Spontaneous Remission – How and Why it Occurs

Spontaneous remission, or unexpected disease disappearance without treatment, remains a rare and poorly understood phenomenon in cancer. Proposed mechanisms include immune reactivation against tumors, epigenetic changes increasing apoptosis, hormone or cytokine shifts altering signaling, viral infection triggering innate immunity, nutritional ketosis effects, and genetic or microenvironmental factors inhospitable to cancer. Psychological influences like reduced stress have also been hypothesized. However, clear biologic mechanisms are lacking, and most knowledge relies on anecdotal case reports. While remissions are rarely complete or permanent, exceptional responders illuminate biology worth probing further. Research to decode molecular underpinnings could uncover novel treatment insights. For now, spontaneous remission remains enigmatic but provides hope that the body has untapped power to overcome cancer without conventional therapies.

Introduction

Spontaneous remission refers to the unexpected and unexplained disappearance or improvement of a medical condition without any medical intervention or treatment. It is a phenomenon characterized by the spontaneous resolution of symptoms or the complete regression of the disease. In certain instances, cancer, a highly fatal condition characterized by malignant tumors, exhibits this phenomenon. 

The significance of understanding spontaneous remission

In light of the present high incidence of cancer patients, it is imperative to emphasize the investigation of the underlying processes of SR. A thorough understanding of the frequency patterns and the fundamental mechanics of SR could unveil interconnected mechanisms of cancer progression and contribute to the advancement of effective therapeutic approaches.

Mechanisms of Spontaneous Remission

Most of the time, a tumor shrinks on its own because of apoptosis, the action of the immune system, and the environment inside the tumor. There is sometimes a link between these factors and DNA tumor suppressors. For example, in people with hepatocellular cancer, the levels of cytokines like tumor necrosis factor and interleukin (IL)-18 rise. In another case, estrogen receptors affect the expression of insulin-like growth receptor factor 1 by making its positive effect stronger and lowering the amount of a protein that stops cells from dying called BCL2.

Studies have also shown that infections can cause tumors to shrink, and they have been linked to SR in some cases. Immunogenic cell death (ICD) is a new type of cell death that can stimulate the immune system of the host. This can lead to immune memory and good effects on the whole body. Chemotherapy, radiation treatment, photodynamic therapy, or physical therapy can all lead to ICD.

Studies have shown that patients whose cancer went away on its own improved in terms of their personal freedom, sense of meaning in life, and social relationships before their health got better.

Factors Influencing Spontaneous Remission

Cancer has gone into remission on its own for a long time after pneumonia, pulmonary edema, bleeding, low hemoglobin, tumor hypoxia, nephrectomy, liver cirrhosis, jaundice, and biopsy, among other medical conditions and treatments. All of these tumors get too little oxygen from the blood.

Immune-modulating therapies

Stimulated Immunotherapy

Regressions that happen on their own are often caused by past illnesses or fevers. Pathogens that cause fever may make the immune system work harder to fight both the pathogens and cancer cells. Whether the fever is normal or caused by something else, it activates many different parts of the immune system and makes it release substances that are hard to make in a laboratory setting or 'in vitro'.

Anti-inflammatory effects

A mild acute inflammatory response caused by endotoxin and a serious acute inflammatory response caused by an allergic reaction can both cause cancer remission. The allergic response involved is a delayed hypersensitivity response. Along with a delayed hypersensitivity response, an acute inflammatory reaction can happen. Cancer patients tend to have less delayed-type hypersensitivity reactions, especially if the site is close to a growing tumor. When a cancer patient has both an acute inflammatory response and a delayed-type hypersensitivity response, this can trigger a full-blown delayed-type hypersensitivity response, which can cause cancer remission.

SR of specific cancers

Some cancers can go away on their own. There are a lot of cases of remissions like this. Metastatic melanoma (MM), leukemia, lung cancer, and Merkel cell carcinoma are all important to talk about. Even though SR of MM is linked to an immune response by cytotoxic T cells, it can happen without an infection in 1 out of 400 cases. 

Most AML remissions don't last long, and a high relapse rate ( 1 year) has been observed. Infection-based treatments for AML that are better designed may improve the outlook. During the effort to get rid of smallpox, the smallpox vaccine was found to make chronic lymphocytic leukemia go away. In another case, a person with splenic marginal-zone lymphoma was healed by the hepatitis B virus. 

Breast and prostate cancers may go to rest when hormones are changed or when cancer-causing substances are taken away. Regression is thought to be caused by metalloproteinase inhibitors and anti-angiogenesis factors in the tumor microenvironment.

Medical Interventions and Spontaneous Remission

Treatment modalities include bacteria-based formulations like Coley's Toxin, Bacillus Calmette-Guerin (BCG), and oncolytic virus-mediated strategies.

  1. Coley's Toxin promoted the regression of tumors by inducing infection. This toxin was made of Streptococcus pyogenes and Serratia marcescens which had been inactivated by heat. When tumors went away because of an infection, it showed how important the immune system is in beating cancer. Immunotherapy protocols for treating cancer were built on Coley's work. 

  2. BCG (Bacillus Calmette-Guerin) and SR
    It is not clear exactly how BCG kills cancer cells. However, it is believed that tumor cells take in BCG, which causes them to show antigens on their surface and release cytokines like IL-2, TNF-, INF-, IL-4, and IL-6. This is thought to bring about recovery. But the tumor came back in about 30% of people after they went into remission.

  3. Oncolytic viruses (OV)
    The "abscopal effect" is what happens when the immune system finds viral pathogen-associated molecular patterns (PAMPs) and activates T-cells to kill metastasized tumors. In clinical settings, viruses like adeno, herpes, vaccinia, polio, and measles are tried as single therapies or in combination with other therapies. T-VEC is the first herpes simplex virus (HSV) that has been approved to treat advanced melanoma. T-VEC kills cancerous cells and makes the immune system react.

Mechanisms of Spontaneous Remission

Immune system responses

Spontaneous tumor regression is mainly related to apoptosis, immune system activity, and the tumor microenvironment. These factors are sometimes linked to DNA oncogenic suppressors.

Spontaneous regression of tumors is likely caused by multiple factors, with certain causes being more significant for specific tumors. Most cases of spontaneous regression have not undergone genome testing, only laboratory analyses and examinations of pathologic findings. In particular, testicular germ cell tumors rarely have specific characteristics. Cytokines like tumor necrosis factor α and interleukin (IL)-18 increase in hepatocellular carcinoma cases.

Other factors can improve the prognosis of ER+ breast cancer by increasing long-term relapse rates. Estrogen receptors control the expression of insulin-like growth receptor factor 1 by enhancing its positive effect and decreasing BCL2, an antiapoptotic protein, without impacting the expression of Bax, a pro-apoptotic protein. The epidermal growth factor can counteract estrogen receptors and negatively impact cancer growth.

Other infections

Acute infections are common in many SR cases. German physicians Wilhelm Busch and Friedrich Fehleisen established the scientific basis for the concept of infections triggering the immune system to eliminate tumors. They found that erysipelas (an infection caused by bacteria such as Streptococcus pyogenes) can cause tumor regression. Their studies led to indirect interventions that can regress aggressive tumors.

Cellular and genetic factors

Immunogenic cell death (ICD) is a newly defined form of cell death that can activate the host immune system, leading to immune memory and beneficial systemic effects. ICD of cancer cells can activate dendritic cells (DCs) and specific T-cell responses, leading to effective antitumor immune responses. ICD involves calreticulin translocation to the cell surface, signaling DCs to engulf the cell. It also releases danger signals like HMGB1 and ATP, necessary for promoting CD8 T-cell anticancer responses. ICD can be caused by chemotherapy, radiotherapy, photodynamic therapy, or physical therapies.

Psychosocial effects

Studies have found that patients who experienced spontaneous regression of cancer showed improvements in personal autonomy, purpose in life, and social relationships before clinical improvement. Patients with spontaneous regression of cancer showed clinical improvement after engaging in satisfying activities and experiences, sometimes coinciding with the conclusion of an associated exacerbated life situation.

Examples

SR of specific cancers

Some cancers can regress spontaneously. There are many examples of such remissions. Special mention should be given to metastatic melanoma (MM), leukemia, lung cancer, and Merkel cell carcinoma. MM is interesting because it can regress from end-stage disease. SR of MM occurs in 1 out of 400 patients and can occur without infection, despite its association with immune response by cytotoxic T cells. MM has also been shown to be regressed after the diphtheria-tetanus-pertussis (DTP) vaccine.

AML remissions are usually not long-lasting with a high relapse rate (< 1Y) reported. Design-optimized infection-based therapies for AML may improve prognosis. During the smallpox eradication, the smallpox vaccine was found to induce remission of chronic lymphocytic leukemia. In another example, the hepatitis B virus cured a patient of splenic marginal-zone lymphoma. The virus and immune response cleared atypical lymphocytes from the patient's blood and bone marrow.

Notably, SR of non-small cell lung cancer (NSCLC) is rare. No reported cases of lung cancer showed an association with concurrent or preceding infections but were linked to postoperative trauma. One patient claimed that using Rock pine herbal extract (Orostachys japonicus) caused their remission. Rock pine, grown on rocks in Korea, Japan, and China, has anticancer compounds. Some compounds in the extract may contribute to remission.

Blood transfusions and herbal extracts may trigger SR in leukemic patients. Hormonal influence and removal of carcinogenic agents may promote remission in breast and prostate cancers. Non-targeted bystander inputs may inhibit telomerase and cause cytostatic or cytocidal effects in cancer cells. Non-apoptotic cell death pathways could also facilitate SR, not just apoptosis. These pathways may be used for future interventions or therapies. Metalloproteinase inhibitors and anti-angiogenesis factors in the tumor microenvironment are thought to contribute to regression.

Factors Influencing Spontaneous Remission

Prolonged spontaneous cancer remission has been reported after various medical conditions and procedures, such as pneumonia, pulmonary edema, hemorrhage, low hemoglobin, tumor hypoxia, nephrectomy, liver cirrhosis, jaundice, and biopsy. All share low blood oxygen delivery to the tumor. 

Pneumonia, metastases, and edema can hinder oxygen delivery in the lungs. Hemorrhage and low hemoglobin can cause decreased oxygen transport. Spontaneous remission of hepatocellular carcinoma can be preceded by blockage or reduced blood oxygen to the tumor. 

Spontaneous remission of renal cell carcinoma is often preceded by nephrectomy with pulmonary metastases. The kidney produces erythropoietin to signal the bone to produce red cells. Low erythropoietin and pulmonary metastases can reduce blood oxygen supply. 

Cirrhosis can cause microcytic anemia while hepatic jaundice can cause anemia. Biopsy can cause vessel breakage and bleeding in Merkel cell carcinoma, leading to low blood oxygen.

Medical Interventions and Spontaneous Remission

Treatment modalities include bacteria-based formulations like Coley's Toxin, Bacillus Calmette-Guerin (BCG), and oncolytic virus-mediated strategies.

Coley's toxin

Coley's Toxin promoted the regression of tumors by inducing infection. Dr. William Bradley Coley developed Coley's Toxin in 1891. It was made of heat-inactivated Streptococcus pyogenes and Serratia marcescens.

Coley's Toxin was effective against various cancers including sarcoma, lymphoma, melanomas, and myelomas. Over time, radiation therapy and chemotherapy gained popularity alongside the breakthrough treatment strategy. Uncertainty about the toxin's mechanism of action, the risks of infecting patients with harmful bacteria, and unpredictable responses led to the abandonment of this treatment strategy. 

Infection-induced remission of tumors highlighted the important role of the immune system in fighting cancer, according to scientists like Paul Ehrlich. Coley's Toxin was last successfully used in China in 1980 for a patient with terminal liver cancer who received 68 injections of the toxin over 34 weeks. Coley's efforts laid the foundation for anticancer immunotherapy regimens. 

BCG (Bacillus Calmette-Guerin) and SR

The exact anti-tumor mechanism of BCG is unclear. However, it is believed that BCG is internalized by tumor cells, which then display antigens on their surface and release cytokines like IL-2, TNF-α, INF-γ, IL-4, and IL-6. This is believed to induce remission. Mice without CD4+ and CD8+ T-cells had a minimal response to BCG. T-cells, granulocytes, macrophages, and dendritic cells are important for remission and their numbers increase during treatment.

However, BCG therapy has its caveats. The tumor returned in about 30% of patients after remission. Notably, BCG is the only bacterial therapy used for non-muscle invasive bladder cancer (NMIBC) treatment for 40 years.

Oncolytic viruses (OV)

Viruses can enter specific host cells, replicate, and impact neighboring tumor cells, making them potential therapeutic agents. Additionally, when the immune system detects viral pathogen-associated molecular patterns (PAMPs), it activates T-cells to eliminate metastasized tumors, known as the "abscopal effect". Viral species like adeno, herpes, vaccinia, polio, and measles are tested in clinical settings as monotherapy or combination therapies.

T-VEC is the first approved oncolytic herpes simplex virus (HSV) for advanced melanoma. T-VEC destroys tumor cells and triggers an immune response. The lysed tumor cells release tumor-associated antigens locally. These antigens attract macrophages and help clear dying and dead tumor cells. Dendritic cells present viral antigens to T-helper cells and cytotoxic T-cells, triggering a strong immune response.

Immune-modulating therapies

Stimulated Immunotherapy

Coley considered key factors for patient survival. The main goal was to simulate a natural infection, so inducing a fever was necessary. Injections were given daily or every other day for the first month or two. The vaccine dosage was gradually increased over time based on the patient's response to prevent immune tolerance. A 6-month course of weekly injections was taken to prevent disease recurrence. Coley emphasized that inducing fever was crucial for treatment, as a strong fever was strongly linked to tumor regression.

Spontaneous regression is often linked to past infections and fever. Fever-causing pathogens may activate the immune system to fight both the invading pathogens and cancer cells. Fever, whether natural or induced, stimulates complex pathways of the immune system, releasing products that are difficult to reproduce in vitro. Single cytokine therapy or immune products are not effective in cancer therapy. They are expensive, toxic, and can be fatal due to their unnatural challenge to the human system.

Anti-inflamitory effects

Cancer remission or regression may occur with a mild acute inflammatory response caused by an endotoxin and a severe acute inflammatory response caused by an allergic reaction. The allergic response is a delayed hypersensitivity response. An acute inflammatory response occurs alongside a delayed hypersensitivity response. Delayed-type hypersensitivity responses are generally depressed in cancer patients, especially if the site is near a growing tumor. An acute inflammatory response combined with a delayed-type hypersensitivity response in cancer patients may reactivate a full-blown delayed-type hypersensitivity response, leading to cancer remission or regression. Tuberculin skin test induces delayed hypersensitivity response.

Inflammation with infection may lead to cancer remission or regression. One possible explanation is that the inflammation competes with the systemic inflammation caused by the malignant growth of inflammatory mediators. This competition may lead to a depletion of inflammatory mediators, which can suppress the systemic inflammation induced by the malignant growth. As a result, the immunosuppressive effects of the systemic inflammation caused by the malignant growth are negated.

Future Research and Implications

After recognizing the limitations of Coley's toxin, researchers started looking for effective recombinant microbes for cancer treatment in the 21st century. These engineered organisms produce toxins to trigger an immune response against tumors. Programmable bacteria could deliver anti-CD47 nanobodies into B-cell-lymphoma tumors. A new addition to this repertoire is engineered non-pathogenic bacteria that can activate cytotoxic T-cells to shrink tumors. Anaerobic bacteria are also suitable for delivering treatments to the deep interiors of solid tumors because they thrive in low-oxygen environments.

Since antibiotics are available for most bacterial strains, it may be easier to regulate infection possibility or severity in treatment regimens. Bacterial spores have been studied for their ability to kill tumors, in addition to full-grown bacteria. Certain bacterial spores can promote tumor regression when they germinate, become metabolically active, and grow under favorable conditions. Clostridium novyi-NT (nontoxic) spores have been extensively studied in this context. These spores are in phase 1 clinical trials, either alone or with chemotherapeutic drugs, for treating solid tumors that are unresponsive to conventional treatments. 

Apoptosis is the main mechanism for the self-regression of tumor cells. During neuroblastoma SR, tumor cells undergo a non-apoptotic form of cell death associated with RAS and caspase independence. Besides apoptosis, other regulated cell death (RCD) mechanisms like ferroptosis, necroptosis, pyroptosis, parthanatos, etc. may be important in SR. 

Studying non-apoptotic mechanisms involved in tumor cell self-regression can provide important insights for therapy. Understanding infection-based immune system activation against tumors has led to the development of more effective bacteriotherapy and virotherapy treatments. Research on non-infection-based mechanisms of SR is still in its early stages.

It's difficult to determine all the factors causing tumor regression. Bio-banking tumor biopsy samples from patients who had spontaneous remission without treatment will enable retrospective studies. Studying SR case reports and the diet and microbiome composition of recovered patients can help develop new therapies with fewer side effects. Insights from these studies may help guide lifestyle choices to create conditions that are unfavorable for cancer cells.