Intestinal environment and various diseases

Fundamentals of Immunotherapy and Immune Checkpoint Inhibitors

Immune checkpoint inhibitors, which are attracting attention in cancer treatment.

Its innovative action is opening new avenues for treating advanced cancers that were previously difficult to treat.

This article introduces the relationship between immunotherapy and immune checkpoints, along with the latest findings that form the foundation of treatment strategies. Finally, we highlight a notable academic conference.

Basic Concepts and Objectives of Immunotherapy

Immunotherapy is a treatment that aims to activate the patient’s own immune system against cancer cells to eliminate tumors.

In recent years, treatment using immune checkpoint inhibitors has garnered particular attention.

This drug releases the immune response that had been suppressed by cancer cells, enabling T cells to attack cancer cells once again.

For example, imagine cancer cells deceiving T cells by saying, “I’m not the enemy,” to stop them from attacking. This drug steps in and tells the T cells, “Actually, it is the enemy—go ahead and attack.”

This enables T cells to recognize cancer cells clearly once again and attack them.

For example, in patients with melanoma (malignant melanoma), treatment using PD-1 inhibitors—one type of immune checkpoint inhibitor—has confirmed survival for several years even in stage IV disease, which was previously considered to have a poor prognosis.

Furthermore, even in cases of non-small cell lung cancer patients with high PD-L1 expression, treatment with immune checkpoint inhibitors has demonstrated significant efficacy, with reported cases surviving for over five years without recurrence.

Furthermore, in cases where the combination therapy of the immune checkpoint inhibitors ipilimumab and nivolumab was administered for renal cell carcinoma, complete responses (complete disappearance of the cancer) were observed in some patients, and these patients have remained recurrence-free for extended periods following treatment.

Such long-term effects are difficult to achieve with other treatments, demonstrating the true value of immunotherapy.

The Role and Importance of Immune Checkpoints

Our immune system has the function of attacking and eliminating viruses, bacteria, and abnormal cells such as cancer cells that invade the body.

However, it also incorporates a brake mechanism to prevent it from “running wild.”
This is what is called an “immune checkpoint.”

What exactly is an immune checkpoint?

Immune checkpoints act as control mechanisms that prevent immune cells such as T cells from attacking normal cells.

Representative control molecules include PD-1 and CTLA-4. When these molecules function, they apply the “immune brake,” preventing runaway responses such as autoimmune diseases before they occur.

Why are immune checkpoints necessary?

The immune system is a powerful weapon, but precisely because of that, it is also difficult to control.
Thanks to the existence of checkpoints, the following benefits are realized:

• Benefits: Prevention of autoimmune diseases, avoidance of chronic inflammation, protection of healthy cells
• Disadvantage: Abnormal cells, such as cancer cells, can sometimes exploit this brake by masquerading as normal cells, thereby evading the immune system.

In other words, while immune checkpoints are essential for our bodies, they can also serve as a “cover” for cancer cells.

Why haven’t we been able to inhibit immune checkpoints until now?

For a long time, checkpoints have been regarded as “essential self-regulatory mechanisms for the body.”

Therefore, the very idea of deliberately removing it was considered almost taboo within the medical field.

Furthermore, inhibition carries a high risk of paradoxically inducing autoimmune diseases, making clinical application difficult.

Furthermore, the detailed mechanisms of molecules such as PD-1 and CTLA-4 have only been elucidated relatively recently, and it is only now that their potential as therapeutic targets has begun to gain attention.

Why are immune checkpoints attracting attention now?

In modern cancer treatment, it is considered extremely important to neutralize the immune evasion mechanisms of cancer cells.

Immune checkpoint inhibitors represent a truly groundbreaking approach that releases the brakes on T cells, enabling them to target cancer cells once again.

This has enabled significant effects to be achieved even in cases where conventional chemotherapy and radiation therapy had limitations.

Against this backdrop, let us introduce several cases illustrating how immune checkpoint inhibitors are actually being utilized in cancer treatment settings.

Latest Case Studies on Immune Checkpoints

For example, in patients with non-small cell lung cancer, those with high PD-L1 expression demonstrated significant response to anti-PD-1 antibody therapy, resulting in a substantial improvement in survival rates.

In patients with advanced gastric cancer, there have been cases where disease stabilization and prolonged survival were achieved following the introduction of nivolumab as third-line therapy or later.

Additionally, in Hodgkin lymphoma, there are reports of immune checkpoint inhibitors being effective in patients resistant to standard therapy, achieving complete remission.

These examples demonstrate that appropriately releasing the “immune brakes” known as immune checkpoints is a crucial key to next-generation cancer treatment.

Types and Functions of Immune Checkpoint Molecules

Multiple immune checkpoint molecules exist, each performing distinct functions.

Multiple immune checkpoint molecules exist, each performing distinct functions.

Ipilimumab, a CTLA-4 inhibitor, promotes early T-cell activation and has yielded significant results in melanoma treatment.

Additionally, combination therapy targeting both LAG-3 and PD-1 is currently under investigation, and it is generating significant interest as a potential re-treatment strategy for recurrent cancer.

TIGIT is an immunosuppressive receptor expressed on T cells and natural killer (NK) cells that suppresses immune responses by binding to its ligand, CD155.

TIGIT inhibitors are gaining attention as a new target that helps activate immune cells and boost their ability to attack cancer cells.

VISTA (V-domain Ig suppressor of T cell activation) is a molecule that suppresses the initial activation of T cells and is strongly expressed particularly in the immunosuppressed tumor microenvironment.

By targeting VISTA, it may be possible to achieve efficacy even in tumors that have been resistant to immunotherapy.

BTLA (B and T Lymphocyte Attenuator) is a molecule that suppresses T cell responses by binding to a ligand called HVEM.

BTLA functions in immunosuppressive environments associated with chronic inflammation and cancer, and its inhibition is anticipated as a novel therapeutic strategy for chronic tumors.

The Relationship Between Cancer and the Immune System

Cancer cells are entities that should be eliminated by immune cells as foreign substances within the body.

However, cancer employs various immune evasion mechanisms to avoid attack by immune cells.

This immune evasion plays a major role in cancer progression and metastasis.

Studies in breast cancer patients have shown that cases with greater T-cell infiltration have a better prognosis.

This indicates that the innate immune response against cancer is functioning effectively, and it also provides clues for determining which patients will respond to immunotherapy.

Furthermore, in pancreatic cancer, cases where T-cell activation was observed also reported tumor shrinkage when combined with chemotherapy, leading to long-term survival.

Furthermore, in some cases of prostate cancer, administration of immune checkpoint inhibitors has resulted in reduced tumor markers and improved clinical symptoms, suggesting that individual differences in immune response significantly influence treatment outcomes.

The Effects and Side Effects of Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have demonstrated dramatic efficacy in cancer treatment.

On the other hand, careful consideration is required regarding side effects, the assessment of individual indications, and the possibility of combination therapy.

Treatment Course of Immune Checkpoint Inhibitors and Combination Therapy

Immune checkpoint inhibitors are drugs that reactivate T cell function by inhibiting inhibitory receptors (such as PD-1 and CTLA-4) present on the surface of T cells and their ligands.

However, while some patients see results within a few weeks of starting treatment, it may take several months for others.

In particular, cases where long-term effects are expected have demonstrated sustained tumor suppression through immune memory.

As a combination therapy, co-administration with anti-CTLA-4 antibodies has been shown to be effective in advanced melanoma and renal cell carcinoma, and research is also progressing on combinations with chemotherapy and radiation therapy.

Additionally, there are case reports of successful outcomes in retreatment cases when combined with fecal microbiota transplantation (FMT) to improve the intestinal environment.

When recurrence occurs after initial response to immune checkpoint inhibitors, the timing and approach of re-treatment are critical.

For example, in cases of melanoma recurrence, there have been reports of patients who responded to PD-1 inhibitors during initial treatment achieving a response when administered the same therapy again.

On the other hand, cases of resistance to antibody drugs have been observed, necessitating the identification of new targets and reevaluation of the immune profile.

The success rate of retreatment depends on the patient’s biomarkers and immune status prior to treatment, making regular immune monitoring key to determining the treatment strategy.

Long-term data has shown that the five-year survival rate for patients treated with immune checkpoint inhibitors reaches 20 to 30 percent for certain cancer types, and this figure may be exceeded if re-treatment proves effective.

Side Effects and Precautions of Immune Checkpoint Inhibitors

Immune checkpoint inhibitors may cause autoimmune side effects.

Major side effects include dermatitis, diarrhea, endocrine disorders (such as thyroiditis and adrenal insufficiency), and pneumonia.

For example, cases of severe interstitial pneumonia have been reported in patients treated with nivolumab, making early monitoring and intervention essential.

To maximize efficacy while controlling side effects requires meticulous management by the medical team.

The Latest Research and Future Prospects in Immunotherapy

Advances in Personalized Medicine and Technological Innovation

Research on immune checkpoint inhibitors is advancing at a rapid pace.

In particular, personalized medicine utilizing overseas case studies and genetic biomarkers is an important topic that points to the future direction of healthcare.

For example, in cancer immunotherapy, research on biomarkers to predict treatment efficacy is accelerating, with tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 expression levels attracting particular attention.

In MSI-High colorectal cancer patients, high response rates to immune checkpoint inhibitors have been confirmed, and the FDA has approved an expanded indication based on this biomarker.

Furthermore, advancements in evaluating the tumor immune microenvironment through immune profiling have enabled personalized treatment planning.

In recent years, the analysis of circulating tumor DNA (ctDNA) and T-cell repertoires has advanced, expanding their use as evaluation tools throughout treatment—before, during, and after.

Additionally, AI-based predictive models are still in the research phase, with hopes for a future where patient-specific responsiveness can be determined with high accuracy.

Such technological innovations may contribute not only to improving treatment success rates but also to reducing the risk of side effects.

International Trends and Their Impact on Japan

Internationally, the establishment of new treatment protocols is rapidly advancing, primarily in the United States and Europe.

In the United States, clinical trials are underway combining it with CAR-T cell therapy and with new immune checkpoint inhibitors such as TIGIT inhibitors.

Meanwhile, in Europe, combination therapies utilizing immune memory are gaining attention. In France, a case has been reported where complete remission was achieved using a treatment combining FMT (fecal microbiota transplantation) and anti-tumor vaccines.

These advanced initiatives offer significant insights for Japan’s clinical settings, where expanding treatment options and earlier implementation are highly desired.

However, in Japan, drug approvals often take over a year on average, a significant difference compared to the U.S. accelerated review system (a few months).

To bridge this gap, Japan also needs to further expand its conditional approval system and early access programs.

Combination of Immune Checkpoint Inhibitors and Fecal Microbiota Transplantation Controls Appendiceal Cancer

Against the backdrop of the latest international research and advances in personalized medicine, attention is also focusing on the relationship between the gut environment and cancer immunity.

For example, in a male patient with stage 4 appendiceal cancer, simultaneous administration of an immune checkpoint inhibitor and fecal microbiota transplantation (FMT) resulted in no tumor growth for over 10 months, halting disease progression.

The restoration of gut microbiota diversity and reactivation of antitumor immunity are considered key factors in its efficacy, drawing attention to the potential of combining fecal microbiota transplantation with cancer treatment.

Details of this case were presented by Dr. Yoshitaka Tanaka at the 9th Annual Meeting of the Clinical Research Society for Gut Microbiota Transplantation, held in September 2025.

This presentation will be a valuable opportunity for healthcare professionals and researchers at the forefront of cancer immunotherapy seeking to deepen their understanding of its connection to the gut environment.

This event was successfully concluded with the participation of many attendees.
We are currently accepting applications for [Archive Streaming].
For those who were unable to attend on the day, please take this opportunity to view the latest insights.

For those wishing to deepen their understanding of the relationship between cancer immunotherapy and fecal microbiota transplantation, or to gain knowledge that will help maintain their own or their family’s health, this is an unparalleled opportunity to learn the latest information. We encourage you to apply.

Details of Professor Tanaka’s lecture can be found here.

References

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Supervisor: Dr. Hideaki Shima, Ph.D. in Agriculture (Symbiotics Co., Ltd.)

Release Date: June 21, 2025
Last Updated: October 15, 2025