The goal of cancer immunotherapy is to eliminate cancer cells by initiating or reinitiating the anti-cancer immune response.1 Immuno-oncology has transformed the standard of care across multiple cancer types with many immunotherapy approvals over the past decade.2 TESARO is investigating various immune-modulating antibodies that stimulate immune cells or block immune inhibitory checkpoint pathways in combination with one another or other targeted agents. Combining checkpoint inhibitors with other therapies may have a synergistic effect and broaden the spectrum of patients that may benefit from these treatments.3
In recent years, the immune checkpoint blockade has emerged as one of the most promising therapeutic options for patients in the history of cancer treatment.2
Antibodies to immune checkpoint receptors have demonstrated promise in the treatment of certain solid tumors, including metastatic melanoma, renal cell carcinoma, and non-small cell lung cancer (NSCLC).4 Although the normal function of immune checkpoint is to maintain immune homeostasis, they can be co-opted by certain tumors to evade immune surveillance.5
Our pipeline includes different investigational checkpoint inhibitors, including dostarlimab (TSR-042, anti-PD-1), TSR-022 (anti-TIM-3), and TSR-033 (anti-LAG-3), and other bi-specific agents. PD-1, TIM-3, and LAG-3 are checkpoint regulators that modulate the function of the immune system via different mechanisms and may limit the ability of the immune system to respond effectively to tumors.5
By blocking the interaction of PD-1, TIM-3, and LAG-3 with their respective ligands, antibodies to these targets aim to restore immune anti-cancer function across a variety of tumor types.5
These potential combinations could have an impact on the landscape in ovarian, triple-negative breast, and non-small cell lung cancers, and have the potential to provide treatment options to thousands of patients.7
The PD-1, or programmed death-1/PD-L1, axis is relevant in many tumor types.6 Upregulation of the PD-1 pathway reduces the immune system’s ability to eliminate tumor cells.5 Blocking PD-1 has been shown to increase anti-tumor immune responses (regression).4 The presence of the PD-1 ligand, PD-L1, has been identified with many tumor types, and expression of PD-L1 has been linked to poor clinical outcomes in a variety of cancers.8 PD-1 checkpoint inhibitors have yielded results, leading to multiple US FDA approvals in a variety of tumor types.4,5
Dostarlimab is an investigational humanized anti-PD-1 monoclonal antibody that binds with high affinity to the PD receptor and effectively blocks interactions with PD-1 ligands, PD-L1, and PD-L2 receptors.
Dostarlimab is being evaluated as monotherapy and in combination with other immuno-oncology agents. It is also being studied with niraparib, a PARP 1/2 inhibitor. Dostarlimab is being investigated in endometrial, NSCLC, and MSI-H tumors as monotherapy.
TIM-3, or T cell immunoglobulin and mucin domain 3, is a key immune checkpoint receptor found on T cells. Upregulation of TIM-3 expression is associated with low levels of T cell proliferation and cytokine production, both of which are important for anti-tumor activity. TIM-3 is expressed on the T cells of patients diagnosed with a variety of tumor types.9
Expression of TIM-3 on killer T cells prevents activation of these cells by PD-1 therapies and diminishes anti-tumor immune effects. Emerging data suggest that TIM-3 expression on dendritic and other immune cells may prevent these cells from recruiting and priming T cells.9
TSR-022 is a humanized anti-TIM-3 monoclonal antibody that increases proliferation and activation of human T cells in experimental systems. In combination with dostarlimab, TSR-022 enhances the activation of T cells and in preclinical models was shown to produce improved anti-tumor activity over dostarlimab alone.
TSR-022 is currently being assessed in patients with advanced solid tumors as monotherapy and in combination with dostarlimab, including in the NSCLC, melanoma, and colorectal cancer setting.
LAG-3, or lymphocyte activation gene 3, is an immune checkpoint receptor found on effector and regulatory T cells that controls T cell response, activation, and growth.10 Progressive expression of immune checkpoint receptors, including LAG-3, contributes to T cell exhaustion and compromises anti-tumor immune response.11 LAG-3 is widely expressed on the T cells of patients diagnosed with different tumor types.12
LAG-3 is often co-expressed with PD-1.10 The LAG-3 blockade with TSR-033 in combination with dostarlimab boosts immune function and elicits anti-tumor immunity in preclinical models.12
TSR-033 is currently in early clinical development in advanced solid tumors. TSR-033 is an investigational, potent, humanized, anti-LAG-3 monoclonal antibody that blocks the interaction of the LAG-3 receptor with its ligand, major histocompatibility complex class II, on antigen-presenting cells.13
Clinical data suggest that the combined anti-PD-1 and anti-LAG-3 checkpoint blockade may lead to increased anti-tumor activity compared with anti-PD-1 alone in patients who have progressed on anti-PD-1 therapy.13
References: 1. NCI Dictionary of Cancer Terms: immunotherapy. National Cancer Institute website. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immunotherapy. Accessed April 16, 2019. 2. Tang J, Shalabi A, Hubbard-Lucey VM. Comprehensive analysis of the clinical immune-oncology landscape. Ann Oncol. 2017;29(1):84-91. doi:10.1093/annonc/mdx755. 3. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237-51. doi:10.1038/nrc3237. 4. Mullard A. New checkpoint inhibitors ride the immunotherapy tsunami. Nat Rev Drug Discov. 2013;12(7):489-492. doi:10.1038/nrd4066. 5. Chen DS, Mellman I. Oncology meets immunology: The cancer-immunity cycle. Immunity. 2013;39(1):1-10. doi:10.1016/j.immuni.2013.07.012. 6. Koyama S, Akbay EA, Li YY, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commu. 2016;7(1). doi:10.1038/ncomms10501. 7. Morrissey K, Yuraszeck T, Li C-C, Zhang Y, Kasichayanula S. Immunotherapy and novel combinations in oncology: current landscape, challenges, and opportunities. Clin Transl Sci. 2016;9(2):89-104. doi:10.1111/cts.12391. 8. Yu J, Wang X, Teng F, Kong L. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016;(9):5023-5039. doi:10.2147/ott.s105862. 9. Yoneda A, Jinushi M. T cell immunoglobulin domain and mucin domain-3 as an emerging target for immunotherapy in cancer management. Immunotargets Ther. 2013:135. doi:10.2147/itt.s38296. 10. Woo S-R, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2011;72(4):917-927. doi:10.1158/0008-5472.can-11-1620. 11. Jing W, Gershan JA, Weber J, et al. Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma. J Immunother Cancer. 2015;3(1). doi:10.1186/s40425-014-0043-z. 12. Puhr HC, Ilhan-Mutlu A. New emerging targets in cancer immunotherapy: the role of LAG3. ESMO Open. 2019;4. doi:10.1136/esmoopen-2018-000482. 13. Ghosh, Srimoyee, et al. TSR-033, a novel therapeutic antibody targeting LAG-3, enhances T-cell function and the activity of PD-1 blockade in vitro and in vivo. Mol Cancer Ther. 2019 Mar;18(3):632-64. doi:10.1158/1535-7163.mct-18-0836.