The Smart Immunotherapy for Cancer Patients 

Immunotherapy is a type of anti-cancer therapy that stimulates Mother Nature’s built-in ability to fight against malignant cells through our own immune systems. To understand the importance of immunotherapy as a cancer treatment, it is necessary to understand why cancer continues to be a leading cause of death despite major progress in medicine.

Why does cancer continue to be a leading cause of death?

Despite significant medical advancements, cancer remains a leading cause of morbidity and mortality worldwide. 

Some types of cancer can be cured effectively using the conventional treatments available now. However, many types of cancer cells develop progressive resistance against available anti-cancer modalities. Furthermore, some cancers are resistant to conventional treatment from the beginning, and in the majority of cases, the cancer-initiating cells (often called cancer stem cells) are resistant to all available anti-cancer treatments, including chemotherapy and radiation therapy. This explains the many unsuccessful attempts to prevent recurrent disease and disease progression.  

In addition, cancer cells mutate spontaneously, especially after being exposed to chemotherapy and other anticancer modalities. This can cause the development of progressive multi-drug resistance.

The problem of developing resistance against available anti-cancer medications is compounded by several other mechanisms that protect the rapidly-developing malignant cells from the anti-cancer medications, such as the patient’s immune system recognizing abnormally-mutated cells as “safe” and therefore leaving them alone.

Cancer develops when the normal surveillance mechanisms of the immune system fail to eliminate the first cancer initiating cell.

In other words, every cancer develops from the mutation of a single cell, which explains why a complete cure of cancer depends on the capacity to eliminate every last malignant cell. This is something that conventional anti-cancer modalities frequently fail to accomplish. 

Yet, rarely, the immune system and other cancer resistance mechanisms may successfully block progression of existing cancer cells. Then, patients may survive long-term and even maintain good quality of life. This can be regarded as “operational cure”. However, the safest approach to cure cancer relies on successful elimination of all cancer cells. This could sometimes be accomplished through surgery, chemotherapy, hormonal therapy, or radiation therapy. 

Whenever applicable, targets for innovative anti-cancer medications may be discovered by the so-called precision medicine. These are usually identified through detailed molecular analysis of the malignant cells. In the event that available medication against recognizable mutation is discovered, tailor-made treatments may help control otherwise resistant cancer cells. When conventional medicine runs out of treatment options, cancer progression and death are unavoidable. 

Malignant or cancerous cells may appear in the body spontaneously or following exposure to carcinogenic agents, viruses, or radiation. In most cases, the cause is unknown. In others, there may be a genetic predisposition that increases the risk of cancer development. Under normal circumstances, the immune system can detect and eliminate abnormal or potentially-malignant cells, provided they are being recognized as being different from normal cells belonging to the same tissue. 

When such cells escape recognition by the immune system, they can begin multiplying in an uncontrolled manner locally or in remote metastases. This results in a recognized disease – cancer. When cancer develops in a visible location or in a sensitive part of the body, it may be recognized at an early stage. However, when cancer grows inside a large or relatively less important space, it may grow to a very large size before anything wrong is recognized. 

As such, there are two important things to remember: every cancer begins with mutation of a single cell;  under normal circumstances, the immune system protects us against cancer.

Taken together, it follows that whenever the immune system is suppressed, impaired or missing due to a genetic disease, development of cancer may be unavoidable alongside with serious acute or chronic infections that can increase the inflammatory reactions that can also enhance cancer progression. 

Under normal circumstances, the immune system’s job is to react against anything different from the normal “self,” including cancer cells if such can be recognized. Regardless of their resistance to conventional anti-cancer agents, activating the immune system to maximize its ability to recognize and kill cancer cells represents one of the most promising tools in the warfare against cancer. 

Failure of the immune system to eliminate invading malignant cells may also result from several mechanisms that actively suppress the capacity of the immune system to react against cancer cells.

Therefore, optimal immunotherapy always combines three synergistic procedures: 

  • Blocking all the factors that suppress the immune system.
  • Activating and targeting all available anti-cancer effector mechanisms.
  • Using medications with scientific documentation of anti-cancer activity in order to enhance the activity and efficacy of anti-cancer immunotherapy.

There are five main types of immunotherapy – targeted antibodies, immunomodulators, adoptive cell therapy, cancer vaccines and oncolytic virus therapy. Immunotherapy works by exploiting elements of a patient’s and/or donor’s immune system to fight cancer, always remembering that the efficacy of immunotherapy for cancer can be optimal if applied against minimal residual disease

The potential therapeutic role of anti-cancer immunotherapy

The exact cause of most types of cancers is presently unknown. The reason why cancer, which probably starts with the mutation of a single cancer-initiating cell, can continue to grow locally and eventually metastasize to remote locations, is due to malfunctioning of the immune system or to failure of  patient’s immune system to recognize the malignant cells as being “non-self”. Under normal conditions, the immune system can rapidly and most efficiently eliminate any cells that have been recognized as “non-self”. This explains why recipients of organ transplants that have to maintain immunosuppressive treatment for life to prevent graft rejection, as well as patients with inborn or acquired immune deficiency (e.g., patients with AIDS) are at constant risk of cancer development. 

Due to the fact that the immune system offers protection against cancer under normal circumstances, maximizing the capacity of the immune system to recognize and/or kill cancer cells represents an important strategy for treatment of cancer. Indeed, activated immune system killer cells can also eliminate multi-drug resistant cancer cells, and even cure cancer patients considered incurable. This explains the important role of immunotherapy for treatment of cancer, especially if applied at the stage of minimal residual disease. 

The war waged by immunotherapy against cancer can be compared to the war against any enemy: if the number of soldiers exceeds the number of enemies, or if your soldiers are better trained and better equipped, the likelihood of winning the war increases. In other words, if the replication of cancer cells is faster than the replication of the immune system cells and their capacity to kill, chances are the battle will be lost. 

Conversely, if activated anti-cancer effector cells can replicate rapidly or be activated to their maximum capacity in order to kill a smaller number of cancer cells, a cure may be accomplished. 

Unfortunately, under normal circumstances, cancer cells grow much faster than normal cells. Therefore, in order to increase the chance of successfully controlling cancer, it is important to maximize the capacity of the immune system cells to kill cancer cells on the one hand, and apply immunotherapy against as small as possible number of cancer cells on the other. 

This is why, when conventional cytoreductive agents can no longer be effective against multi-drug resistant cancer cells, synergistic off-label medications with known anti-cancer activity may be applied in order to try and maximize the overall anti-cancer effects, sometimes based on a trial and error basis and reliable anecdotal success stories. 

What are the special anti-cancer procedures at Biotherapy International focusing on immunotherapy?

At Biotherapy International, we don’t simply believe cancer is a treatable disease: we believe it may even be sometimes curable, provided all principles of optimal treatment are fully accomplished. However, when cancer cannot be eliminated, we offer non-aggressive anti-cancer treatments focusing on all available anti-cancer modalities, including potentially effective off-label medications. Yet, we focus on immunotherapy to try to slow down progression of existing disease. 

Biotherapy International’s treatment protocols are based on fundamental scientific basis and cumulative pre-clinical and clinical experience, including out-of-the-box procedures not yet gained “evidence-based medicine” status. We always take into full consideration the fact that if successful control of cancer progression cannot be accomplished, a patient’s quality of life should be considered with any future treatment recommendation.

Each patient in our clinic receives an individualized protocol of anticancer therapy because no two cancers are exactly the same and not two patients are identical. Therefore, recommended treatment always takes into consideration disease-specific and patient-specific parameters in order to design the most suitable synergistic therapeutic protocols.

Depending on the diagnosis and patient’s condition, the following stages of treatment can be recommended

Step 1

At this stage, we use conventional cancer treatment methods in order to benefit from available global experience, aiming to minimize residual tumor lesions and to slow the progression of resistant residual disease. 

Ideally, innovative immunotherapy should be applied at a stage of minimal residual disease, preferably at an early stage of the disease, following optimal conventional treatment. Molecular analysis of tumor samples by the so-called Precision Medicine may sometimes discover new targets for treatment by available or experimental medications. 

Other supporting measures may include using anti-angiogenic agents to restrict the blood supply of metastases, as these that cannot grow beyond 1 millimetre without any direct blood supply, as cancer metastases normally induce rapid growth of supporting blood vessels. Other supportive measures may include heat therapy using involved field oncothermia to damage the cell wall of cancer cells and to enhance penetration of anti-cancer medications.

Step 2

Next, we eliminate all recognizable factors that can inhibit the activity of the immune system against cancer.

Step 3

We begin the activation of a patient’s immune system using innovative medications to induce anti-cancer immunotherapy, such as monoclonal antibodies, interferon and activating cytokines as well as additional agents that may amplify the anti-cancer effects of the immune system. 

When indicated, we may use radiation therapy to help kill visible cancer lesions. Sometimes, an inflammatory attack against cancer cells damaged by ionizing radiation may also induce a local immune response against cancer antigens, which could result in induction of systemic anti-cancer effects against remote metastases. This is known as the abscopal effect.

Step 4

If activating a patient’s immune system is not enough to eradicate residual resistant malignant cells, then we begin with much more effective anti-cancer effects. These can be induced using the immune cells of a family member or even of an unrelated volunteer. 

A donor’s lymphocytes can be activated before or after cell infusion in order to maximize their cancer-killing potential. Such a procedure can help “reject”  otherwise resistant cancer cells, including cancer stem cells that are a priori resistant to conventional anti-cancer modalities.

Step 5

Additional experimental cancer treatments may be considered when applicable, including anti-cancer vaccines, harmless oncolytic (cancer killing) viruses, and off-label drugs with proven antitumor activity.

Step 6

More innovative experimental methods of treatment currently under development may become available in order to eliminate resistant cancer cells by selective targeting of activated donor lymphocytes against cancer cells in order to eliminate existing resistant malignant cells and try to accomplish, induce long-lasting anti-cancer vaccination against escaping malignant cells and to protect against recurrent disease.

The rationale for cancer immunotherapy, particularly for patients responding to conventional treatment. 

Although immunotherapy is mainly indicated to treat cancer patients who fail to respond to conventional anticancer modalities, the clinical application of innovative immunotherapy should be highly recommended for patients at risk in remission who are at a stage of invisible minimal residual disease and who have successfully responded to conventional treatment that may believe they were already cured. 

Unfortunately, when no residual malignant cells can be visualized, patients —and frequently also their treating physicians— believe they may already be cured. For patients with no evidence of disease, most haematologists and oncologists may also decide to “wait & see” and avoid recommending further treatment as long as there is no positive evidence of disease. Yet, according to Biotherapy International’s policy, patients with high-risk disease are always at  a high risk of recurrent or metastatic disease due to undetectable resistant residual disease including few residual cancer stem cells (remembering that every cancer begins with a single cancer-inducing cell).

We now know that even a 1-mm cancerous tumor, although undetectable by available instrumental methods, already consists of up to one million cancer cells. These can rapidly divide and spread around the body, forming metastasis even in distant organs. Considering the fact that every cancer develops from a single cancer initiating cell and that cancer stem cells are a priori resistant to available treatments, it is important to eliminate also the invisible residual malignant cells. 

This is why, if the goal is to try to cure rather than to merely treat visible or symptomatic disease, every patient with a high-risk disease should be a candidate for preventive anti-cancer immunotherapy, especially if available treatment is safe, when there is a good option to win and nothing to lose . 

We should always remember that immunotherapy can be most effective when applied for patients at the minimal residual disease stage. Furthermore, in our opinion, the stage of minimal residual disease may not only be the best timing for attempting to cure the patient, but possibly the only window of opportunity to cure the patient.

The “wait & see” policy and concern of conventional haematologists and oncologists to offer treatment for patients “with no evidence of disease” may be justified for treatment of patients with “good risk” disease who may be cured by conventional anticancer modalities, or if available immunotherapy procedures to eradicate minimal residual disease were risky. 

However, whenever safe and user-friendly immunotherapy procedures can be offered, it should be the patient’s decision to decide about the choice of additional treatment, yet, realizing that there is never guarantee for cure. Unfortunately, confirming that treatment of MRD with available immunotherapy procedures is justified will depend on successful prospective randomized clinical trials involving many thousands of patients collected by several collaborating institutions, with results obtained after 5-10 years follow up. This explains why treatment of MRD remains a controversial issue and it should be the patient’s decision to “take it or leave it”.

How can the immune system be activated against resistant cancer cells, possibly even resulting in cure? 

Failure to activate a patient’s lymphocytes to induce effective anti-cancer treatment may happen due to the combination of 3 factors: 

  1. Cancer antigens that distinguish malignant cells from normal ones that belong to the same tissue are only weakly immunogenic.
  2. Development of several types of suppressor cells that shut-off the capacity of the immune system to fight against cancer cells.
  3. Development of unresponsiveness, or tolerance, against the malignant cells that are no longer seen as foreign, mimicking normal “self”.

Accordingly, successful immunotherapy of cancer can be accomplished by developing effective solutions against these 3 factors. 

First, non-immunogenic cancer cells can be treated to force expression of stronger cancer antigens by treatment with interferon that can increase expression of cancer’s cell-surface antigens. In addition, non-immunogenic cancer cells can become strongly immunogenic by forcing expression of new antigens that will now be visible by the patient’s immune system as foreign cells, thus resulting in an immune attack in order to reject them. “Decorating” non-immunogenic cancer cells with new antigens can also turn them into anti-cancer vaccines, as will be detailed below.

Secondly, successful immunotherapy depends on down-regulation of all known suppressor mechanisms. Currently, this  involves the use of low dose cyclophosphamide (Endoxan) to suppress regulatory T cells,  using checkpoint inhibitors, monoclonal antibodies to neutralize CTLA-4 using ipilimumab (Yervoy) and using nivolumab (Opdivo) or pembrolizumab (Keytruda) against PD-1. Additional modalities are indicated to neutralize myeloid-derived suppressor cells (MDSC), mesenchymal stromal cells (MSCs) and their secreted extra-vesicular nanoparticles, as well as tumor associated macrophages (TAM) that protect tumor microenvironment against an attack by patient’s lymphocytes.

Thirdly, there seems to be a need to break the unresponsiveness between a patient’s immune system and cancer, either by using strongly immunogenic anti-cancer vaccines, or by introducing intentionally mismatched donor lymphocytes trained to become anti-cancer killer cells. Such donor lymphocytes, including both T and natural killer (NK) cells, are targeted preferentially against cancer cells by monoclonal antibodies like guided missiles. Activated mismatched donor lymphocytes are perhaps the most effective tool for elimination of resistant cancer cells by a mechanism resembling the rejection of foreign organs. 

The activation of donor lymphocytes to become killer cells, either before or after cell infusion, is responsible for effectively killing targeted cancer cells within minutes or a few hours. On the other hand, the elimination of a donor’s killer cells by the patient’s immune system begins only after a few days. Consistent early rejection of donor lymphocytes engaged in anti-cancer cytotoxicity occurs before such cells can cause any toxic effects against the patient. As such, by using intentionally mismatched killer cells, the anti-cancer effects induced by the “reverse rejection” of cancer cells is maximized. At the same time, the risk of an attack against the patient is minimized because of consistent rejection of mismatched lymphocytes long after killing of targeted cancer cells. 

As much as the use of intentionally mismatched donor lymphocytes can be effective against cancer, due to short circulation time of non-engrafting donor cells (which last only a few days) such treatment is likely to be curative, but only if applied when the patient has achieved the stage of minimally residual disease.

In contrast, although the induction of anti-cancer immunotherapy by a patient’s own immune system may be less intensive if it follows successful anti-cancer vaccination, durable circulation of anti-cancer effector cells and memory T cells can induce anti-cancer effects for an unlimited longer period. This stresses the importance of preserving cancer tissue whenever possible in order to provide an opportunity for future anti-cancer vaccination in case of need. 

Questions and Answers

Additional treatment methods that can result in induction of warfare against multi-drug resistant cancer cells? 
One of the most promising treatment options for patients with otherwise resistant cancer involves the use of oncolytic viruses. An oncolytic virus is a virus that is harmless against normal cells but can kill cancer cells, either directly or by activating the patient's immune system to react against the same cancer cells it was previously ignoring. Another potentially effective treatment is based on forcing activation of a patient's immune system against sterile bacterial toxins.  This type of treatment was introduced 120 years ago by Dr. William Coley from the Sloan Kettering Cancer Center in New York, following his observation that regression of cancer was sometimes observed after overwhelming bacterial infection. . Another promising approach for safe and potentially effective treatment of cancer includes the use of anti-cancer vaccines. Anti-cancer vaccines can be prepared for patients who have available cryopreserved cancer tissue. Cancer cells that fail to activate a patient's immune system can become immunogenic following modification by oncolytic viruses or Coley’s toxin that result in expression of foreign antigens that distinguish such cancer cells from similar normal cells.    Whereas some of the aforementioned therapeutic procedures are already available at Biotherapy International clinic in Tel Aviv, some recommended procedures may be only accomplished at one of our Satellite Clinics abroad, or in centre with relevant regulatory approval.
When should immunotherapy be recommended for patients with cancer?
Immunotherapy should be recommended to any patient with residual disease or at risk of recurrent disease, but only after completing full courses of traditional cancer therapy, such as surgery, chemotherapy, radiation therapy and other available medications relevant for a patient's particular disease. The goal is to eliminate cancer “to the last cell”, since every cancer begins with development of a single cancer-initiating cell. If such a goal cannot be accomplished, the second best option is to try to block or to slow the progression of residual malignant cells. As discussed earlier, this is done by focusing on innovative immunotherapy, alongside other supportive medications and therapeutic procedures. 
When should anti-cancer immunotherapy not be strongly recommended?
Although immunotherapy can be remarkably effective, successful immunotherapy is time consuming and therefore not suitable for every patient that seeks help when it is already too late, when the patient is moribund, at a pre-terminal stage. Accordingly, patients with rapidly progressive cancer, with multiple bulky metastatic disease, or with very short life expectancy, are unlikely to benefit from immunotherapy.  Representative therapeutic agents and procedures available for cancer immunotherapy at Biotherapy International.

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