Conventional Immunotherapy

CFCs (chronically fermenting cells or cancer) do not develop in isolation. A healthy, optimally functioning immune system can recognize and eliminate abnormal cells before they progress into clinically detectable tumors. The presence of a tumor therefore means that immune surveillance has failed, either because the immune system has been chronically imbalanced, overwhelmed, or both.

Humans have long recognized that the body’s own innate forces influence and control tumor growth. From ancient Egypt, some 3,000 years ago, to the early nineteenth century physicians have reported cases in which tumors disappear after severe infections accompanied by high fever. 

The Ancient Greek physician Galen was the first to suggest a connection between CFCs and chronic inflammation indicating a continued assault within the body by persistent exposure to irritants, e.g., toxins different forms of environmental exposure including diet and any of the myriads of unnatural substances to which humans voluntarily seek exposure, e.g., alcohol, drugs and artificial personal hygiene. Additionally, an impaired immune system from persistent exposure to electromagnetic fields (EMF), gut dysbiosis, multiple metabolic disturbances and uncontrolled, persistent psychological stress. 

In the 19th century, German physicians Busch and Fehleisen independently observed tumor regressions in patients who developed erysipelas, a severe skin infection caused by bacterium Streptococcus pyogenes. 

In the late 19th century, William Bradley Coley, MD now regarded as the Father of Immunotherapy, documented numerous cases of spontaneous CFC remission following bacterial infections. He ultimately developed “Coley’s toxins,” consisting of two attenuated bacteria Streptococcus pyogenes and Serratia marcescens.  Through trial and error, he discovered that by heating the bacteria, although still capable of causing fever (pyrogenic), they were unable to multiply. Coley would then inject this bacterial cocktail sequentially into the patient resulting in fever and TH1 polarization with compete resolution of the CFCs. T-helper type-1 (TH1) polarization, a shift towards a cellular immune response characterized by the release of pro-inflammatory cytokines like interferon-gamma (IFN-γ), which allows the immune system to recognize and eliminate tumor cells.  In fact, this is the only medical intervention that has demonstrated 30+ year remission, and Dr Coley continued using these treatments until his death in 1936.

After his death, the use of Coley’s Toxins gradually declined, but it was not until 1962 that the U.S. Food and Drug Administration (FDA) officially banned the therapy by reclassifying it as an unapproved “new drug” under the Kefauver-Harris Amendment, which required rigorous testing for efficacy and safety. As would be expected, Coley’s Toxin, not having the financial backing to conduct the research necessary to meet these standards, this powerful, non-toxic modality fell into the annals of history. Dr Coley’s contributions to immunology and CFC treatment remained underappreciated and unacknowledged for decades.

Despite obtaining excellent results, these toxins faced continuous criticisms and disapproval by many leading surgeons, primarily because at that time, the only treatment for sarcomas was surgical removal, although claiming to be concerned about the “inconsistencies”. And, then long after Dr Coley died, researcher Murray Shear and his colleagues were able to demonstrate that a bacterial lipopolysaccharide is the active component in the Streptococcal concoction, leading to tumor regression. W.O.’ Malley found that the tumor regressing potency of the lipopolysaccharide was due to an endotoxin, which was activated upon injection. This endotoxin, responsible for hemorrhagic necrosis of tumors, was named as – tumor necrosis factor-alpha (TNFα), in the year 1975 by Carswell et al. 

Interest in CFC immunology returned after World War II with the discovery of interferons, identification of T cells, natural killer (NK) cells, dendritic cells, and the development of bone marrow transplantation. These advances confirmed that the immune system plays a central role in controlling CFCs.

The modern era of immunotherapy began in the 1980s and accelerated rapidly in the 21st century with the development of immune checkpoint inhibitors and other ongoing efforts to overcome the immune system’s own regulatory limits. 

However, understanding the complex interactions between CFCs and the immune system, and trying to control them, has turned out to be the most challenging areas in modern medicine. Although immunotherapy was initially thought to be a breakthrough in CFC treatment, its success has been limited, benefiting only a minority of individuals. In the following sections, we will explore the reasons behind this limited efficacy. To understand immunotherapy, we first need to look at how the immune system behaves when CFCs appear.

How Does the Immune System Respond to Tumors?

The immune system is constantly monitoring the body for abnormal cells. When it encounters CFCs, it mounts a highly coordinated response that involves multiple immune cell types working together.

The immune system is exceedingly complex, and although one system, in order to make it easier to understand, it has been divided into two parts: innate immunity and adaptive immunity.

The innate immune system provides the body’s initial defense against threats such as infections and CFCs. In addition to acting quickly, it has an essential role in shaping the adaptive immune response that follows.

Key cells of the innate immune system include:

Macrophages

Macrophages patrol tissues throughout the body, identifying, engulfing CFCs, and then bring a part of it to the T-cells, which activates them.

Dendritic Cells (DCs)

Dendritic cells are central to initiating targeted immune responses against tumors. When they encounter CFCs, they ingest them and collect tumor antigens, distinct molecular markers from CFCs. These antigens are then presented to T cells of the adaptive immune system, instructing them on how to recognize and attack CFCs.

Natural Killer (NK) Cells

NK cells are essential for tumor elimination because they can directly recognize and eliminate CFCs without relying on specific tumor antigens. This allows them to detect CFCs that may evade other immune defenses. NK cells also activate other immune cells by releasing signaling molecules (cytokines).

The adaptive immune system responds more slowly, as it must first recognize tumor antigens presented by innate immune cells, particularly dendritic cells. Once activated, however, it produces strong and precise responses and establishes immune memory, enabling faster and more effective responses if the same threat (e.g. CFC with same antigens) is encountered again. This immune memory is essential for preventing tumors from growing back.

What Are Tumor Antigens?

Tumor antigens are molecules found on the surface of CFCs that allow the immune system to distinguish them from healthy cells. They fall into two main categories:

• Tumor-specific antigens (neoantigens):
  These arise from mutations unique to CFCs and are not found in normal tissues. Because they are truly foreign to the immune system, they provoke strong and highly targeted immune responses.
• Tumor-associated antigens:
  These antigens are also present on normal cells but are overproduced by CFCs. As they are not entirely foreign, immune responses against them are generally weaker.
  
  

Key Cells of the Adaptive Immune System

T Cells

• Killer T cells (CD8⁺ cytotoxic T cells):
  These cells directly destroy CFCs. Once they recognize a tumor antigen, they rapidly multiply, forming a large population of cells specialized to target that antigen. Strong T-cell responses are critical for tumor elimination and a key determinant of favorable prognosis.
• Helper T cells (CD4⁺ T cells):
  Helper T cells coordinate immune responses by releasing cytokines and directing the activity of other immune cells. They can differentiate into specialized subtypes that either enhance or suppress anti-tumor immunity.
• Regulatory T cells (Tregs):
  Tregs restrain immune responses to prevent excessive inflammation. In the tumor microenvironment, however, they suppress beneficial anti-tumor immune activity.
  
  

B Cells

B cells contribute to long-term immune protection by producing antibodies that bind specifically to tumor antigens, marking CFCs for destruction by other immune cells. Some B cells persist as memory cells, allowing the immune system to respond more rapidly and effectively if the same tumor antigens reappear.

Here is how the immune system works together to eliminate a tumor:  

1. Dying CFCs release tumor antigens into the surrounding tissue.
   
   
2. Antigen-presenting cells, including dendritic cells and macrophages, collect these antigens and present them to T cells.
   
   
3. This antigen presentation activates T-cells, that multiply and migrate into the tumor microenvironment.
   
   
4. Activated T cells recognize tumor antigens expressed by CFCs and eliminate them.
   
   
5. Continued CFC killing leads to additional antigen release, which sustains antigen presentation and maintains T-cell–mediated tumor elimination.

The immune response, however, is tightly regulated by stimulatory and inhibitory signals. This innate regulation functions as a safety mechanism to prevent autoimmunity (responses to healthy tissues) and tissue damage caused by excessive immune activation. A key component of this regulation is the expression of inhibitory receptors, known as immune checkpoints, which act as “brakes” on T cells.

Inside a tumor, chronic exposure to tumor antigens and inflammatory cytokines produced by CFCs enhances these inhibitory pathways, leading to T-cell dysfunction or exhaustion, therefore reducing their killing capacity.

Conventional medicine has developed therapies that aim to block this immune suppression.  

Main Types of Immunotherapies  

Immune Checkpoint Inhibitors  

Activated T-cells can be disabled when a CFC binds to a particular receptor on the T-cell. The part of the CFC that binds the T-cell is called the ligand, called PD-L1 and the part of the T-cell that connects with the ligand is the receptor, PD-1. Immune checkpoint inhibitors work by blocking inhibitory receptors releasing the “brakes” on T cells and enhancing their ability to respond with binding to the PD-1 or the PD-L1, so that the CFC cannot bind to the T-cell and prevent it from doing its job of killing the CFC. 

Checkpoint inhibitors are monoclonal antibodies, “mono” indicates that they are a single type of antibody that will bind to either the PD-1 or PD-L1. “Clonal” means they are produced in large quantities to achieve a therapeutically effective dose.

To date, multiple checkpoint inhibitors have been developed for treating CFCs originating in different locations, including melanoma (skin), lung CFCs and kidney CFCs. 

• CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) inhibitors ipilimumab and tremelimumab. CTLA-4 is an inhibitory receptor that prevents T cells from effectively killing CFCs. This inhibitory effect can be reversed with monoclonal antibodies that block CTLA-4, thereby restoring T-cell activity.
  
  
• PD-1 (programmed cell death protein 1) inhibitors nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab and toripalimab.
  
  
• PD-L1 (programmed cell death ligand 1) inhibitors atezolizumab, durvalumab, and avelumab.
  
  

PD-1 is expressed on T cells, while PD-L1 is commonly expressed on CFCs and antigen-presenting cells. 

Binding of PD-1 to PD-L1 delivers an inhibitory signal that suppresses T-cell function, allowing CFCs to evade immune attack. 

Blocking either PD-1 or PD-L1 prevents this inhibitory interaction and enables T cells to regain their anti-tumor activity.

Adoptive Cell Therapy (ACT)

ACT involves infusing patients with immune cells engineered or expanded to fight CFCs:

• CAR T cells: T cells are isolated from a person, genetically engineered to target specific tumor antigens, and then re-infused back into the person
• Tumor-infiltrating lymphocytes (TILs): expanded from a person’s own tumor
• Bispecific CD3 antibodies: artificially link T cells to CFCs
  
  

These approaches have shown some success in leukemia and lymphoma but have weak effect on solid tumors.

CFC vaccines

CFC vaccines contain tumor antigens combined with an adjuvant, which acts like an alarm signal to wake up the immune system. The goal is to teach the immune system exactly what to look for and attack. Despite thousands of clinical trials, only one therapeutic CFC vaccine, Sipuleucel-T, is currently FDA-approved. It is used to treat advanced prostate CFCs and works by training a person’s own immune cells to recognize a prostate-specific tumor antigen. However, its benefit is modest improving survival by few months.

Why Does Immunotherapy Fail?

Although considered revolutionary, only a minority of individuals respond to immunotherapy, and complete responses remain rare. There are several obstacles that make it hard for the immune system to eliminate CFCs, both inside the tumor itself and throughout the body, including:

1. Tumors Hide by Changing and Losing Antigens
   

One major challenge in immunotherapy is that CFCs can evade detection by changing or completely losing their antigens, the signals that make immune cells recognize them. When this happens, once-identified CFCs become invisible, making it harder for the immune system to find and destroy them. 

This constant alteration of antigens happens through changes in cell signaling and metabolism, or epigenetic “switches” that turn antigen expression off.

In addition, tumors are not made up of identical cells. Instead, they are highly diverse, with different CFCs expressing different antigens. As a result, immunotherapies that target specific antigens may kill some CFCs but leave others behind, allowing the tumor to adapt and become resistant over time.

Many tumors also produce very few tumor-specific antigens that clearly distinguish them from normal tissue. With so few obvious targets, the immune system struggles to mount an effective response. This limits therapies such as CAR-T cells, which rely on specific antigens to guide engineered T cells, as well as immune checkpoint inhibitors, which requires pre-existing immune response triggered by antigen recognition. 

Therefore, many of the antigens used as targets in immunotherapy are not unique to CFCs. They are “self” antigens that are also found in healthy tissues. Targeting these antigens reduces treatment precision and increases the risk that immune cells will attack other organs, leading to dangerous side effects.

To boost immune recognition, immunotherapy is sometimes combined with chemotherapy or radiation. These treatments kill CFCs which breaks them apart and exposes hidden antigens from within. This gives the immune system more clues to work with. However, these approaches come at a cost: chemotherapy and radiation also suppress the immune system and cause significant toxicity, limiting how much they can truly enhance anti-tumor immunity.

2. Physical Barriers Preventing Immune Cells Reach Tumors

A dense, stiff tumor matrix together with poorly organized blood vessels and weak blood flow restrict T cells from reaching and attacking the tumor. These barriers create so-called “cold tumors,” which are resistant to immunotherapy. 

3. Immunosuppressive Tumor Microenvironment

Tumors create a harmful environment that shuts down the immune system and can even reprogram infiltrating immune cells to support tumor progression. As a result, the body’s natural defenses, which are supposed to attack CFCs, can end up supporting tumor growth. The state of immune cells in the tumor is key in determining the tumor’s fate, its ability to spread (metastasize) and the survival of the person.

Multiple factors in the tumor contribute to immune dysfunction, including low oxygen (hypoxia), lack of nutrients, accumulated waste products such as lactic acid, and inflammatory molecules produced by CFCs. These conditions change the behavior of immune cells: T cells turn into regulatory T cells (Tregs) that turn off cytotoxic (killer) T cells that are trying to attack CFCs and macrophages shift to M2 type macrophages that helps the tumor instead of the M1 type that kills CFCs and boosts T-cell and NK cell activity.

As a result, immunotherapies, whether they enhance the body’s own T cells with checkpoint inhibitors or use specially engineered T cells such as CAR-T therapy, struggle to work properly inside tumors.

As the tumor grows and produces more inflammatory molecules, the immune-suppressing environment spreads further. Without changing the tumor microenvironment to restore normal immune function, even highly activated immune cells cannot effectively eliminate the tumor.

4. Upregulation of Alternative Immune Checkpoints

Blocking a single immune checkpoint can make tumors adapt by turning on other inhibitory molecules, creating new “brakes” on T cells and evade the immune system despite therapy.

5. CFC Stem Cells

Within tumors, some CFCs can acquire stem cell-like properties through a process called epithelial-mesenchymal transition (EMT). This transformation enables them to migrate and form metastases. CFC stem cells are also more resistant to immunotherapy: they can evade recognition and destruction by T cells and upregulate immune checkpoints such as PD-L1 to further suppress immune responses.

6. Lack of Immune Memory

Immunotherapies often work only for a short time because they do not create lasting “immune memory” to keep CFCs under control. This happens both because the tumor environment weakens the immune system and because immunotherapies target only a single component of the immune system. For long-term protection, many different types of immune cells need to work together, not only T cells. Without this full immune response, some CFCs can survive and the tumor may grow back even after an initial shrinkage.

7. Severe Immune-Related Toxicities

Another major challenge is immune-related adverse effects ranging from mild (such as diarrhea) to severe or life-threatening (such as cytokine release syndrome, neurological toxicity, or autoimmune conditions). Individuals with pre-existing autoimmune issues are often advised against immunotherapy due to higher risk.

Especially therapies that use antigens that are not specific to tumors but exist also in other tissues can cause severe toxicity and damage other tissues.

To manage autoimmunity and severe immune-mediated side effects corticosteroids are often used alongside immunotherapy. However, corticosteroids suppress T-cell activity blunting anti-tumor immune responses and counteracting the very therapeutic effect of the treatment. 

8. Gut Microbiome

The composition and diversity of gut microbiota, a complex ecosystem of microbial species (bacteria, fungi, viruses etc.) in the gastrointestinal tract profoundly shapes the immune function and consequently greatly influences how well immunotherapy treatments work in eliminating CFCs.

• People who respond to immunotherapy often have high microbial diversity and an abundance of beneficial bacteria such as Faecalibacterium, Ruminococcaceae, Akkermansia muciniphila, and Bifidobacterium.
• Non-responders frequently have low diversity or higher levels of bacteria such as Bacteroidales, Ruminococcus obeum, and Roseburia intestinalis, which can suppress immune responses.

9. Lifestyle Factors

Several environmental and lifestyle factors that are mostly overlooked by conventional medicine, including environmental toxins, psychological stress, diet, sleep, and physical activity, shape immune function, influence responses to therapy, and significantly affect overall survival.

In conclusion, conventional immunotherapies face multi-layered resistance, with mechanisms acting together that limit their effectiveness. Resistance arises from processes within CFCs, including changes and losses of antigens which limit treatment targets, and weaken immune recognition and activation. It is further reinforced by the physical inaccessibility of tumors, the immunosuppressive tumor microenvironment, and systemic factors such as gut microbiome composition. Together, these factors influence how effectively immune cells can detect CFCs, reach tumors and function within the tumor microenvironment, ultimately determining whether tumors respond to immunotherapy. 

The fundamental problem of current treatments is that they target only one aspect of the immune response, attempting to control it while leaving many underlying processes unaddressed. A truly effective strategy that enables the immune system to fully eliminate CFCs will require combining multiple approaches. These include therapies that directly kill CFCs to increase antigen exposure and reduce overall tumor burden, strategies that remodel the tumor microenvironment to permit immune cell infiltration and reverse immunosuppression, and interventions that activate the person’s entire immune system while promoting long-term immune memory for durable responses.

Importantly, all this can be achieved in a less toxic manner by working with the immune system rather than trying to command it, respecting its inherent intelligence and allowing it to function as designed. In the next article, we will explore this integrative approach to immunotherapy.

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