PD-1 inhibitors enhance future value of anticancer treatment

“PD-1 inhibitors will enhance future value and utility of anticancer drugs”

[Interview] Professor Eui-Cheol Shin, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST) Korea Advanced Institute of Science and Technology (KAIST)

PD-(L)1 is the strongest biomarker…personalized cancer vaccines may work as alternative when developing resistance

Immunotherapy+immunotherapy combination may be a good option that makes up for the other therapy's shortcoming

Professor Eui-Cheol Shin

Since its first appearance in 2011, cancer immunotherapies have opened a new paradigm in the field of cancer treatment.

 

Moving on from the era of targeted therapies that target specific gene mutation, the new era had opened where a patient’s immune system is activated to remove the malignant tumor.

 

The immunotherapies that have been commercialized until now, such as Opdivo, Yervoy, and Keytruda, are all immune checkpoint inhibitors that target immunomodulators such as CTLA-4 or PD-(L)1.

 

Immunologists Professor James P.

 

Allison and Professor Tasuku Honjo were jointly awarded the Nobel Prize in Physiology or Medicine in 2018 for their discovery of this mechanism.

 

In the wide and complex field of immunity, much is still left to be identified and remains uncharted territory.

 

This is why cancer immunotherapies work according to theory in 30% of the patients, but not as expected in the other patients.

 

To increase the response rate, pharmaceutical companies have been attempting to combine their immunotherapy with other immunotherapies that have different MOAs, or with existing targeted therapies or chemotherapies.

 

Finding a good biomarker to predict the response rate also remains an important task.

 

So how do immunologists view the present and future of cancer immunotherapies?

 

Eui-Cheol Shin, Professor of Graduate School of Medical Science and Engineering at Korea Advanced Institute of Science and Technology (KAIST), said, “PD-1/PD-L1 inhibitors will be essential in all combination therapies that will be established for cancer treatment in the future.

 

The PD-(L)1 and CTLA-4 immune checkpoint inhibitors can also be used in combination to complement the shortcomings of each other.” Professor Shin also added that treatment methods will be established for each cancer type and stage using viable biomarkers and that personalized cancer vaccines may become the next-generation anticancer therapy.

 

The following is the question and answers from an interview with Professor Shin.

 

-The paradigm that was dominated by targeted cancer therapies had shifted with the introduction of cancer immunotherapies.

 

How is immunotherapy different from targeted anticancer drugs in terms of its mechanism of action? =The main difference between cancer immunotherapy drugs and targeted cancer therapies is in the durability of response.

 

Strictly speaking, it is different, but a cancer immunotherapy drug is similar to a vaccine.

 

Both use immunological memory to fight diseases.

 

Just as people can live without concern of a certain disease after vaccination as many vaccines have a lifelong effect, treatment with immunotherapy will allow the immunologic memory to remove cancer even after it starts spreading again.

 

The effect of the drug can last for the rest of the patient's life, even after discontinuing administration of the immunotherapy drug.

 

-The cancer immunotherapies that have been released until now are PD-1/PD-L1 and CTLA-4 inhibitors.

 

I know research is being conducted for new markers, how much progress has been made in this regard? =No one knows how many undiscovered mechanisms remain in the field of cancer immunotherapy.

 

So, it is difficult to say how much progress has been made.

 

Also, how many mechanisms were discovered is not important.

 

Although CTLA-4 inhibitors and various PD-1/PD-L1 inhibitors have been introduced to the market, research results have reported that they work differently from the originally expected principle of action.

 

This means that you do not need to know all the mechanisms to develop a drug.

 

In some cases, the mechanism that you thought you knew well cannot be developed into a drug, and in other cases, you luckily find a drug another way.

 

Research is of course conducted with sufficient theoretical grounds, but even with a solid theoretical base, clinical success cannot be guaranteed 100%.

 

-Is there a reason why many of the developed drugs are PD-1/PD-L1 inhibitors? =In my research, I found PD-1 was the best anticancer immunotherapy target that can be modulated in the process of fighting cancer.

 

Of course, the effect may be different for each cancer type and patient, but as PD-1 has a good effect and has the least side effects, much study has been focused on PD-1.

 

Even in 50 years when cancer immunotherapies that target various other mechanisms are introduced in the market, I (strongly) believe PD-1 and PD-L1 inhibitors will hold their ground as a basic cancer immunotherapy drug.

 

-Studies of combination therapies are also being conducted actively to enhance the effect of cancer immunotherapies.

 

Some studies have been investigating the use of two immunotherapies.

 

Mechanism-wise, is it effective to combine the use of a PD-1 inhibitor and a CTLA-4 inhibitor?

 

=Well, the two are the only immune checkpoint inhibitors that were formally approved as of now, and using the two in combination does have a better effect.

 

Separately, CTLA-4 inhibitors were introduced before PD-(L)1 inhibitor, but have relatively more side effects than the latter.

 

In this sense, response in using the two drugs with the different MOAs has been unexpectedly good in general.

 

It is rare, but using PD-(L)1 inhibitors may trigger hyperprogression of cancer in the treated patient.

 

However, fundamental research findings have shown that hyperprogression may not show up when a CTLA-4 inhibitor is used in combination with a PD-(L)1 inhibitor.

 

Much still needs to be verified, but I believe the immunotherapies may be able to complement each other’s shortcomings.

 

-Patients may develop resistance to cancer immunotherapies as well.

 

What alternatives could the patients use?

 

=One of the reasons for ‘secondary resistance’ is mutation.

 

The body needs to perceive the tumor as a foreign cell, however, the tumor antigen mutates and develops resistance.

 

Cancer cells mutate just as well as viruses.

 

Although it has not been commercialized yet, I expect ‘personalized cancer vaccines’ fit for each patient to become the next-generation anticancer therapy that would address the issue of resistance.

 

These ‘cancer vaccines’ would be different from conventional vaccines that are administered in a healthy state, these are therapeutic vaccines that will prevent growth or recurrence of cancer in patients who have undergone surgeries for cancer removal.

 

In other words, a vaccine that is made based on the changes identified in the mutated cancer cell of each patient to contain new antigens will allow patients to overcome resistance in the future.

 

Of course, these cancer vaccines would also need to be used in combination with PD-1 inhibitors.

 

As such, PD-1 is and will continue to be essential in the field of cancer immunotherapies.