Is PD-1 still worth watching in 2023?
Worth. In 2022, the sales of the two PD-1 inhibitors, K-drug and O-drug alone, reached $29.1 billion, equivalent to RMB 202.2 billion. In 2022, the scale of China's innovative drug market is expected to not exceed 164 billion yuan.
In the face of overwhelming data, no one doubts the potential of PD-1.
You may say that the United States is the United States, and China's PD-1 has its own national conditions. After all, the reality in China is that more than a dozen PD-1 models roll up and die, and the price of PD-1 breaks through the floor.
But in fact, there is still a piece of untapped land in the domestic PD-1 market, which is the PD-1 resistance market.
Although PD-1 has a strong effect, it cannot escape the fate of drug resistance. Research shows that about 60% of patients do not respond to PD-1 treatment, and many responders develop acquired resistance after the initial response. More importantly, the potential mechanisms of drug resistance are still largely unknown.
This leads to significant unmet clinical needs in the field of PD-1 resistance. How to arrange follow-up treatment for such patients and overcome the problem of PD-1 resistance is a major practical issue in tumor treatment.
More importantly, as prices decline, PD-1 is already within reach for domestic patients. This also means that how vast the market for PD-1 is today, how hot the market for PD-1 resistance will be in the future.
For PD-1, we still have many unknowns and need to always maintain reverence and enterprising spirit.
In the face of such a Promised Land, pharmaceutical enterprises with a keen sense of smell have also taken action.
01
The Secret of the Medicine King
Even if PD-1 wants to become the new drug king, there is still a big problem - drug resistance.
According to a study on the safety, activity, and immune correlation of PD-1 in the top medical journal The Lancet, up to 60% of patients develop primary resistance to PD-1. That is to say, 60% of cancer patients have no response to PD-1 at all.
Among the few remaining patients, there are still some who will gradually develop resistance to PD-1, which is acquired resistance, as the medication time increases.
At present, there is no clear statistics on the incidence of acquired drug resistance, and the probability of patients developing PD-1 acquired drug resistance varies among different tumor types.
However, we can still use several clinical trials as windows to roughly understand the incidence of PD-1 acquired resistance.
In the Checkmate032 trial conducted by drug O and the Keynote180 trial conducted by drug K, the incidence of PD-1 acquired resistance in esophageal cancer patients ranged from 42% to 71%; In the Keynote048 trial conducted by drug O and the HAWK clinical trial of drug D, the incidence of PD-1 acquired resistance in head and neck cancer patients ranged from 35% to 54%.
From the above experimental data, it can be seen that the proportion of PD-1 resistance is not low. Imagine that if we could solve the problem of PD-1 resistance, a considerable number of patients would benefit from it.
So how can we solve this problem? As the saying goes, knowing oneself and the enemy is invincible in all battles, especially in the battle against cancer cells. To solve the drug resistance problem of PD-1, it is necessary to understand the mechanism of drug resistance.
In fact, the mechanism of PD-1 resistance is quite complex, and researchers have not yet fully studied the mechanism of PD-1 resistance. However, according to existing research, the drug resistance of PD-1 is more or less related to T cell problems.
We know that the function of PD-1 inhibitors is to "brake", relieve immune system suppression, and enable immune guard T cells to kill cancer cells.
But soldiers who fight with iron may also want to "fish", and T cells are no exception. Once T cells no longer want to fight, no matter how much PD-1 fights chicken blood in this situation, it cannot stimulate T cells' fighting spirit.
The reasons for T cell inactivity are not few. When the antigen presentation mechanism is blocked or downregulated, the signal cannot be received and cancer cells cannot be recognized, resulting in T cell proliferation; When IFN- γ Loss of abnormal sensitivity of the pathway and T cell strike; When continuously stimulated by chronic inflammation, leading to T cell depletion and another strike.
In addition to internal reasons, external reasons may also lead to PD-1 drug resistance, such as inhibition of tumor microenvironment.
In order to survive better, tumors will create a piece of soil suitable for growth, that is, tumor microenvironment. The tumor microenvironment not only makes the surrounding cells immunosuppressed, but also helps tumor cells escape from immune attacks.
For example, when chemokines in tumors such as CCL2, CCL5, CCL7 and CXCL8 bind to receptors, immune cells will be recruited into the tumor microenvironment to inhibit T cell function, thus leading to the occurrence of PD-1 drug resistance.
Simply understood, T cells are surrounded by a group of fox friends and dog friends. In this situation, even if PD-1 cries out loud, the T cells that have been bewitched refuse to work.
Of course, the reasons for drug resistance in PD-1 are numerous and complex, and the above are only some of the reasons. However, this also provides researchers with ideas for developing strategies to combat drug resistance.
02
Countermeasures for PD-1 Resistance
As the saying goes, Troops for the enemy, earth for floods. Currently, researchers are exploring various ways to address PD-1 resistance.
For example, starting from the tumor microenvironment, since the tumor microenvironment will affect the effect of PD-1, we can start from changing the tumor microenvironment.
There are many ways to change the tumor microenvironment. For example, PD-1 combined chemotherapy can be used to change the tumor microenvironment and respond to PD-1 resistance.
Specifically, chemotherapy can improve the immunogenicity of cancer cells by adding new antigen complexes, induce the death of immune cells, and change the cytokine environment in the tumor microenvironment.
The efficacy of PD-1 combined with chemotherapy has also been confirmed in clinical trials. In a clinical trial, patients who developed their condition after receiving PD-1 treatment were re treated with the chemotherapy drug dexcitabine combined with PD-1 carlizumab. The results showed that the progression free survival period of the patients was significantly longer than that of patients using PD-1 alone.
Similarly, PD-1 combined with anti vascular drugs can also change the tumor microenvironment.
The growth and development of tumors cannot be separated from the supply of blood vessels. Blood vessels not only provide oxygen and nutrients, but also remove waste, making them a major accomplice in tumor growth. Anti angiogenesis drugs can reverse the immunosuppression caused by tissue hypoxia and immunosuppressive cells, making the tumor microenvironment change from immunosuppressive to immune supportive, which is crucial to the development of cancer resistance.
In response to the depletion of T cells, we can find ways to reignite their fighting spirit.
Since only relying on the stimulation signal emitted by PD-1, T cells that do not wake up and pretend to sleep can be stimulated by acting on multiple targets together. For example, collaborative treatment with immune checkpoint inhibitors such as PD-1, CTLA-4, and LAG-3. The upregulation of co inhibitory immune checkpoint receptors can amplify co stimulatory signals to activate the combat power of T cells.
The pair of LAG-3 and PD-1 are attempting to overcome the problem of PD-1 resistance. At the 2023 ELC conference, a clinical trial of LAG-3 monoclonal antibody combined with K-drug demonstrated the potential to overcome PD-1 resistance. Clinical trials have shown that for PD-1/PD-L1 resistant second line metastatic non-small cell lung cancer, 83% of patients experienced tumor growth deceleration and target lesion reduction after receiving dual immunotherapy.
Of course, in addition to the above methods, there are still many strategies to fight PD-1 resistance, such as oncolytic virus combined with PD-1 therapy, ADC combined with PD-1 therapy, personalized new antigen vaccine, and so on.
In summary, the magic rises by a foot, and through continuous exploration, the problem of PD-1 resistance will always find a solution.
03
Next Promised Land
Are there any opportunities in the PD-1 field?
Of course there is. In the field of PD-1 resistance, there is a vast unmet clinical demand.
Due to the varying incidence of PD-1 resistance among different cancer species, we will take lung cancer as an example.
According to the data released by the National Cancer Center in 2022, there were 828000 new lung cancer patients in China in 2016, of which 70% patients with advanced lung cancer met the PD-1/L1 inhibitor single drug or combination chemotherapy as the first-line standard treatment.
Among these patients, about 70% of them will develop drug resistance. This also means that 400000 patients may develop PD-1/PD-L1 resistance. And for this group of patients, there are still not many good treatment methods available.
This is only lung cancer, considering the nature of PD-1 broad-spectrum anticancer drugs, drug development for PD-1 resistant patients can be called a new blue ocean.
This also provides a breakthrough solution for the PD-1 market, starting from solving the problem of PD-1 resistance.
In fact, many players in China have launched a layout around this unmet clinical need. For example, domestic players such as Xinda Biotech/Laikai Pharmaceutical, ThinkTok/Microchip Biotech, and Wanchun Pharmaceutical have all conducted clinical trials of PD-1 combination therapy for PD-1 resistance.
Some players have also taken a different approach and opted to respond to PD-1 resistance in the form of dual antibodies. Currently, clinical research has been conducted on PD-1/CTLA-4 dual antibody Cardenilli from Kangfang Biotechnology, targeting advanced non-small cell lung cancer resistant to PD-1/PD-L1.
In the past, immunotherapy represented by PD-1/PD-L1 immune checkpoint inhibitors has changed the treatment pattern of tumors, but drug resistance issues have limited the imagination space of PD-1.
Finding and expanding the beneficiaries of PD-1 is a new challenge and opportunity in the era of immunotherapy. Whoever can successfully open this door may receive rich rewards.
Are you ready to explore this Promised Land?
