This material reflects the GSK research pipeline as of December 2021
Pipeline
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Immuno-Oncology
Harnessing The Body’s Immune System
The growing understanding of tumor cells' ability to evade immune surveillance has led to advances in the field of immuno-oncology.1
Malignant cells manipulate a variety of physiological mechanisms involved in antigenicity, immune activation, T-cell priming and recruitment, and upregulation of checkpoint molecules.1 Many of these mechanisms may be impacted simultaneously to promote tumor cell survival.1 Immunotherapies harness the body's own immune system to fight cancer by using different immunological pathways to enhance antitumor responses.1,2
GSK is exploring different clinical assets aimed at augmenting the immune response, reducing immune suppression, and modulating the tumor microenvironment.3,4
Oncology Cell Therapy
Engineering Immune Cells to Target Cancer
The physiologic role of central and peripheral tolerance mechanisms is to limit unchecked immune responses that can lead to autoimmunity.12 In cancer, these mechanisms are major limitations to effective T-cell-mediated antitumor immunity.12 T-cell immunotherapy that uses autologous genetically modified T cells may mediate improved antitumor effects. T cells are isolated from the patient, modified to express a T-cell receptor (TCR) with greater affinity for a specific cancer antigen–alone or in combination with other modifications to T-cell function–and then reintroduced into the patient.12,13 This innovative approach generates T cells that may be more efficient at recognizing cancer cells and overcoming the barriers of tolerance mechanisms.13 GSK is developing a platform of investigational TCR T-cell immunotherapies designed to target a tumor-specific antigen and eliminate malignant cells in solid tumors and hematologic malignancies.9
Tumor Cell Targeting
Targeting Cancer Cell-Specific Alterations
Cancer cells exhibit differences from somatic cells due to alterations that promote growth, proliferation, survival, and metastasis.8 These tumor-specific attributes can be selectively targeted through established modalities such as antibody-drug conjugates (ADCs), small molecules, and other biological therapies, including gene therapy.8,9 GSK is investigating multiple targeted cell therapies in ongoing clinical studies.7
Synthetic Lethality
Inhibiting Pathways That Contribute to Aberrant DNA Repair and Cellular Metabolism
Accumulation of DNA damage, genomic instability, and altered cellular metabolism are pervasive characteristics of human tumors.10-12 Disruption of essential DNA damage repair or cellular metabolism in cancer cells may increase dependency on alternate repair pathways for cell survival or make tumors more susceptible to modulation of metabolic enzymes.11,13 Synthetically lethal therapies aim to combine pharmacologic inhibition of targeted pathways with tumor-inherent defects in key cellular processes that promote aberrant proliferation to selectively kill tumor cells while sparing healthy tissue.11,13-15 GSK is investigating clinical assets that utilize the power of synthetically lethal interactions to fight malignant cells in a variety of cancers.
Footnotes
†Not yet recruiting as of October 1, 2021.
‡The trial is no longer enrolling patients with endometrial cancer.
§Collaboration and License Alliance between GSK and iTeos Therapeutics.
ᶲIn collaboration with 23andMe.
ᶳIn collaboration with ENGOT, the European Network for Gynaecological Oncological Trial groups.
References
Allard B, Aspeslagh S, Garaud S, et al. Immuno-oncology-101: overview of major concepts and translational perspectives. Semin Cancer Biol. 2018;52(pt 2):1-11. doi:10.1016/j.semcancer.2018.02.005. - Medicines in development for immuno-oncology 2017 report. PhRMA. June 1, 2017. Accessed January 30, 2019. https://phrma.org/resource-center/Topics/Research-and-Development/Medicines-in-Development-for-Immuno-Oncology-2017-Report
- Tai Y-T, Anderson KC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy. 2015;7(11):1187-1199.
- Knudson KM, Hicks KC, Luo X, Chen J-Q, Schlom J, Gameiro SR. M7824, a novel bifunctional anti-PD-L1/TGF trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. Oncoimmunology. 2018;7(5):e1426519. doi:10.1080/2162402X.2018.1426519.
- Perica K, Varela JC, Oelke M, Schneck J. Adoptive T cell immunotherapy for cancer. Rambam Maimonides Med J. 2015;6(1):e0004. doi:10.5041/RMMJ.10179.
- Sharpe M, Mount N. Genetically modified T cells in cancer therapy: opportunities and challenges. Dis Model Mech. 2015;8(4):337-350.
- ClinicalTrials.gov. Accessed September 21, 2021. www.clinicaltrials.gov/
- Lee YT, Tan YJ, Oon CE. Molecular targeted therapy: treating cancer with specificity. Eur J Pharmacol. 2018;834:188-196.
- Hafeez U, Parakh S, Gan HK, Scott AM. Antibody-drug conjugates for cancer therapy. Molecules. 2020;25(20):4764. doi:10.3390/molecules25204764.
- Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481(7381):287-294.
- O’Connor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015;60(4):547-560.
- Coller HA. Is cancer a metabolic disease? Am J Pathol. 2014;184(1):4-17.
- Marjon K, Cameron MJ, Quang P, et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep. 2016;15(3):574-587.
- Kelley MR, Logsdon D, Fishel ML. Targeting DNA repair pathways for cancer treatment: what’s new? Future Oncol. 2014;10(7):1215-1237.
- O’Neil NJ, Bailey ML, Hieter P. Synthetic lethality and cancer. Nat Rev Genet. 2017;18(10):613-623.
NX-CA-AOU-WCNT-210001 | February 2022
