Bristol Myers Squibb is
leading advancements in:

  • Immuno-
    Oncology
  • Cell
    Therapy
  • Protein
    Degradation

  • Using multiple approaches to advance the next generation of cancer therapies

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    • Improve recognition of cancer cells

      The immune system naturally defends and protects the body against infection, involving a complex network of cells and signaling molecules. Bristol Myers Squibb is investigating multiple pathways and targets with the aim of amplifying the ability of the immune system to recognize and eliminate cancer cells.

      SIRPα
      • SIRPα is an inhibitory receptor expressed on macrophages and dendritic cells.1-3
      • CD47, a protein found on the surface of cells, binds SIRPα, initiating an inhibitory signaling pathway that helps maintain immunotolerance to normal cells.1-3
      • In cancer, overexpression of CD47 on the surface of tumor cells allows tumors to escape detection, acting as a “don’t eat me” signal, limiting the anti-cancer immune response.1-3
      • Inhibition of the CD47-SIRPα signaling pathway is intended to improve the recognition and enhance phagocytosis of cancer cells by macrophages.4
      References
      1. Advances in anti-tumor treatments targeting the CD47/SIRPα Axis. Front Immunol. 2020;11:18. doi:10.3389/fimmu.2020.00018
      2. Recognition of tumors by the innate immune system and natural killer cells. Adv Immunol. 2014;122:91-128. doi:10.1016/B978-0-12-800267-4.00003-1
      3. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer. 2019;19(10):568-586. doi:10.1038/s41568-019-0183-z
      4. The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol. 2012;24(2):225-232. doi:10.1016/j.coi.2012.01.010
      Fucosyl-GM1
      • Targeting the fucosyl-GM1 tumor-associated antigen is intended to improve the recognition of cancer cells by phagocytes and natural killer (NK) cells.1,2
      References
      1. A novel, fully human anti–fucosyl-GM1 antibody demonstrates potent in vitro and in vivo antitumor activity in preclinical models of small cell lung cancer. Clin Cancer Res. 2018;24(20):5178-5189. doi:10.1158/1078-0432.CCR-18-0018
      2. Molecular recognition of gangliosides and their potential for cancer immunotherapies. Front Immunol. 2014;5:325. doi:10.3389/fimmu.2014.00325
      STING
      • Activation of the STING pathway, which induces the production of cytokines, is intended to improve recognition of tumor cells by stimulating an innate and adaptive anti-cancer response.1,2
      References
      1. Molecular pathways: targeting the stimulator of interferon genes (STING) in the immunotherapy of cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2015;21(21):4774-4779. doi:10.1158/1078-0432.CCR-15-1362
      2. P525 Preclinical characterization of BMS-986301, a differentiated STING agonist with robust antitumor activity as monotherapy or in combination with anti–PD-1. Poster presented at: 33rd Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018): November 7-11, 2018; Washington, DC.
      CD47
      • CD47, a protein found on the surface of cells, binds SIRPα, initiating an inhibitory signaling pathway that helps maintain immunotolerance to normal cells.1-3
      • In cancer, overexpression of CD47 on the surface of tumor cells allows tumors to escape detection, acting as a “don’t eat me” signal, limiting the anti-cancer immune response.1-3
      • Inhibition of the CD47-SIRPα signaling pathway is intended to improve the recognition and enhance phagocytosis of cancer cells by macrophages.4
      References
      1. Advances in anti-tumor treatments targeting the CD47/SIRPα Axis. Front Immunol. 2020;11:18. doi:10.3389/fimmu.2020.00018
      2. Recognition of tumors by the innate immune system and natural killer cells. Adv Immunol. 2014;122:91-128. doi:10.1016/B978-0-12-800267-4.00003-1
      3. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer. 2019;19(10):568-586. doi:10.1038/s41568-019-0183-z
      4. The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol. 2012;24(2):225-232. doi:10.1016/j.coi.2012.01.010
      CD20
      • CD20 is a protein found on the surface of normal and cancerous B lymphocytes, a type of white blood cell.1
      • Dual engagement of the CD47/SIRPa pathway and CD20 on tumor cells can lead to cell destruction.1
      References
      1. Anti-CD20 monoclonal antibodies: historical and future perspectives. Haematologica. 2010 Jan;95(1):135-43. doi: 10.3324/haematol.2008.001628.
    • Prevent immunosuppression

      The tumor microenvironment (TME) contains cells and signaling molecules that suppress an anti-tumor immune response. Bristol Myers Squibb is investigating ways to block the tumor’s ability to recruit immunosuppressive cell types to the TME and inhibit signaling that contributes to immunosuppression.

      CTLA-4
      • CTLA-4 is an immune checkpoint receptor found on the surface of effector T cells and on regulatory T cells (Tregs).1,2
      • When the CTLA-4 pathway is engaged, Tregs in the TME suppress the immune response, inhibiting T cell activation.3
      • Targeting CTLA-4 with antibodies designed to deplete Tregs in the TME is intended to increase the anti-cancer immune response.4
      References
      1. Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators. Front Immunol. 2015;6:418. doi:10.3389/fimmu.2015.00418
      2. Regulation of CTLA-4 expression during T cell activation. J Immunol Baltim Md 1950. 1996;156(11):4154-4159.
      3. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192(2):303-310. doi:10.1084/jem.192.2.303
      4. 393 First-in-human phase 1/2a study of the novel nonfucosylated anti–CTLA-4 monoclonal antibody BMS-986218 ± nivolumab in advanced solid tumors: initial phase 1 results. J Immunother Cancer. 2020;8(suppl 3). doi:10.1136/jitc-2020-SITC2020.0393
      IL-8
      • The release of IL-8 by cancer cells promotes immune evasion by recruiting immunosuppressive cell types to the TME, thereby reducing immune response against the tumor.1
      • Prevention of IL-8 signaling is intended to inhibit the recruitment of immunosuppressive cell types to the TME.2
      References
      1. Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin Cancer Res Off J Am Assoc Cancer Res. 2016;22(15):3924-3936. doi:10.1158/1078-0432.CCR-15-2463
      2. The IL-8/IL-8R axis: a double agent in tumor immune resistance. Vaccines. 2016;4(3). doi:10.3390/vaccines4030022
      CCR8
      • is a protein found mainly on the surface of regulatory T cells (Tregs) within tumors and is a regulator of immune response.1,2
      • CCR8 is upregulated on a highly immunosuppressive subset of Tregs in multiple cancer types.2,3
      • Targeting CCR8 is intended to deplete Tregs and drive a pro-inflammatory response, resulting in inhibition of tumor growth.3
      References
      1. Clinical and prognostic significance of CC chemokine receptor type 8 protein expression in gastrointestinal stromal tumors. World J Gastroenterol. 2020;26(31):4656-4668. doi:10.3748/wjg.v26.i31.4656
      2. Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Sci. 2019;110(7):2080-2089. doi:10.1111/cas.14069
      3. Abstract 6694: Highly selective anti-CCR8 antibody-mediated depletion of regulatory T cells leads to potent antitumor activity alone and in combination with anti-PD-1 in preclinical models. Cancer Res. 2020;80(suppl 16):6694. doi:10.1158/1538-7445.AM2020-6694
      TGF-β1 and TGF-β3
      • TGF-β is a critical mediator of immuno-oncology resistance.1,3
      • Neutralization of cytokines TGF-β1 and TGF-β3 is intended to decrease immune exclusion and increase effector cell function.1,2
      References
      1. Targeting the TGFβ pathway for cancer therapy. Pharmacol Ther. 2015;147:22-31. doi:10.1016/j.pharmthera.2014.11.001
      2. P856 AVID200, first-in-class TGF-beta1 and beta3 selective inhibitor: results of a phase 1 monotherapy dose escalation study in solid tumors and evidence of target engagement in patients. J Immunother Cancer. 2020;8(suppl 1):A6-A7. doi: 10.1136/LBA2019.10
      ILT4
      • ILT4 is an immunosuppressive molecule expressed in myeloid cells and present in the tumor microenvironment (TME).1
      • Inhibition of the ILT4 receptor is intended to promote a proinflammatory response and result in subsequent cancer cell death.1
      References
      1. ILT4 functions as a potential checkpoint molecule for tumor immunotherapy. Biochim Biophys Acta Rev Cancer. 2018 Apr;1869(2):278-285. doi: 10.1016/j.bbcan.2018.04.001.
    • Enhance effector cell function

      Cancer cells can suppress effector cells (short-lived activated cells of the immune system), but these cells can also be modified to mount a cytotoxic attack. Bristol Myers Squibb is investigating ways to increase the ability of effector cells to act on cancer cells, direct cytotoxic activity toward cancer cells and engineer cell therapies that exhibit continued anti-cancer activity.

      CTLA-4
      • CTLA-4 is an immune checkpoint receptor found on the surface of activated T cells.1,2
      • Cancer cells use the CTLA-4 pathway to decrease T cell activation, proliferation and effector function—effectively turning “off” the immune response.3,4
      • Bristol Myers Squibb pioneered the first approved immune checkpoint inhibitor, a monoclonal antibody targeting CTLA-4, which ushered in a historic era of harnessing the immune system to treat cancer and ignited exploration into the TME.
      • Researchers are exploring strategies to optimize the CTLA-4 blockade by building on the existing CTLA-4 science through second- and next- generation compounds, with a goal of improving the risk-benefit profile of CTLA-4–directed therapy.5,6
      References
      1. Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators. Front Immunol. 2015;6:418. doi:10.3389/fimmu.2015.00418
      2. Regulation of CTLA-4 expression during T cell activation. J Immunol Baltim Md 1950. 1996;156(11):4154-4159.
      3. Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells. Eur J Immunol. 1998;28(10):3137-3143. doi:10.1002/(SICI)1521-4141(199810)28:10<3137::AID-IMMU3137>3.0.CO;2-X
      4. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106. doi:10.1097/COC.0000000000000239
      5. Abstract SY09-01: Next-generation anti-CTLA-4 antibodies. Cancer Res. 2017;77(suppl 13):SY09-01. doi:10.1158/1538-7445.AM2017-SY09-01
      6. Anti-CTLA-4 probody BMS-986249 alone or in combination with nivolumab in patients with advanced cancers: Initial phase I results. J Clin Oncol. 2020;38(suppl 15):3058. doi:10.1200/JCO.2020.38.15_suppl.3058
      NKG2-A
      • Inhibition of NKG2-A is intended to enhance effector cell function by blocking the inhibitory NKG2-A immune checkpoint signaling pathway.1,2
      References
      1. Setting traps for NKG2A gives NK cell immunotherapy a fighting chance. J Clin Invest. 129(5):1839-1841. doi:10.1172/JCI128480
      2. NKG2A, a new kid on the immune checkpoint block. Cell. 2018;175(7):1720-1722. doi:10.1016/j.cell.2018.11.048
      TIGIT
      • Inhibition of TIGIT is intended to restore effector cell function by blocking the inhibitory TIGIT immune checkpoint signaling pathway.1,2
      References
      1. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014; 26(6):923-937. doi: 10.1016/j.ccell.2014.10.018
      2. TIGIT: A key inhibitor of the cancer immunity cycle. Trends Immunol. 2017;38(1):20-28. doi:10.1016/j.it.2016.10.002
      AHR
      • Inhibitors of AHR are intended to block the activation of the AHR pathway—a pathway that promotes immunosuppression and immune cell dysfunction—leading to enhanced effector cell function.1,2
      • Activated AHR is also associated with resistance to immune checkpoint blockade.2
      References
      1. 448 Discovery of clinical candidate IK-175, a selective orally active AHR antagonist. J Immunother Cancer. 2020;8(suppl 3). doi:10.1136/jitc-2020-SITC2020.0448
      2. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine. Nat Commun. 2020;11(1):4011. doi:10.1038/s41467-020-17750-z
      IL-12
      • IL-12 is a proinflammatory cytokine that plays a central role in regulating both innate and adaptive anti-tumor immune response.1
      • IL-12 stimulates innate and adaptive immunity through increasing effector T cell and natural killer (NK) cell activity and IFN-γ production.1
      • IL-12 agonism is intended to stimulate effector cell activation and proliferation1
      References
      1. New insights into IL-12-mediated tumor suppression. Cell Death Differ. 2015;22(2):237-246. doi:10.1038/cdd.2014.134
      BCMA
      • BCMA is a transmembrane protein that plays a key role in the proliferation, maturation and differentiation of B cells into plasma cells and is important for plasma cell survival.1
      • BCMA can be overexpressed in cancer cells.2
      • BCMA can be targeted using multiple types of anti-cancer therapeutics, such as cell therapies, recognizing the BCMA receptor and subsequently killing the cancer cell.1,3,4
      References
      1. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. Front Immunol. 2018;9:1821. doi:10.3389/fimmu.2018.01821
      2. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood. 2004;103(2):689-694. doi:10.1182/blood-2003-06-2043
      3. BCMA-targeted immunotherapy for multiple myeloma. J Hematol Oncol. 2020;13:125. doi:10.1186/s13045-020-00962-7
      4. Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment. Cancer Cell. 2017;31(3):396-410. doi:10.1016/j.ccell.2017.02.002
      CD19
      • CD19 is a protein that is expressed in B-cell malignancies, including multiple cancer types.1,2
      • CD19 can be targeted using multiple types of anti-cancer therapeutics, such as cell therapies, recognizing the CD19 receptor and subsequently killing the cancer cell.3
      References
      1. Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes: a new member of the immunoglobulin superfamily. J Immunol. 1989;143(2):712-717.
      2. CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol. 2012;1(1):36. doi:10.1186/2162-3619-1-36
      3. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet Lond Engl. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0
      MAGE A4/8
      • MAGE A4/8 is a highly prevalent antigen present in multiple solid tumors.1
      • MAGE A4/8 can be targeted using anti-cancer therapies such as cell therapies, immune engagers and antibody drug conjugates, which recognize the antigen and subsequently kill the cancer cell.1
      References
      1. Adoptive cellular therapy in solid tumor malignancies: review of the literature and challenges ahead. J Immunother Cancer. 2021 Jul;9(7):e002723. doi: 10.1136/jitc-2021-002723.
      ROR1
      • ROR1 is overexpressed in many tumor types and plays a key role in cancer cell survival signaling.1
      • ROR1 can be targeted using anti-cancer therapies such as cell therapies, immune engagers and antibody drug conjugates, which recognize the antigen and subsequently kill the cancer cell.1
      References
      1. Tyrosine Kinase ROR1 as a Target for Anti-Cancer Therapies. Front Oncol. 2021 May 28;11:680834. doi: 10.3389/fonc.2021.680834.
      CD33
      • CD33 is a protein that is expressed on acute myeloid leukemia cells.1
      • CD33 can be targeted using anti-cancer therapies such as cell therapies, immune engagers and antibody drug conjugates, which recognize the antigen and subsequently kill the cancer cell.1
      References
      1. The role of CD33 as therapeutic target in acute myeloid leukemia. Expert Opin Ther. Targets. 2014;18:7, 715-718, DOI: 10.1517/14728222.2014.909413.
      GPRC5D
      • GPRC5D is a myeloma cell surface antigen overexpressed by cancer cells and associated with poor prognosis.1
      • GPRC5D can be targeted using anti-cancer therapies such as cell therapies, immune engagers and antibody drug conjugates, which recognize the antigen and subsequently kill the cancer cell.1
      References
      1. Al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med. 2019;11(485):eaau7746. doi: 10.1126/scitranslmed.aau7746.
    • Target tumor-intrinsic pathways

      Cancer cell growth and survival is dictated by molecular mechanisms within the tumor. Bristol Myers Squibb is working to leverage these various pathways to enhance cancer cell death.

      Aiolos and Ikaros
      • Aiolos and Ikaros regulate gene expression in tumor cells and T cells and contribute to myeloma cell survival.
      • The destruction of Aiolos and Ikaros, mediated through protein degradation, is intended to result in cancer cell death and stimulation of immune effector cells.1,2
      • With targeted protein degradation, researchers are harnessing cells’ own machinery to degrade several whole new classes of proteins that were previously considered “undruggable.”
      References
      1. Cereblon modulators: low molecular weight inducers of protein degradation. Drug Discov Today Technol. 2019;31:29-34. doi:10.1016/j.ddtec.2019.02.004
      2. Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN. Leukemia. 2020;34(4):1197-1201. doi:10.1038/s41375-019-0620-8
      AR
      • Androgen receptor (AR) plays a key role in prostate cancer cell proliferation, but increased AR expression and mutations lead to developed resistance to AR inhibitors.1
      • The selective destruction of AR, mediated through protein degradation, is intended to inhibit the proliferation of cancer cells.2,3
      References
      1. Androgen signaling in prostate cancer. Cold Spring Harb Perspect Med. 2017;7(9). doi:10.1101/cshperspect.a030452
      2. Androgen receptor-directed molecular conjugates for targeting prostate cancer. Front Chem. 2019;7. doi:10.3389/fchem.2019.00369
      3. Bivalent ligands for protein degradation in drug discovery. Comput Struct Biotechnol J. 2019;17:160-176. doi:10.1016/j.csbj.2019.01.006
      GSPT1
      • GSPT1 plays a key role in the cell life cycle; loss of GSPT1 activates a response leading to cell death.1,2
      • The selective destruction of GSPT1, mediated through protein degradation, is intended to lead to cell death.3,4
      • With targeted protein degradation, researchers are harnessing cells’ own machinery to degrade several whole new classes of proteins that were previously considered “undruggable.”
      References
      1. The integrated stress response: from mechanism to disease. Science. 2020;368(6489). doi:10.1126/science.aat5314
      2. Structural insights into eRF3 and stop codon recognition by eRF1. Genes Dev. 2009;23(9):1106-1118. doi:10.1101/gad.1770109
      3. CC-90009, a novel cereblon E3 ligase modulator, targets GSPT1 for degradation to induce potent tumoricidal activity against acute myeloid leukemia (AML). Blood. 2019;134(Suppl 1):2703. doi:10.1182/blood-2019-127892
      4. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells. Blood. 2021;137(5):661-677. doi:10.1182/blood.2020008676
      BET
      • Inhibition of the BET pathway, which perpetuates tumor cell growth and survival, is intended to modulate genetic drivers of oncogenesis, leading to a decrease in tumor growth.1,2
      References
      1. Pharmacological targeting of BET bromodomain proteins in acute myeloid leukemia and malignant lymphomas: from molecular characterization to clinical applications. Cancers. 2019;11(10). doi:10.3390/cancers11101483
      2. Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin’s lymphoma. Ann Oncol Off J Eur Soc Med Oncol. 2020;31(6):780-788. doi:10.1016/j.annonc.2020.03.294
      LSD1
      • Inhibition of the LSD1 pathway, which can regulate certain tumor gene expression, is thought to modulate gene expression related to tumor growth, leading to tumor reduction.1,2
      References
      1. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119(7):941-953. doi:10.1016/j.cell.2004.12.012
      2. 559P Phase Ib study of CC-90011 plus etoposide and cisplatin (EP) in patients with first-line extensive-stage (ES) small cell lung cancer (SCLC). Ann Oncol. 2020;31:S482-S483. doi:10.1016/j.annonc.2020.08.673
      CK1α
      • CK1α is a kinase that influences regulatory proteins involved in multiple signaling pathways important to cancer cells.1,2
      • The selective destruction of CK1α, mediated through protein degradation, is intended to inhibit the proliferation of cancer cells.1,2
      References
      1. Casein kinase 1α: biological mechanisms and theranostic potential. Cell Commun Signal. 2018 May 24;16(1):23. doi: 10.1186/s12964-018-0236-z.
      2. Targeting Casein Kinase 1 (CK1) in Hematological Cancers. Int. J. Mol. Sci. 2020;21(23):9026; https://doi.org/10.3390/ijms21239026.
      DGK
      • DGKs are a family of enzymes that modulate molecules that help regulate T cell activity.1
      • Inhibition of DGKs is designed to improve T cell activity in cancer.1
      References
      1. Diacylglycerol Kinases (DGKs): Novel Targets for Improving T Cell Activity in Cancer. Front Cell Dev Biol. 2016 Oct 17;4:108. doi: 10.3389/fcell.2016.00108.
      SHP2
      • SHP2 is a protein phosphatase associated with many types of cancer and is involved in multiple cancer-related processes.1
      • SHP2 is an attractive therapeutic target due to its wide-ranging role in cancer survival and growth.1
      References
      1. Functions of Shp2 in cancer. J Cell Mol Med. 2015 Sep;19(9):2075-83. doi: 10.1111/jcmm.12618.

  • With an expansive arsenal of modalities

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    • Organic compounds that are relatively small in size, usually taken orally and easily absorbed by the body.

    • Autologous chimeric antigen receptor (CAR) T cell therapy reprograms immune cells to attack cancer.

    • Molecules that redirect the body’s immune response toward cancer cells.

    • “Masked” antibodies that are activated within the tumor microenvironment. Designed to limit activity—and toxicity—in healthy tissue.

    • Engineered antibodies that can bind to 2 different antigens.

    • By tethering a small molecule to a biologic, antibody-drug conjugates are engineered to deliver small molecules to targeted locations using biologic monoclonal antibodies as honing mechanisms.