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Immune escape of tumor

In the last article, I talked about the process of Munn finding IDO immunosuppression. However, when Munn is cultured for macrophage /T cells, tryptophan may not be a simple nutrient, but more likely to be a signal molecule.
For many people, this view is really unacceptable. Because there are a lot of tryptophan in the food we eat, so how can tryptophan become a signal molecule that inhibits the function of T cells?
It is not easy for Munn to convince other scientists to accept this view. Many researchers at that time only thought that Munn labs were a bunch of lunatics. At the time, tryptophan was only found to affect the function of T cells.
But later scientists found that other nutrient concentrations, including blood sugar levels, could also affect the activation process of T cells, so that people began to accept tryptophan as a signal molecule that affects the function of T cells.
Nevertheless, tryptophan inhibited the whole signal pathway of T cell function until six years later. But at the same time, researchers have also found that many types of tumor cells can also express different levels of IDO.
And more importantly, researchers have found that IDO1 overexpression in tumors is associated with Bin1 status in tumor cells. Bin1 is one of the most frequently suppressed tumor suppressor genes in the tumor. The study found that the lack of Bin1 in cancerous cells is sufficient to make the cancer cells use only the signal pathways within the cell and mediate the escape of the immune response through IDO1.
I think most people in the pharmaceutical industry are now well aware that IDO is actually only one of the mechanisms that can prevent the immune system from attacking its own antigens or harmless antigens. During the same period when IDO was discovered, scientists discovered other proteins involved in the process of immune tolerance, such as CTLA4 and PD1/PD-L1.

The human immune system is really very complex. The immune system can continuously monitor foreign antigens, but some proteins including PD-1 can inhibit the function of T cells. PD1 and CTLA4 can express at different stages of T cell life process and inhibit immune response. On the surface of tumor cells, PD-1 ligand PD-L1 can also be used to inhibit immune function.
But these checkpoints are crucial to certain normal physiological processes, while scientists at the time found that IDO was rarely expressed in other tissues, and the mice that knocked out IDO1 did not produce symptoms of autoimmune disease, so scientists found the side effects of IDO1 inhibitors may be lower than that of PD-1/L1.
At that time, several Biotech Corp realized the importance of IDO in tumor immunity, and began to develop IDO inhibitors. In fact, in the early days, large pharmaceutical companies were just a wait-and-see attitude, and there were only two companies that had long been open for IDO research and development projects, Incyte and NewLink Genetics.

Pharmaceutical company admission

Incyte began its research on IDO inhibitors in 2004. In fact, it is not very difficult to develop IDO1 inhibitors from the perspective of medicinal chemistry. IDO1 is a catalytic activity only containing a single chain, and several other tryptophan catabolic enzymes, including IDO2, TDO2 and TPH, may not be as difficult to control compound selectivity as kinase inhibitors.
Moreover, IDO1 has high specificity and strong substrate specificity. As for the evaluation of the activity of compounds, it is not difficult to measure the tryptophan of IDO and the product of canine. Therefore, it seems not too difficult to develop such inhibitors.
But this is not the case. At least, Incyte did not go very smoothly at the beginning of the IDO1 project. In fact, when Incyte started the IDO project, people did not know much about the mechanism of IDO1, and there were not very good small molecular probes to study the function of IDO1 (the probe 1-MT used by Munn had a big problem).
In addition, it is not clear how to establish the evaluation system of compounds and the extent of activity optimization. They then sifted three hundred thousand compounds to find a suitable precursor for medicinal chemists.
A year and a half later, the company’s medicinal chemists synthesized about two thousand compounds based on the lead compound. Through screening and optimizing preclinical and preclinical experiments, one of the compounds Epacadostat was eventually promoted to clinical research.
Soon after Incyte began studying IDO1 inhibitors, Newlink Genetics started the development of IDO1 inhibitors in 2005. But Newlink did not choose to screen the compounds with IDO1 inhibitory activity from scratch, but chose to reach a cooperative agreement with the Munn group to obtain the compound 1-MT (1- methyl -D, L- tryptophan), used by Munn to study pregnant mice.
But when Munn used 1-MT as a probe to study the IDO function, it did not make a comprehensive study of 1-MT. At least he did not test the activity of compounds in D configuration and L configuration. It should be clear to those familiar with the field of medicinal chemistry that the pharmacological activity of this type of isomer sometimes varies greatly, or even the opposite of its activity.
Later studies found that 1-MT of D configuration could not bind IDO1 or inhibit its function. The L configuration had relatively weak binding activity with IDO1, so it was thought that the 1-MT of L configuration was the reason for its IDO1 inhibitory activity.

But as the research goes in, researchers have found that although 1-MT has a weak inhibitory effect on the growth of tumor cells, 1-MT is not actually a real IDO1 inhibitor.
Later, the anti-tumor activity study finally confirmed that its anti-tumor activity was mediated by D configuration, and its mechanism was unique, because the researchers found that the 1-MT of D configuration could not inhibit the enzyme activity of IDO1, but it could relieve the function inhibition of T cells.
This is actually the role of D 1-MT in relieving the decrease of mTORC1 activity due to tryptophan deficiency. In fact, the 1-MT of the D configuration is exactly the compound indoximod, which we later know.
Since indoximod is not a real IDO inhibitor, a selective compound navoximod is found after Newlink. The EC50 value of Navoximod cell level was 75 nM, and the selectivity for IDO1/TDO was only 10 to 20 times. Therefore, from this point of view, navoximod may have some unique antitumor effects that are different from epacadostat for the tumor expressing IDO1/TDO simultaneously.
The epacadostat activity of Incyte is stronger, 12nM and selectivity is higher. Therefore, there may be some obvious differences between the two compounds epacadostat and Navoximod in both clinical and clinical trials.
It was also because navoximod had better indoximod activity and selectivity, and Genentech agreed with Newlink in 2014 to cooperate with Newlink to develop the compound by paying $150 million for the first payment and about $1 billion milestone payment.

In addition to the above two companies, Flexus, founded jointly by Terry Rosen and Juan Jaen in 2013, is also a strong contender in the field. The reason they set up the company was very simple, because they thought the tumor immune field had a target like PD-1/L1, but there was still a lot of potential and seriously undervalued targets in the field.
And when they first set foot in the IDO field, they already had a very clear idea of R & D. Because data have been found that such inhibitors require a large degree of inhibition of IDO1 activity in order to produce anti-tumor effects. Incyte, which has a high dose of drugs, has reduced the concentration of blood before taking the next dose, so they need to look for longer half-life drugs.
After completing $38 million in financing, Flexus scientists quickly got a series of IDO1 inhibitors, including the unique BMS-986205 of the mechanism. The compound is an irreversible inhibitor of IDO1, and its pharmacokinetics is indeed better than that of epacadostat and navoximod.
And this has made them the target of many pharmaceutical companies. After fierce competition, in February 2015, BMS bought the company which had just been established for 18 months at an astonishing $1 billion 250 million price.
But there are many controversies about IDO project of Flexus company. In September 2015, Incyte prosecuted Flexus, Rosen and Jaen. The reason is that Incyte thinks that Jordan Fridman, the core employee of Flexus, was once the chief scientist of Incyte, and Fridman was one of the few employees who knew the results of the Incyte’s IDO clinical trial project.
Incyte had signed a confidentiality agreement with Fridman, but they still believed that Fridman had used these commercial secrets to help Flexus carry out research on the IDO project, eventually making the company be bought by BMS at the sky at a price 18 months later.

In addition to BMS-986205, iTeos’s PF-06840003 (EOS200271) is also a very interesting compound because this compound also has a significant difference in mechanism from BMS-986205, epacadostat and navoximod: PF-06840003 is a non competitive inhibitor of tryptophan, and does not combine heme (heme) in IDO1.
In fact, from the heme point of view, BMS’s IDO inhibitor BMS-986205 is also a unique chemical compound, because the compound is combined with apo-IDO1, not heme-IDO1.

However, whether the non IDO1 direct inhibitory activity of indoximod, the high selectivity of epacadostat, the double inhibition of TDO/IDO1 of navoximod, the irreversible inhibition of BMS-986205 and the non heme binding activity, or the non competitive and non heme binding activity of PF-06840003, the difference in its therapeutic effect is much, Even a step back, whether IDO1 is an effective tumor immune target, these problems are rare from pre clinical research and can only be verified through large-scale clinical trials.

The IDO1 inhibitor epacadostat (above) of Incyte can interact with heme (below) in IDO1. The BMS-986205 of BMS can be combined with non heme apo-IDO1. Source: ACS Med.Chem. Lett.


In fact, not long after the interaction between IDO1 and tumor was discovered, it was clear to the staff members that the inhibition of IDO1 activity was not effective in relieving the inhibition of the immune system. The clinical study also confirmed this, for example, in a randomized two phase study of epacadostat, which found that epacadostat was well tolerated, but had no therapeutic advantage over tamoxifen.
In 2013, an experiment by James Allison, a tumor immunologist, laid the foundation for the combination of IDO1 and CLTA4 or PD1 inhibitors. The checkpoint inhibitors are usually effective only for a small number of melanoma patients, and Allision found that after Yervoy, the tumor cells can escape the immune system monitoring through IDO1. The combination of CTLA4 inhibitor and IDO1 inhibitor can effectively reduce the tumor of melanoma mice and prolong their survival time.
After Allison, IDO inhibitors combined with PD1 or PD-L1 also produced similar anti-tumor effects. People familiar with the field of tumor immunotherapy should be very clear that improving the efficiency of checkpoint inhibitors has always been a hot topic in the field of tumor immunology.
Last June, Incyte announced the results of a clinical trial of epacadostat in conjunction with pembrolizumab at the ASCO conference. Data showed that the combination regimen in the treatment of advanced NSCLC could achieve ORR and disease control rates of 35% (14/40) and 63% (12/40) respectively. From the therapeutic data, the combined regimen seems to be superior to the checkpoint inhibitor in the treatment of advanced NSCLC. But the study is non randomized and the sample size is relatively small.
In September last year, Incyte also released data on the treatment of advanced melanoma with epacadostat combined with pembrolizumab at the ESMO2017 conference. The ECHO-202 study evaluated the safety and efficacy of epacadostat combined with Mercedes pembrolizumab in patients with advanced melanoma. The data showed that the patient’s ORR reached 56% (35/63).
But if we look at the PFS data of clinical trials, it is hard to find the difference between the three groups of patients in PFS. The single arm test is difficult to see clearly the efficacy of the drug, and the data of the single arm test combined with the drug are more difficult to analyze.

The data of the III phase clinical ECHO-301 published in the previous days may be more convincing. Epacadostat combined with pembrolizumab therapy can not be excised or metastatic melanoma, and PFS can not be significantly improved compared with the use of pembrolizumab alone. It is also estimated that this study is not expected to achieve the main endpoint of improving overall survival. This is indeed a very dangerous signal, because if melanoma is not well treated, the probability of success in other types of tumors may be very low.
The fate of Navoximod and iTeos’s EOS200271 is also bumpy. In June last year, the overall response rate of navoximod to atezolizumab was only 10% in all types of tumors. Genentech chose to return the drug to Newlink. In January of this year, Pfizer also chose to stop working with iTeos to develop IDO inhibitor EOS200271 due to the doubt of its efficacy.
There may be many explanations for the failure of the above clinical trials. First compounds may have defects in themselves. But for the compounds themselves, the mechanisms of action of these drugs are different, and the PK properties are different. For example, indoximod is a non direct IDO1 inhibition, and EOS200271 can penetrate the blood brain barrier (which is one of the main causes of Pfizer’s selection), and navoximod has a weaker selectivity to TDO/IDO1, BMS-986205 is an irreversible inhibition of IDO1 and does not combine heme-IDO1. These differences are likely to cause differences in efficacy / side effects.
Second, rational clinical trial design is also critical. For example, screening effective potential biomarkers for potential responders. The content can refer to my previous article on PARP inhibitors.

But there is a very important reason for the failure of clinical trials, that is, there are problems in the target itself. This is actually the most worrying thing for everyone. I have no answer to this question, because it is far from the conclusion.
Perhaps many people now have a pessimistic attitude towards IDO. In fact, the new drug research and development is essentially a kind of research exploration, we can not predict what the future, even if the probability will fail, it will also have the possibility of success, or that sentence, always hope for the best.

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