Immuno-Oncology 2.0: How Regeneron is Utilizing its Expertise in Antibodies to Lead the Next Wave of Combinatorial Approaches in Cancer Care
Amazingly, it is only a little more than a decade since the first approval of a checkpoint blockade antibody for the treatment of cancer, which has led to a paradigm shift in cancer treatment.1 Prior to that, despite prior occasional successes, there was a great deal of skepticism that the immune system could be harnessed to battle malignancy.2 Now immunotherapy (including checkpoint inhibitors, tumor-targeted CD3 bispecifics, personalized cellular therapies, and other modalities) is accepted as a fundamental pillar of cancer care, alongside surgery, radiation and chemotherapy.1,3
While recent advances in the field of immuno-oncology have been transformational, significant unmet need remains for new cancer treatments that increase survival, reduce progression and improve quality of life for patients.1
The Universe of Immune Oncology Approaches
Approaches to augmenting the immune response to fight cancer range from those that directly enhance specific anti-tumor antigen reactivity to those that indirectly augment immune system function.
Classic examples of the direct approach are tumor infiltrating lymphocytes (TILs) that were hypothesized to be enriched in T cells that recognize tumor antigens. The isolation of TILs or peripheral T cells, expansion with/without gene engineering, and return to patients is a variation of directed personalized cellular therapies that have been approved or are in development.4 Personalized cellular immunotherapies have garnered substantial attention in the past few years.
Examples of indirect approaches include the original “Coley’s toxins,” cytokine based therapies such as high-dose interleukin 2 or, most prominently, checkpoint blockade, particularly CTLA-4 as the first to reach the market followed closely by PD-1/PD-1 ligand (PD-L1) based treatments.5,6 Checkpoint inhibitors help release the brakes that tumor cells exploit to prevent the system from reacting to them and further enhance the ability of immune cells to recognize and eliminate those cancer cells from the body.7 Some tumors express significant amounts of PD-L1, which interacts with the PD-1 receptor on cytotoxic T cells to block T cell activation. Anti-PD-1 and anti-PDL1 therapies block the PD-1 and anti-PD-L1 receptors on the T cells, respectively, thus re-enabling T cell activation against the cancer cells. Anti-PD-1 treatments have been approved both as a monotherapy, as well as part of combination therapies, irrespective of PD-L1 expression, for a variety of cancers.8 Particularly, anti-PD-1 therapies are now a cornerstone in cancer treatment due to their ability to help overcome one of tumors’ greatest survival mechanisms: suppression of the immune system.1,9
Between the poles of direct and indirect mechanisms lie newer efforts to focus immune activation towards tumor antigens, including tumor vaccines, protein therapeutics such as CD3 bispecifics, or tumor targeted cytokines. In particular, CD3 redirecting bispecific agents bridge tumor antigens to T cells and have been approved in several hematologic malignancies and are in development in solid tumors.9,10
Regeneron’s Approach to Oncology
A major focus of our research is to better harness and complement the immune system’s mechanisms for targeting and eliminating cancer cells with greater specificity while sparing as many healthy cells as possible. Regeneron recognizes that one of the key principles for successful deployment of the immune system is multi-targeting, the notion that multiple effector arms or specificities in combination will be required for optimal and durable anti-tumor activity. This is a lesson learned from the ostensible original purpose of the immune system, namely, to protect organisms from infectious pathogens.1,11
Regeneron’s tradition of physician-scientist leadership and deep knowledge of human biology guides us to look at cancer differently than other biopharmaceutical companies, following the science to fuel continued innovation and enable the development of novel combinatorial therapies. We are actively working to harness the body’s natural abilities to fight cancer via the immune system in new ways.
In particular, we invested in developing a toolkit of agents that target different aspects of the immune system and lend themselves to facile combinations with the goal of deploying the most potent immune effector responses against cancer.
Laying the Foundation with Anti-PD-1 Research
Regeneron initiated efforts researching the PD-1 pathway, and we have applied this experience to identify additional investigational pathways with the potential to address unmet medical need.
Research focused on PD-1 inhibition has made great strides in overcoming the immunosuppressive mechanisms of cancer cells, and combination therapies have progressed our understanding of how to harness the immune system’s abilities to fight cancer. We believe there is more to be done.1 We are currently developing additional combinations of checkpoint inhibitors and bispecifics.
Building a Future of Immunotherapy with Bispecific Antibody Approaches
Bispecific antibodies utilize the multi-targeting function of antibodies to enhance existing methods of cancer cell destruction.1 Regeneron’s Veloci-Bi® platform builds upon our antibody expertise and allows us to create full-length bispecific antibodies with no linkers or artificial sequences.12 Bispecific antibodies can thus be generated to bind to a target of choice, such as a tumor cell marker, and manufactured as a potential anti-cancer therapeutic. Due to the absence of artificial linkers, the bispecific antibodies mimic the structure and function of monoclonal antibodies but bind to multiple targets to enhance immune system function and targeted destruction of cancer cells.1,13
Being able to research these multiple pathways under one roof provides flexibility to easily explore different combination approaches.
Delivering on the Clinical Potential in Oncology
For 35 years, Regeneron has remained steadfast in our mission to use the power of science to repeatedly bring new, life-transforming medicines to patients. We’re applying this end-to-end formula to oncology, with the goal of revolutionizing the way cancer is treated. We are pursuing research with the goal of enhancing the natural functions of the human immune system to fight cancer.
Ultimately, we are proud to stand at the forefront of innovation for novel treatments in oncology and are committed to utilizing therapeutic flexibility to pioneer potential new solutions for previously untreatable cancers.
References
1Dahlen E, Veitonmaki N, Norlen P. Bispecific antibodies in cancer immunotherapy. Ther Adv Vaccines Immunother. 2018; 6(1):3–17. doi: 10.1177/2515135518763280
2Dobosz P, Dzieciątkowski T. The Intriguing History of Cancer Immunotherapy. Front Immunol. 2019; 10:2965. doi: 10.3389/fimmu.2019.02965
3National Cancer Institute. Immunotherapy to Treat Cancer. Published September 24, 2019. Accessed April 9, 2023. www.cancer.gov/about-cancer/treatment/types/immunotherapy
4Paijens S, Vledder A, Bruyn M, Nijman H. Tumor-infiltrating lymphocytes in the immunotherapy era. Cell Mol Immunol. 2020;18(4):842–859. doi: 10.1038/s41423-020-00565-9
5Asao, H. Interleukin-2. Reference Module in Biomedical Sciences. 2014. doi: 10.1016/B978-0-12-801238-3.040587
6Szeto G, Finley S. Integrative Approaches to Cancer Immunotherapy. Trends Cancer. 2019;5(7);400-410. doi: 10.1016/j.trecan.2019.05.010.
7Papaioannou, NE, Beniata, OV, Vitsos P, Tsitsilonis O, Samara P. Harnessing the immune system to improve cancer therapy. Annals of Translational Medicine. 2016;4(14):261–261. doi.org/10.21037/atm.2016.04.01
8Jiang H, Ni H, Zhang P, Guo X, Wu M, Shen H, et al. Oncoimmunology, 10(1), 1943180. Doi: 10.1080/2162402X.2021.1943180
9KC, Miljkovic MD, Walkdmann TA. Cytokines in the Treatment of Cancer. J Interferon Cytokine Res. 2019;39(1):6–21. doi: 10.1089/jir.2018.0019
10Benonisson H, Altintas I, Sluijter M, Verploegen S, Labrijn AF, Schuurhuis DH, et al. CD3-Bispecific Antibody Therapy Turns Solid Tumors into Inflammatory Sites but Does Not Install Protective Memory. Mol Cancer Ther. 2019;18(2):312–322. doi: 10.1158/1535-7163.MCT-18-0679
11Petrelli A, Giordano S. From single- to multi-target drugs in cancer therapy: when aspecificity becomes an advantage. Current Medicinal Chemistry. 2008;15(5):422-432. doi: 10.2174/092986708783503212
12Data on file. Regeneron.com: Technology.
13Wu Z, Cheung NV. T cell engaging bispecific antibody (T-BsAb): From technology to therapeutics. Pharmacology & Therapeutics. 2018; 182:161–175. Doi: 10.1016/j.pharmthera.2017.08.005
UNB-23-04-0001 06/2023
© 2023 Regeneron Pharmaceuticals Inc. All rights reserved.