Cancer Discovery The next decade of immune checkpoint inhibitors

In the past 10 years, immune checkpoint therapy (ICT) led by PD-1/PD-L1 and CTLA-4 inhibitors has made great breakthroughs in clinical practice, and the survival of advanced patients with various cancers, including lung cancer, gastric cancer, colorectal cancer, melanoma, etc.
, has been improved
to a certain extent.

In 2011, the US Food and Drug Administration (FDA) approved the launch of Ipilimumab, the first immune checkpoint-targeted drug, officially opening the history of ICT.
Subsequently, the approval of PD-1/PD-L1 immune checkpoint inhibitors set off a new wave
in tumor treatment.
In 2011~2021, ICT provided the understanding and practice
of clinical therapy targeting T cells.

Where should ICT therapy go in the next 10 years?

The top international journal Cancer Discovery published an article
entitled "The Next 10 Years of Immune Checkpoint Inhibitors".

Let's take a look at how ICTs can play a better therapeutic role
in cancer treatment in the next decade.

Origin: activation and inhibition of T cells

T cells are one of the main fighters of specific immunity, and T cell activation mainly involves a synergistic process
of 2 signals.

The first process is the recognition of MHC (CD3 signaling pathway) on antigen-presenting cells (APCs) by T cell receptors (TCRs);

The second process is to give the T cells a co-stimulatory signal (CD28 co-stimulatory signaling pathway).

The synergistic completion of these two processes will promote the activation of T cells, begin to differentiate and expand, and further form memory T cells to form long-term immune memory
.

T cell activation process

T cells can be divided into 2 main subpopulations, including CD4+ T cells and CD8+ T cells
.
CD4+ T cells can be further subdivided into Th1, Th2, Th17, follicular Th (Tfh), regulatory T cells (Treg), and Th9 cells, which have different transcription factors that regulate the function and cytokine profile
of the T cell population.

At present, Th1 CD4+ T cells and CD8+ T cells are effector cells responsible for driving anti-tumor responses, but T cells also have a corresponding feedback regulation process: when both the TCR and CD28 pathways are activated T cells begin to proliferate and produce cytokines, there will be a variety of inhibition mechanisms in and outside the cell to control the T cell response to prevent it from overactive and harmful to normal cells
.

With the deepening of clinical research, it has been found that in this process, the pathway that inhibits the activity of T cells may be hijacked by cancer cells, thereby reducing the killing effect of T cells and ultimately promoting the development and metastasis
of cancer cells.

CTLA-4-mediated T cell inhibition effect

In T cells, CTLA-4 is a typical inhibitory molecule, when TCR is involved in the recognition of CTLA-4 will begin to express, and peak about 48~72 hours after T cell activation, which can produce competitive inhibition with the co-stimulatory signal CD28 signaling pathway, thereby inhibiting T cell signaling and inhibiting T cell activity
.

PD-1-mediated T cell inhibition

PD-1 is also an inhibitory molecule, and its main biological activity is to avoid false killing effects
on surrounding normal cells after T cell activation.
During the reaction of T cells, PD-1 can bind to PD-L1 and PD-L2, thereby being widely expressed in non-lymphoid tissues and inhibiting peripheral T cell activation
.

In early clinical studies, it was found that blocking the CTLA-4 pathway can prolong the reaction time of T cells and destroy cancer cells, and can mediate T cell infiltration into tumor tissue, resulting in tumor regression and prolonged survival.
PD-L1 has been found to be highly expressed in a variety of tumor models, and blocking this pathway can also effectively improve the killing effect of T cells and mediate tumor regression
.

It can be seen that although the mechanism of CTLA-4 and PD-1-mediated T cell response is different, both can improve the tumor killing effect
of T cells.
Due to different activation pathways, CTLA-4 immune checkpoint inhibitors can also be combined with PD-1/PD-L1 inhibitors to improve the effect of tumor treatment, and this combination strategy has been widely used in clinical
practice.

Just in time: ICTs approved for therapy

Within the first 10 years since the first ICT therapy was approved in 2011, the FDA has approved ICT for up to 50 cancer treatments
.

Immune checkpoint inhibitor therapy approved by the FDA for treatment within the first 10 years.

It is worth noting that due to the special phenomenon of "pseudo-progression" that may occur after receiving ICT, that is, the phenomenon that the tumor enlarges for a period of time after the patient's treatment, but the tumor gradually regresses with time, so some traditional tumor measurement indicators cannot fully evaluate the treatment effect of ICT, and people need to evaluate the treatment effect of ICT in terms of overall survival time: in fact, about 20% of patients achieve long-term survival for more than 3 years after receiving Ipilimumab treatment.
And some patients can survive more than 10 years
.
Extended reading: How to distinguish between false progress and real progress in the process of tumor immunotherapy?

However, Ipilimumab remains the only approved anti-CTLA-4 therapy, and other drugs are still under
development.
Compared with CTLA-4, PD-1/PD-L1 immune checkpoint inhibitors have made great progress
in the first decade.

In 2014, PD-1 inhibitors were first approved for the treatment of patients with unresectable or metastatic melanoma, and in just a few years, PD-1/PD-L1 inhibitors have been approved for a variety of cancers
such as lung, skin, genitourinary cancer, lung cancer, head and neck cancer, breast cancer, lymphoma, gynecological cancer and gastrointestinal cancer.

PD-1/PD-L1 inhibitors are approved for these common cancers, regardless of the specific cancer, due to some common features of tumors,
such as high microsatellite instability (MSI-H), mismatch repair defects (dMMR), and high tumor mutation burden (TMB-high).

Although ICT monotherapy has a good response, the overall response rate of monotherapy is only 20%~30%.

Therefore, in clinical practice, people have begun to turn their attention to ICT immunotherapy
combination.
In the treatment of various cancers such as melanoma, hepatocellular carcinoma, renal cell carcinoma, non-small cell lung cancer, malignant pleural mesothelioma, and colorectal cancer, the combination of CTLA-4 inhibitors and PD-1/PD-L1 inhibitors has been found to improve the treatment effect of patients, and it has been found to prolong the survival of
patients in subsequent long-term follow-up.

In addition, immunotherapy combination chemotherapy has been shown to improve the survival of patients with non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, bladder cancer and head and neck squamous cell carcinoma, although further research is needed on the effect
of chemotherapy on ICT therapy.
In addition, ICT combined with targeted drug therapy can also improve patient clinical response: VEGF-targeted drugs combined with PD-1 inhibitors can improve the treatment effect
of endometrial cancer, hepatocellular carcinoma and melanoma.

Although these combination therapies can improve patient outcomes, these results are still limited to specific tumor types, and multiple ICT combination therapies are being actively explored to better improve treatment outcomes
.
Actively exploring effective ICT combination therapy is an important direction to explore in the next decade, and another general direction is how to find those who
can achieve good results by receiving treatment.

Next step: how to find the most suitable treatment population

One of the major challenges in the ICT sector is the lack of predictive biomarkers for optimal patient selection
.

Traditionally, biomarkers have focused on intrinsic tumor factors or single immune-specific markers; But as our understanding of the determinants of immune counter-tumor grows, a single biomarker may not be enough to identify the best population to treat
.

Therefore, people began to jointly look for which combinations can predict treatment outcomes according to the influencing factors of tumors and special immune factors, and this strategy has also been verified
by clinical treatment.

Biomarker Illustrated Book, which responds or resists ICT therapy, predicts the effect of patients after treatment by different combinations of biomarkers.

Recent studies have shown that combinations of multiple biomarkers may predict patient outcomes
better than single biomarkers.
In an analysis of more than 1,000 cancer patients with 7 different tumor types treated with ICT, it was found that the combined biomarker indicators were better than individual biomarker indicators and could better predict the survival of
patients after treatment.

Five key areas of ICT progress in the next decade include:

1.
To further understand the primary and adaptive immunotherapy mechanisms of ICT;

2.
Find suitable biomarkers to optimize patient selection;

3.
Integrate multiple new technologies to deepen the biological understanding of ICT therapies;

4.
Mechanism and clinical understanding of side effects of ICT therapy;

5.
Find the right combination of
ICT therapies.

Overall, in the next decade, the field of cancer immunotherapy needs to develop vertically, with a deep understanding of different immune cell subsets and their regulatory response mechanisms, and also needs to develop horizontally, combined with cancer biology, epigenetics and computational biology; In addition, ICT needs to be extended to all areas of oncology, including surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy drugs, to better improve the outcomes of
patients after treatment.

It is believed that in the next decade, ICT will become another cornerstone of cancer treatment after continuation, surgery, radiotherapy and chemotherapy with targeted drugs, and further improve the prognosis
of cancer patients.