Abstract
Immunotherapy shows promise for positively changing the landscape of the management of many advanced solid tumors, including gastrointestinal (GI) malignancies. Many of these developments have been focused on vaccine-based, monoclonal antibody therapies and more recently, checkpoint inhibitors, although many small molecule inhibitors can function as immunomodulators. Small molecule compounds have several advantages over conventional immunotherapeutic agents including: ease of production and the potential for oral administration. There is a potential niche for small molecule immunomodulators to enhance the efficacy of existing immunotherapeutic and cytotoxic agents. This article focuses on two categories of small molecule compounds with immunomodulatory effects: IDO and MEK inhibitors. Indoleamine -2, 3- dioxygenase (IDO) is known for its effects in tumor immunity. IDO inhibitors are generally well-tolerated and have the potential to enhance anti-tumor responses when combined with checkpoint inhibitors. MEK inhibitors affect signal transduction of the RAS-RAF-MEK pathway and numerous MEK inhibitors are currently being investigated in solid tumors. Small molecule immunomodulators are currently being investigated for their potential role in augmenting the effects of conventional immunotherapeutic agents although further research is required to identify those patients most likely to respond to combination therapy.
Abbreviations
| APC | = | Antigen presenting cell |
| BID | = | Twice daily |
| CR | = | Complete response |
| CRC | = | Colorectal cancer |
| CTLA-4 | = | Cytotoxic T-lymphocyte-associated protein-4 |
| DC | = | Dendritic cell |
| DNA | = | DNA |
| DNMT | = | DNA methyltransferase |
| EGFR | = | Epidermal growth factor receptor |
| FDA | = | Food and Drug Administration |
| GI | = | Gastrointestinal |
| HDAC | = | Histone deacetylase complex |
| IDO | = | Indoleamine-2,3-dioxygenase |
| IFNγ | = | Interferon gamma |
| IV | = | Intravenous |
| LPS | = | Lipopolysaccharide |
| MAPK | = | Mitogen-activated protein kinase |
| 1-MT | = | 1-methyltryptophan |
| MTD | = | Maximum tolerated dose |
| NSCLC | = | Non-small cell lung cancer |
| PBMC | = | Peripheral blood mononuclear cell |
| PR | = | Partial response |
| RORγt | = | RAR-related orphan receptor |
| TDO | = | Tryptophan 2,3-dioxygenase |
| Th17 | = | T helper 17 cell |
| TNFα | = | Tumor necrosis factor α |
| Treg | = | Regulatory T cell. |
Introduction
Cytotoxic chemotherapies have traditionally been used to treat advanced solid tumors but these are generally non-curative, are associated with significant toxicities and do not produce durable response rates. There is increasing interest in the role of immunotherapy as an attractive strategy in the management of advanced solid tumors previously assumed to be non-immunogenic. Checkpoint inhibitors (ipilimumab, nivolumab) have had unprecedented durable responses in subsets of patients with advanced melanoma and non-small cell lung cancer (NSCLC).Citation1,2 Even patients with metastatic pancreatic cancer, known for its poor survival rates, were recently shown to have improved survival when treated with the GVAX and CRS-207 vaccine therapies.Citation3 While immunotherapy has historically involved cell or antigen-based vaccine therapies and monoclonal antibodies, there has been considerable focus on the development of small molecule drugs which have immunomodulatory effects. Small molecule drugs have the advantage of the potential for oral administration and ease of production relative to standard biologic agents. The preclinical development of small molecule drugs requires extensive knowledge of the biology of a particular target in a given cancer, is amenable to high-throughput screening of thousands of compounds and potentially allows administration of more personalized medicine to patients.Citation4
Currently, there are numerous efforts to develop small molecule inhibitors with immunomodulatory effects in cancer. Many of these compounds are at an early stage of development (). The importance of epigenetic changes in cancer has prompted research efforts into HDAC and DNMT inhibitors. The HDAC inhibitors romidepsin and vorinostat have already been FDA-approved in hematologic malignancies.Citation5 There is a significant interplay between components of the immune system (IFNγ) and the anti-tumor effects of HDAC inhibitors.Citation6 The DNA methyltransferase (DNMT) inhibitors azacitidine and decitabine are FDA-approved in high risk myelodysplastic syndrome.Citation7 Azacitidine has been shown to have immunomodulatory effects in colon cancer by converting CD11b myeloid cells into antigen presenting cells (APCs).Citation8 Thalidomide analogs are small molecule glutamic acid derivatives which have been FDA-approved in multiple myeloma.Citation9 Thalidomide is renowned for its immunomodulatory effects including T cell costimulation and increasing the effects of NK and cytotoxic T cell functions. Toll-like receptor agonists can initiate both innate and adaptive immune systems. Imiquimod is FDA-approved for the treatment of superficial basal cell carcinoma.Citation10 It functions by potently inducing IFNγ and other cytokines leading to activation of APCs and a Th1-driven response.Citation11 RORγt inhibitors function by blocking the function of pro-inflammatory Th17 cells.Citation12 Several small molecule compounds which inhibit RORγt are in development, mostly targeting hematologic malignancies.
Table 1. Categories of small molecule compounds with immunomodulatory functions in solid tumors. Abbreviations: DC: dendritic cell, DNMT: DNA methyltransferase, HDAC: histone deacetylase complex. IDO: indoleamine-2, 3-dioxygenase, RORγt: Retinoic acid receptor-related orphan nuclear receptor gamma, TNFα: tumor necrosis factor α
In this commentary, we will discuss IDO and MEK inhibitors in detail, focusing on gastrointestinal malignancies where appropriate.
IDO Inhibitors
Indoleamine-2, 3-dioxygenase (IDO) is an intracellular enzyme that is involved in the rate-limiting step of the catabolism of L-tryptophan in the kynurenine pathway, which is the first step in the biosynthesis of nicotinamide adenine dinucleotide, an important regulator of metabolism. Its role as an immunomodulator was discovered when it was found to have an important role in preventing allogenic fetal rejection by T cells during pregnancy. Its role in tumor immunity is evidenced by the fact that tumor cells transfected with IDO are not rejected in mice which were immunized with a dominant tumor antigen.Citation13 The expression of IDO is controlled by Bin1, a tumor suppressor gene, and studies show that the loss of Bin1 is associated with increased IDO expression through the STAT1 and NF-κB pathways.Citation14,15 IDO deficiency in a preclinical model of lung cancer is associated with decreased vascularization and immune escape.Citation16
IDO expression has been detected in a variety of cancers including pancreatic and colorectal.Citation17,18 IDO functions by mediating immune escape by suppressing the activation of T cells which are sensitive to tryptophan starvation and kynurenine downstream catabolites.Citation19 While IDO expression occurs in tumors, it also occurs in a subset of plasmacytoid DCs (dendritic cells) in tumor-draining lymph nodes.Citation20
IDO expression in regulatory DCs is prompted by an autocrine interferon process controlled by CTLA-4 pathway receptors on regulatory T cells (T reg). This converts the DC into a more quiescent state and reduces its capacity to present antigens to T cells.Citation21 However, IDO+ DCs are also able to prompt CD4+ T cells to become Tregs. If this occurs in a tumor-draining lymph node, IDO can drive the production of Tregs and reg DCs which will further suppress immunity against tumor cells.
Preclinical studies of 1-MT (1-methyltryptophan), a tryptophan mimetic, showed that it reduced tumor growth but did not prevent tumor progression. However, when combined with cyclophosphamide, there was an additional anti-tumor effect compared to chemotherapy alone.Citation22 Resistance to IDO inhibition can be explained by the use of alternative mechanisms which make up for the loss of IDO expression. Tryptophan-2, 3, - dioxygenase (TDO) is a ubiquitous enzyme with a different structure than IDO but has similar activity in tryptophan metabolism which can also mediate the immune response in tumors.Citation23
Based on preclinical evidence that indoximod, the D isomer of 1-MT, has synergistic effects with chemotherapy in a preclinical model of breast cancer, a phase I study showed that it was well tolerated when combined with docetaxel in 27 patients with pre-treated metastatic solid tumors including pancreatic, rectal and esophageal cancers.Citation24 There were no complete responses, 18% had partial responses, 4% had stable disease >6 months and 36% had progressive disease.
A second IDO inhibitor, INCB024360, is currently the focus of several clinical trials encompassing multiple tumor types (). It is an orally available hydroxyamidine small molecule inhibitor which potently and selectively inhibits IDO1 inhibitor (IC50 = 7.1 nM).Citation25 Preclinical data using pancreatic tumor xenografts showed that INCB024360 reduces tumor growth in immunocompetent but not immunodeficient mice.
Table 2. List of clinical trials of IDO inhibitors in patients with cancer (all trials listed are currently recruiting) MTD: Maximum tolerated dose
The phase I dose-escalation study of INCB024360 (NCT01195311) included 52 patients with multiple tumor types including colorectal (45%) and melanoma (12%).Citation26 Patients received daily doses of INCB024360 with doses ranging from 50 mg once daily to 700 mg BID (twice daily). There was no maximum tolerated dose identified and no objective responses were reported although 15 patients (28%) had stable disease at 56 days. Doses ≥300 mg BID achieved greater than 90% inhibition of IDO1 throughout the dosing period. The most common adverse events were fatigue, nausea, anorexia, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain and cough (≥20%). This phase I study also found significant reductions in plasma kynurenine/tryptophan ratios and when whole blood samples collected after treatment were stimulated ex vivo with IFNγ and lipopolysaccharide (LPS), INCB024360 showed >90% inhibition of IDO activity.Citation27 In an effort to detect a biomarker that may guide the selection of IDO inhibitors, a monoclonal antibody (rabbit anti-human) has been generated which can stain human tumor tissue samples and potentially determine which patients are likely to respond to IDO inhibition.Citation28
Correlating with preclinical data which suggested that IDO inhibition is not effective as monotherapy, INCB024360 was combined with the anti-CTLA4 antibody ipilimumab in patients with advanced melanoma in a phase I/II study.Citation29 Preliminary data from this study (NCT01604889) showed that 300 mg BID combined with ipilimumab (3 mg/kg IV every 21 days for 4 cycles) resulted in clinically significant ALT elevations after 30–76 days of treatment but were reversible with steroids and treatment discontinuation. These patients were able to resume therapy albeit with lower doses of INCB024360 (25 mg bid). Six of 8 patients had tumor reductions by the time of first imaging. These preliminary data suggest the role of IDO inhibition in providing enhanced anti-tumor effects with anti-CTLA4 therapy.
Another 2nd generation IDO1 inhibitor, NLG-919, is currently recruiting patients with advanced solid tumors in a phase I clinical trial.Citation30 This drug will be administered orally for 21 days (28 day cycles) with the view to establishing the maximum tolerated dose (MTD).
IDO has also been targeted with peptide vaccine therapy. A phase I study treated 15 HLA-A2-postive patients with metastatic NSCLC with IDO5 vaccines administered every 14 days for 2.5 months and subsequently monthly.Citation31 The vaccine was well tolerated with no grade 3/4 toxicities reported. Vaccinated patients had longer survival than vaccine-untreated patients (25.9 vs. 7.7 months, p = 0.03). Flow cytometry of PBMCs showed significant reduction in the Treg population (p = 0.03) and durable responses were noted with 1 patient developing a partial response after one year of therapy and 6 patients achieving long-lasting disease stability (defined as lasting ≥8.5 months).
IDO has been established as an important player in immune escape in tumor development. It shows limited efficacy when used alone but has significant potential to enhance anti-tumor responses when combined with conventional cytotoxic chemotherapy, peptide-based vaccine therapies and checkpoint inhibitors.
MEK Inhibition
The MAPK (mitogen-activated protein kinase) pathway is one of the most well-defined signaling pathways in human cancer. This pathway consists of kinases which are tightly regulated by a sequence of phosphorylation and activation of protein kinases including the RAS-RAF-MEK1/2- ERK1/2 pathway. MEK1/MEK2 catalyze the phosphorylation of tyrosine and threonine residues in ERK1/ERK2 thereby mediating cellular signals transduced from RAS/RAF.Citation32 Genes encoding RAS (KRAS, NRAS, HRAS) are among the most frequently mutated genes in cancer including biliary tract (33%), large bowel (36%), esophageal (5%), pancreatic (63%) and gastric cancer (12%).Citation33 Dysregulation of the MAPK pathway is associated with effects on the immune system. Animal models of MAPK dysfunction (Mkk3−/−) have evidence of defective IL-12 production by macrophages and dendritic cells.Citation34 The MAPK signaling pathways have also been implicated in the differential regulation of myeloid-derived dendritic cell (MDCC) maturation and the modulation of the Th cells (T helper) toward Th1 or Th2 subsets.Citation35 The phosphorylation of p38 MAPK is essential for the maturation of immature DCs as shown by MAPK inhibitors reducing the DC maturation marker CD83 induced by LPS and TNFα.Citation36
To date, a single MEK inhibitor, trametinib, has been approved by the FDA for its use in unresectable or metastatic melanoma. This was based on a phase III trial in patients with advanced BRAF V600E/V600K melanoma which showed that trametinib improved progression-free and overall survival compared to chemotherapy.Citation37 Numerous other MEK inhibitors have been the subject of clinical trials and have failed to substantially improve survival outcomes in multiple tumor types. Similar to IDO inhibitors, MEK inhibitors have limited efficacy as monotherapy and require combination with other targeted therapies/chemotherapy to achieve their optimal efficacy. The degree of MEK1/2 inhibition to achieve a clinical response is also not known.
A number of MEK inhibitors are the subject of ongoing clinical trials (). Trametinib is a second generation MEK inhibitor shown to potently inhibit p-ERK 1/2 in vitro. The combination of trametinib and dabrafenib has been shown to improve overall survival in metastatic melanoma compared to vemurafenib alone.Citation38 A phase III study is ongoing combining trametinib, dabrafenib (BRAF inhibitor) and panitumumab (anti-EGFR) in patients with BRAF V600E mutant colorectal cancer (CRC). Preliminary data have shown that this combination is tolerable and clinical activity (partial response (PR) /stable disease) has been reported.Citation39
Table 3. Selection of clinical trials of MEK inhibitors in patients with solid tumors (all trials listed are currently recruiting)
Selumetinib is a potent, selective ATP non-competitive MEK inhibitor. It was combined with irinotecan in the second line setting in 31 patients with KRAS mutant metastatic CRC and was shown to have clinical activity (9.7% had partial response, 51.6% had disease stability).Citation40 Despite strong preclinical data of combination MEK and Akt inhibition, the combination of selumetinib and MK-2206 (Akt 1/2/3 inhibitor) did not result in clinical activity in patients with metastatic CRC.Citation41 Selumetinib was shown to be tolerable in a phase II study of 28 patients with advanced biliary cancers and 3 patients (12%) had objective responses with 14 patients having prolonged stable disease (>16 weeks).Citation42
MEK162 (Binimetinib), a selective ATP-noncompetitive MEK1/2 inhibitor, is the subject on numerous ongoing clinical trials (). It is similar to other MEK inhibitors in terms of its toxicity. A phase I study in 28 patients with unresectable/locally advanced or metastatic biliary cancer received MEK162 and clinical responses were seen (1 CR, 1 PR, 11 stable disease).Citation43 This strategy has progressed to a phase I/II study in advanced biliary cancer combining MEK162 with a standard chemotherapy combinations gemcitabine/cisplatin (NCT01828034) and gemcitabine/oxaliplatin (NCT02105350). MEK162 is also the subject of ongoing trials in metastatic CRC in combination with FOLFOX chemotherapy (NCT02041481) and panitumumab (NCT01927341).
Pimasertib is a selective non-competitive inhibitor of MEK 1/2. It had shown promising activity in preclinical studies of pancreatic cancer but a phase II placebo-controlled randomized study of gemcitabine with pimasertib vs. placebo did not show an improvement in PFS.Citation44 Refametinib is a highly selective allosteric MEK1/2 inhibitor which has shown anti-tumor activity in preclinical studies involving numerous tumor types. A phase II study combining refametinib with gemcitabine showed a trend toward clinical benefit in patients with wild-type KRAS metastatic pancreatic cancer.Citation45 Additional MEK inhibitors which have been mostly studied in non-GI cancers to date include: PD0325901, cobimetinib (studied mostly in melanoma), R04987655, AZD08330, TAK-733 and GDC-0623.
In general, MEK inhibitors are well tolerated although several toxicities can occur in common with other kinase inhibitors e.g. rash, diarrhea, fatigue.Citation46 There have been reports of specific ocular toxicities associated with MEK inhibitors which can present with visual loss/blurred vision. Of particular concern are optic neuropathy, retinal venous occlusion and central serous retinopathy which require urgent specialist referral.Citation47 Serious, but rarer, toxicities include dropped-head syndrome,Citation48 markedly elevated CPK levelsCitation49 and left ventricular dysfunction.Citation50
Conclusion
The management of selected advanced solid tumors has been revolutionized by immunotherapy. To date, this has been mostly compromised of vaccine-based therapies and monoclonal antibodies. There is a role in this niche for small molecule compounds to augment these effects on the immune system either alone or in combination with cytotoxic chemotherapy/other immune therapies. Numerous compounds are currently in development and many have reached phase III clinical trials or have been approved by the FDA. However, the lack of a biomarker to predict responsiveness to these therapies, hinders their development and collaborative research investigating potential biomarkers is warranted. Future directions may include the development of small molecule checkpoint inhibitors. Given the advantages that small molecule drugs possess in terms of their relative ease of administration, further research and development of small molecules with immunomodulatory effects is worthwhile in order to improve options for patients with advanced solid tumors.
Disclosure of Potential Conflicts of Interest
Under a licensing agreement between Aduro Biotech and the Johns Hopkins University (University), the University and investigators are entitled to milestone payments and royalty on sales of the GM-CSF-secreting tumor vaccine products (GVAX) described herein. Dr. Zheng received a research grant from iTeos Therapeutics.
Funding
This work was supported in part by the NIH K23 CA148964-01 (L.Z.), NIH 1 R01 CA197296-01 (L.Z.), Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins (L.Z.), the NCI SPORE in Gastrointestinal Cancers P50 CA062924 (L.Z.).
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