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Drugs repurposed to potentiate immunotherapy for cancer treatment
Introduction
Cancer is a leading cause of death worldwide. Given the unmet need for more effective anticancer therapy, intense efforts have been invested in searching for better anticancer drugs in a more efficient manner. Pharmaceutical companies and academic investigators alike have become increasingly interested in finding new uses of the existing drugs, a process referred to as drug repurposing or repositioning, to treat cancer. The existing drugs might have been used in the clinic for different indications. In other cases, the drug candidates might have been halted from further development due to insufficient efficacy in their original intended indications or marketing considerations. Since the safety profile and pharmacokinetic properties of approved drugs have already been well studied in clinical trials, repurposing a drug promises faster access of drugs to patients and it can save time and money. It has been estimated that the classical de novo drug discovery process generally takes about 14 years and US$2.5 billion to approve and launch a new drug starting from hit selection in vitro [ ].
Drug repurposing has been largely a serendipitous process when an off-target effect of a drug was identified for a new medical indication. In recent years, in silico predictive tools and high-throughput screening methods have been developed to facilitate drug repurposing process. Various molecular docking- [ ] and omics-based [ ] approaches have been applied for drug repurposing. Drugs having similar chemical structures and biological activities have been evaluated to find out whether they may have similar clinical indications. Similarity of protein structures, at local ligand binding sites, has been exploited to identify drugs to target diseases beyond their original indications. A few electronic resources are invaluable for this approach, which include Protein Data Bank [ ], Protein-binding Sites (ProBis) [ ], and Protein–Ligand Interaction Profiler [ ], and DrugPredict [ ]. Moreover, databases including the Connectivity Map [ ] and the Library of Integrated Network-based Cellular Signatures [ , ] have been used to identify drugs with similar transcriptional signature for drug repurposing. More recently, a few databases, including Drug Repurposing Hub [ ], Drug Target Commons [ ], and Open Targets [ ], have been established to integrate various computational approaches to enable the search for repurposed drugs using more comprehensive information. Two most recently developed databases, repoDB [ ] and repurposeDB [ ], also incorporate information about clinical results of drug repurposing. Schneider et al. recently reported a comprehensive visual analytics tool, called ClinOmicsTrail bc , that analyzes and visualizes clinical biomarkers, genomics/epigenomics, and transcriptomics datasets to facilitate a holistic assessment of the use of targeted drugs, drug candidates for repurposing, and immunotherapeutic agents in the treatment of breast cancer [ ].
Promise of cancer immunotherapy
Immune checkpoint blockade with anticytotoxic T lymphocyte-associated antigen 4 (CTLA-4) (ipilimumab and tremelimumab), antiprogrammed cell death receptor (PD-1) (nivolumab and pembrolizumab), or anti–PD-ligand (PD-L1) (duralumab, atezolizumab, and avelumab) monoclonal antibodies are shifting cancer therapy paradigm, which induce durable tumor responses and overall survival benefit in a wide variety of cancer types. While the CTLA-4 blockade may be associated with immune-related adverse events (irAEs) (such as colitis, hepatitis, dermatitis, endocrinopathies, and neuropathies), the PD-1 blockade is more tolerated by the patients with minimal irAE.
PD-1 is an inhibitory receptor expressed on activated T cells, B cells, and natural killer cells, which normally function to blunt the immune response. PD-1 is engaged by its major ligand PD-L1, which are expressed in tumor cells and infiltrating immune cells, to suppress the T cell–mediated cancer killing effect. Anti–PD-1/PD-L1 antibodies work by binding to inhibitory PD-1 receptor on tumor-reactive T cells and PD-L1 on tumor cells, respectively, thereby disrupting the PD-1:PD-L1 interaction and reactivating the antitumor T cell–mediated cell cytotoxicity. Clinical benefit from anti-PD-1/PD-L1 therapy is associated with high tumor mutational load, high levels of pretreatment tumor-infiltrating T cells, and high expression of pretreatment PD-L1 on tumor cells and tumor-infiltrating immune cells.
Despite enormous clinical success achieved by immune checkpoint inhibitors, both primary and acquired resistance are preventing cancer patients from responding to these immunotherapeutic agents or having a durable disease control. Cancer resistance to immunotherapy can be mediated by both tumor-intrinsic and tumor-extrinsic mechanisms. A few comprehensive reviews on the resistance mechanisms to cancer immunotherapy can be found in recent publications [ ]. Tumor-intrinsic factors include T-cell exhaustion, loss of antigen protein expression, and absence of antigen presentation. On the other hand, absence of T cells with tumor antigen–specific T-cell receptors and presence of immunosuppressive cells (i.e., regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages [TAMs]) in the tumor microenvironment (TME) represent the major tumor-extrinsic factors leading to resistance [ ].
New opportunities for drug repurposing in cancer immunotherapy
Fueled by the clinical success of immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies) in ever-growing number of tumor types, there has been a resurgence of research interest in immunological approaches to treat cancer. Nevertheless, not all tumors respond to immune checkpoint therapy. In order to maximize the clinical efficacy of cancer immunotherapy, additional approaches for enhancing tumor immunity are urgently needed. Tumors may not respond well to immunotherapy due to either tumor-intrinsic or tumor-extrinsic factors as described above.
Drugs originally approved for noncancer indications have been combined with checkpoint inhibitors to boost antitumor immunity [ ]. It is noteworthy that these repurposed drugs do not need to be directly cytotoxic themselves, thus imposing less toxicity issues to normal tissues. On the other hand, anticancer drugs not initially intended for cancer immunotherapy have been used to modulate the immune system so that these drugs form part of the antitumor immune cocktail (sometimes referred to as “soft repurposing”) [ , ]. The repurposed drugs act by either exerting immunostimulatory activities or abolishing immunosuppressive TME ( Fig. 12.1 ). For example, the angiotensin II receptor blocker (ARB) (valsartan) has been shown to increase the population of the tumor antigen gp70-specific T cells [ ]. Metformin was reported to exert multiple effect to remodel the TME, including (i) protection of CD8 + T cells from apoptosis [ ], (ii) degradation of PD-L1 [ ], and (iii) reduction of intratumoral hypoxia [ ], which collectively preserve functionality of antitumor immune cells and reverse the immunosuppressive TME. Cyclophosphamide [ ] and sunitinib [ ], which are clinically approved anticancer drugs, have been shown to reduce the abundance of immunosuppressive Treg and/or MDSCs. These drugs represent untapped opportunities for new and affordable treatment options for enhancing the efficacy of immunotherapy that can be readily evaluated. More emerging and promising drug candidates for repurposing are described according to their mechanisms of action in the next section.
Promising examples of repurposed drug candidates for cancer immunotherapy
Small molecules for reversal of T-cell exhaustion
Cytotoxic T lymphocytes (CTLs) play a central role in mediating immune surveillance to recognize and remove unwanted virus-infected cells and malignant tumor cells in our body. As a self-protective mechanism, viruses and tumors are able to upregulate several inhibitory checkpoint receptors on the surfaces of CTLs to counteract the host immune surveillance activity (which is also commonly described as T-cell exhaustion). The checkpoint inhibitory therapies (anti-PD-1 or anti-CTLA-4 monoclonal antibodies) neutralize the inhibitory receptors such as PD-1 or CTLA-4 on exhausted T cells, thereby restoring their effector immune responses [ , ]. However, responses in many cancer patients are limited due to insufficient restoration of T-cell function [ ]. Active research is underway to discover additional targets and pharmacologic agents to overcome the limitations of the current immune checkpoint blockade [ ]. To this end, it has been recently shown that low molecular weight therapeutics can complement or replace existing immune checkpoint blockade biologics (comprehensively reviewed in Ref. [ ]). Conventional chemotherapy, targeted therapies, and radiation therapy have been shown to induce antitumor immunity. Well-known examples include anthracycline-class cytotoxic chemotherapeutic drugs (e.g., doxorubicin, which induces immunogenic cell death [ICD] and block immunosuppressive pathways) and vascular endothelial growth factor (VEGF) inhibitors (e.g., bevacizumab, which increases the numbers of intratumoral cytotoxic T cells and reduce accumulation of immunosuppressive Treg cells) [ ]. Therefore, rational combination of these traditional treatment modalities with immunotherapy has been shown to increase the rate of complete and durable clinical response in cancer patients.
A few recent studies have identified new T cell–modifying drugs by phenotypic screening of chemical libraries [ ]. These investigations have a drawback as they relied on artificial activation of T cells from naïve mice via antibody stimulation with CD3/CD28 molecules rather than antigen-experienced T cells exhibiting dysfunctional effector responses. To this end, functional exhaustion of virus-specific T cells was first described in mice infected with the clone 13 (CL13) variant of lymphocytic choriomeningitis virus (LCMV) [ ]. CL13 leads to sustained expression of inhibitory receptors (including PD-1) and immunosuppressive cytokine interleukin-10 (IL-10), suboptimal CD4, and CD8 T-cell activity and persistent viral infection (reviewed in Ref. [ ]). Most recently, a high-throughput screening platform has been developed, which utilized an in vivo LCMV-CL13 model to identify small molecules that reverse T-cell exhaustion [ ]. In this study, C57BL/6 mice were infected with LCMV-CL13. Virus-specific CD8+ T cells lost their capacity to express IFN-γ gradually, which closely mimic the immunosuppressive environment occurring in vivo during T-cell exhaustion. As a result, IFN-γ was used as a disease-linked biomarker to indicate T-cell dysfunction. A total of 19 positive hits was identified from the ReFRAME drug repurposing compound library (∼12,000 repurposed molecules), including known and novel immunomodulatory compounds, that restores cytokine production and enhances the proliferation of exhausted T cells [ ]. Since the ReFRAME compound library comprises mostly clinically evaluated drugs, translation of lead compounds to patient use is expected to be more streamlined.
Drugs navigating metabolic pathways to enhance antitumor immunity
Another major mechanism contributing to unresponsiveness to cancer immunotherapy is the predominance of immunosuppressive TME that limits reinvigoration of antitumor immunity. In the TME, cancer cells are generally depriving nutrients from T cells and redirect glucose and amino acids for their own advantage. To this end, various metabolic machineries are known to regulate the behavior of immune cells in response to the nutrient deprivation in the TME. In particular, tumor-infiltrating immune cells often experience metabolic stress due to the dysregulated metabolic activity of tumors, thus impairing antitumor immune responses. Therefore, the repurposing of drugs capable of targeting cancer metabolism may potentiate cancer immunotherapy by metabolic reprogramming the TME. A few excellent reviews on this topic have been published recently [ ]. Fig. 12.2 illustrates a few promising approaches to restore the metabolic fitness of T cells in TME and to enhance the efficacy of cancer immunotherapy. A summary of recent clinical trials investigating the combination of immune checkpoint inhibitors and drugs modulating metabolic pathways are listed in Table 12.1 .
Table 12.1
Clinical trials investigating combination of immune checkpoint inhibitors with drugs navigating metabolic pathways.
| Drug affecting metabolic pathway | Immune checkpoint inhibitor | Cancer type | Phase | ClinicalTrials.gov registration # |
|---|---|---|---|---|
| Aspirin (COX-1/COX-2 inhibitor) | Pembrolizumab (anti–PD-1 antibody) | Recurrent or metastatic HNSCC | I | NCT03245489 |
| Aspirin | BAT1306 (anti–PD-1 antibody) | Advanced-stage MSI-H/dMMR cancers | II | NCT03638297 |
| Celecoxib (COX-2 inhibitor) | BAT1306 (anti–PD-1 antibody) | Advanced-stage MSI-H/dMMR cancers | II | NCT03638297 |
| Grapiprant (EP4 prostaglandin receptor antagonist) | Pembrolizumab | Advanced-stage CRC | I | NCT03658772 |
| Grapiprant | Pembrolizumab | NSCLC | I/II | NCT03696212 |
| Indoximod (IDO1/IDO2 inhibitor) | Pembrolizumab or nivolumab | Advanced-stage melanoma | II/III | NCT03301636 |
| Indoximod | Ipilimumab (anti–CTLA-4 antibody), nivolumab, or pembrolizumab | Metastatic melanoma | I/II | NCT02073123 |
| Metformin (antihyperglycemic drug) | Nivolumab (anti–PD-1 antibody) | Metastatic NSCLC | II | NCT03048500 |
| Metformin | Pembrolizumab | Advanced stage melanoma | I | NCT03311308 |
COX , cyclooxygenase; CRC , colorectal cancer; EP4 , prostaglandin E2 receptor; HNSCC , head and neck squamous cell carcinoma; IDO , indoleamine 2,3-dioxygenase; MSI-H/dMMR , microsatellite instability high and/or deficient mismatch repair; NSCLC , non–small-cell lung cancer.
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