooks, R., Fuhler, G. M., Iyer, S., Smith, M. J., Park, M.-Y., Paraiso, K. H. T., Engelman, R. W., & Kerr, W. G. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902844 · Cited by 140 · see citing works

TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells

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A2A Adenosine Receptor Gene Deletion or Synthetic A2A Antagonist Liberate Tumor-Reactive CD8+ T Cells from Tumor-Induced Immunosuppression

Kjaergaard, J., Hatfield, S., Jones, G., Ohta, A., & Sitkovsky, M. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1700850 · Cited by 132 · see citing works

Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma

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Cancer Immunotherapy: Selected Targets and Small‐Molecule Modulators

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Inhibitor and activator: dual functions for SHIP in immunity and cancer

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Phase Ib Trial of the Toll-like Receptor 8 Agonist, Motolimod (VTX-2337), Combined with Cetuximab in Patients with Recurrent or Metastatic SCCHN

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Therapeutic Potential of SH2 Domain-Containing Inositol-5′-Phosphatase 1 (SHIP1) and SHIP2 Inhibition in Cancer

Fuhler, G. M., Brooks, R., Toms, B., Iyer, S., Gengo, E. A., Park, M.-Y., Gumbleton, M., Viernes, D. R., Chisholm, J. D., & Kerr, W. G. (2012) · Molecular Medicine · doi:10.2119/molmed.2011.00178 · Cited by 109 · see citing works

Antagonists of the Human A2A Adenosine Receptor. 4. Design, Synthesis, and Preclinical Evaluation of 7-Aryltriazolo[4,5-d]pyrimidines

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Inhibition of bromodomain and extra-terminal (BET) proteins increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of cMYC-IRF4-miR-125b interplay

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Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase, SHIP2

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Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition

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ITK signalling via the Ras/IRF4 pathway regulates the development and function of Tr1 cells

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Prolonged subcutaneous administration of 852A, a novel systemic toll‐like receptor 7 agonist, to activate innate immune responses in patients with advanced hematologic malignancies

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A Phase I Dose-Finding Study of the Novel Toll-like Receptor 8 Agonist VTX-2337 in Adult Subjects with Advanced Solid Tumors or Lymphoma

Northfelt, D., Ramanathan, R. K., Cohen, P. A., Hoff, D. D. V., Weiss, G. J., Dietsch, G. N., Manjarrez, K. L., Randall, T. D., & Hershberg, R. M. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0392 · Cited by 66 · see citing works

Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors

Lim, E. L., Cugliandolo, F. M., Rosner, D. R., Gyori, D., Roychoudhuri, R., & Okkenhaug, K. (2018) · JCI Insight · doi:10.1172/jci.insight.120626 · Cited by 66 · see citing works

Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation

Hoekstra, E., Das, A. M., Willemsen, M., Swets, M., Kuppen, P. J. K., van der Woude, C. J., Bruno, M. J., Shah, J. P., ten Hagen, T. L. M., Chisholm, J. D., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.12321 · Cited by 58 · see citing works

Discovery and Development of Small Molecule SHIP Phosphatase Modulators

Viernes, D. R., Choi, L. B., Kerr, W. G., & Chisholm, J. D. (2013) · Medicinal Research Reviews · doi:10.1002/med.21305 · Cited by 57 · see citing works

Dual enhancement of T and NK cell function by pulsatile inhibition of SHIP1 improves antitumor immunity and survival

Gumbleton, M., Sudan, R., Fernandes, S., Engelman, R. W., Russo, C. M., Chisholm, J. D., & Kerr, W. G. (2017) · Science Signaling · doi:10.1126/scisignal.aam5353 · Cited by 43 · see citing works

Advances in the Treatment of Non–small Cell Lung Cancer: Focus on Nivolumab, Pembrolizumab, and Atezolizumab

Leventakos, K., & Mansfield, A. S. (2016) · BioDrugs · doi:10.1007/s40259-016-0187-0 · Cited by 42 · see citing works

A phase 2 study of TMX-101, intravesical imiquimod, for the treatment of carcinoma in situ bladder cancer

Donin, N. M., Chamie, K., Lenis, A. T., et al. (2016) · Urologic Oncology Seminars and Original Investigations · doi:10.1016/j.urolonc.2016.09.006 · Cited by 41 · see citing works

Late-Stage Cancer Patients Remain Highly Responsive to Immune Activation by the Selective TLR8 Agonist Motolimod (VTX-2337)

Dietsch, G. N., Randall, T. D., Gottardo, R., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0578 · Cited by 38 · see citing works

Impaired T-cell survival promotes mucosal inflammatory disease in SHIP1-deficient mice

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Coordinate Expansion of Murine Hematopoietic and Mesenchymal Stem Cell Compartments by SHIPi

Brooks, R., Iyer, S., Akada, H., Neelam, S., Russo, C. M., Chisholm, J. D., & Kerr, W. G. (2015) · Stem Cells · doi:10.1002/stem.1902 · Cited by 32 · see citing works

A small-molecule inhibitor of SHIP1 reverses age- and diet-associated obesity and metabolic syndrome

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Application of electron conformational–genetic algorithm approach to 1,4-dihydropyridines as calcium channel antagonists: pharmacophore identification and bioactivity prediction

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Inhibitors of the PD-1/PD-L1 Pathway Can Mobilize the Immune System: An Innovative Potential Therapy for Cancer and Chronic Infections

Abdel‐Magid, A. F. (2015) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.5b00148 · Cited by 29 · see citing works

Companies Scaling Back IDO1 Inhibitor Trials

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Protocol for the TIDAL Melanoma Study: topical imiquimod or diphenylcyclopropenone for the management of cutaneous in-transit melanoma metastases—a phase II, single centre, randomised, pilot study

Read, T., Webber, S. A., Thomas, J. M., Wagels, M., Schaider, H., Soyer, H. P., & Smithers, B. M. (2017) · BMJ Open · doi:10.1136/bmjopen-2017-016816 · Cited by 18 · see citing works

SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

Fernandes, S. R. M., Brooks, R., Gumbleton, M., Park, M.-Y., Russo, C. M., Howard, K. T., Chisholm, J. D., & Kerr, W. G. (2015) · EBioMedicine · doi:10.1016/j.ebiom.2015.02.004 · Cited by 17 · see citing works

Are immune checkpoint blockade monoclonal antibodies active against CNS metastases from NSCLC?—current evidence and future perspectives

O'Kane, G. M., & Leighl, N. B. (2016) · Translational Lung Cancer Research · doi:10.21037/tlcr.2016.09.05 · Cited by 17 · see citing works

STINGing Antitumor Immunity into Action

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Dendritic cells, dendritic cell‐based vaccines and Ralph Steinman

Ljunggren, H. (2011) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2011.02495.x · Cited by 5 · see citing works

PROTAC targeted protein degraders: the past is prologue

Békés, M., Langley, D. R., & Crews, C. M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00371-6 · Cited by 3,395 · see citing works

Opportunities for Small Molecules in Cancer Immunotherapy

van der Zanden, S. Y., Luimstra, J. J., Neefjes, J., Borst, J., & Ovaa, H. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.04.004 · Cited by 119 · see citing works

Cancer Immunotherapy and Application of Nanoparticles in Cancers Immunotherapy as the Delivery of Immunotherapeutic Agents and as the Immunomodulators

Debele, T. A., Yeh, C.-F., & Su, W. (2020) · Cancers · doi:10.3390/cancers12123773 · Cited by 85 · see citing works

B7-H3/CD276: An Emerging Cancer Immunotherapy

Zhou, W.-T., & Jin, W. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.701006 · Cited by 295 · see citing works

pH-Responsive Nanoparticles for Cancer Immunotherapy: A Brief Review

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Nanotechnology-Based Bacterial Immunotherapy

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