Innovative combination therapies show promise for improving clinical response rates. By Atif Abbas
Current standard of care approaches to treating patients with cancer include several different modalities such as surgery, radiotherapy, cytotoxic chemotherapy, targeted therapies and more recently immunotherapy as single modalities or combination therapies. Recently, therapeutic agents designed to engage the host immune system, such as the check-point inhibitors (CPIs) (PD-1/PD-L1, CTLA4 etc.), have shown good clinical responses in the management and treatment of solid tumors. The efficacy of checkpoint inhibitors illustrates that cancer immunotherapy can be successfully implemented in routine clinical practice. However, alongside that success, a substantial proportion of patients do not achieve significant clinical benefit from this treatment, underscoring the need to identify additional strategies to treat cancer. To further improve clinical response rates with acceptable toxicity profile, researchers are looking for novel combination regimens, with checkpoint blockade as a backbone of the treatment.
Combination therapies are widely regarded as the future of modern oncology. For many cancer types, we are likely to see a checkpoint inhibitor as a backbone therapy that could be combined with adjunct therapies. Although this strategy is advantageous from an efficacy point of view, researchers are also mindful of the possible clinical safety implications.
Because tumors can suppress proper immune system function, activation of the innate immune system can counteract tumor‐induced immunosuppression and potentially has a synergistic effect with existing cancer therapies. Toll‐like receptors (TLRs) and stimulator of interferon genes (STING) are therefore promising innate immune targets in cancer immunotherapy and present a new combination strategy to bridge the gap between innate and adaptive immunity.
Bridging Innate and Adaptive Immunity with STING Agonist
Stimulator of interferon genes (STING) is known to be a central mediator of innate and adaptive immunity, so STING agonists have become a hot area of scientific exploration for patients with solid tumors. The drugs target STING, a protein that plays an important role in the innate immune system. When STING is activated to ward off an invading pathogen, the body begins to produce inflammatory proteins called cytokines and interferons. Those inflammatory proteins then kick the innate immune system into gear, which then produces T cells to destroy the pathogens. Natural STING pathway activators are small molecules generated by bacteria and immune cells. In order to boost this immune response in patients battling a number of diseases, researchers are diving into the development of medications that will activate the STING pathway in order to boost the body’s T cell response.
More recently, a central role has been attributed to STING in tumor surveillance, immune-mediated antitumor response, and tumor clearance. STING, located in the endoplasmic reticulum (ER) in cells, is activated by tumor-derived DNA that is converted into cyclic dinucleotides to trigger cytokine secretion. Activation of STING via binding of its ligand results in the stimulation of Type 1 and Type 3 interferon (IFN) production and induction and activation of the innate and adaptive immune systems that can mediate tumor clearance.
STING agonist can be combined with other cancer therapies and checkpoint inhibitors for a more comprehensive approach to fighting certain cancers
STING Agonist Compounds in Clinical Development
Due to profound interest in exploring the STING pathway, numerous companies are developing STING agonists. Currently, intratumorally administered STING agonist compound ADU-100 is being tested in a Phase I clinical trial as a single agent and in combination with ipilimumab, and in a Phase Ib trial with spartalizumab (PDR001), an investigational anti-PD-1 compound.
These studies are enrolling patients with cutaneously accessible advanced/metastatic solid tumors or lymphomas. Additionally, MK-1454, an investigational intratumoral STING agonist, is being investigated as both a monotherapy and in combination with checkpoint inhibitor Keytruda, an anti-PD-1 therapy, in patients with advanced solid tumors or lymphomas. Pre-clinical data supported by data from Phase I studies have shown enhanced antitumor activity when STING Agonist is combined with the “check-point inhibitors” (anti-CTLA or anti-PD1).
Need for Intravenously Administered STING Agonist
Despite the recent success in the development of STING agonists in antitumor therapy, an intratumoral injection is necessary in therapies in development to activate the STING receptor efficiently, which may have an impact on the clinical development of this class of molecules. Intratumor administration is much more logistically and financially demanding, in addition to carrying the risks associated with biopsy, such as spreading or infection.
Therefore it is desirable to identify safe and systemically available STING agonists to treat tumors that are inaccessible through direct injection.
Spring Bank’s STING Agonist Investigational Compound – SB 11285
Because of its unique pharmaceutical attributes, Spring Bank’s investigational compound SB 11285 can be administered by the intravenous (IV) route. In preclinical studies, SB 11285 demonstrated highly potent induction of the STING pathway, resulting in recruitment of increased numbers of multiple immune cell types to the tumor microenvironment (TME). In syngeneic murine tumor models, this led to complete tumor regression, highly durable anti-tumor effects, induction of immune memory and abscopal effects. SB 11285 has also been combined with CPIs, anti-CTLA or anti-PD1, and has shown enhanced activity in terms of tumor growth inhibition as a combination in preclinical studies.
Spring Bank’s Small Molecule Nucleic Acid Hybrid (SMNH) compounds are endowed with properties to form nanostructures that enable them to enter cells readily and be captured by immune cells. These attributes enable them to be potent agonists for immunotherapy either alone or when used in combination with other agents. On the other hand, many STING agonist drugs do not enter cells readily, and therefore may not be efficacious, and are also limited to the intratumoral route of delivery.
IV administration is a well-established treatment modality for cancer patients where multiple cancer drugs are often administered via IV route in a hospital setting. IV administration will also help in treatment of many cancers not accessible by intratumoral administration. Therefore, we anticipate a broader clinical utility with SB 11285 in multiple cancers.
Spring Bank’s Clinical Development Strategy
Spring Bank’s IND for intravenous SB11285 was accepted by the FDA in July 2019. Initially, we plan to explore IV SB11285 antitumor activity as monotherapy and in combination with PD-1 (nivolumab) in multiple tumor types – Phase 1a/1b Trial. Further development plans include various combinations with other checkpoints (CTLA-4 and PD-L1) and treatment modalities (radiation and chemotherapy).
The objectives of the Phase 1 trial include determining a safe and pharmacodynamically active dose of SB 11285 and preliminary assessment of antitumor activity/efficacy. Compatibility with checkpoint inhibitors is important, so the Part 1 Dose Escalation study will evaluate ascending doses of IV SB 11285 with respect to dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended phase 2 dose and the pharmacokinetic/pharmacodynamic profile as monotherapy and in combination with nivolumab, a PD-1 blocking antibody. The Part 2 Expansion Cohorts of the study is designed to explore signs of efficacy in pre-specified tumor types using the recommended phase 2 dose of SB 11285 in combination with nivolumab.
Atif Abbas, M.D., is Vice President, Head of Oncology & Immunology Clinical Development at Spring Bank Pharma