'When Tumors Vanish: The Mystery of Spontaneous Regression'

 Spontaneous regression of cancer is an uncommon event observed most often in neuroblastoma, leukemia, lung cancer, and melanoma. 

The underlying mechanisms are not fully understood; however, infections and immune system activation may contribute to treatment development.

Historical Observations

In 1891, William B. Coley, a surgeon, reported the disappearance of recurrent spindle cell sarcoma in a patient after the patient developed erysipelas, a severe bacterial skin infection, and the wound healed after treatment. 

Observing immune-related tumor regression, Coley developed bacterial preparations, later called Coley toxins, to intentionally induce high fever in patients with cancer. 

The regimen produced measurable tumor responses in sarcomas but was less effective for carcinomas and carried notable safety risks. By the mid-20th century, radiation therapy largely replaced this approach. 

However, Coley was the first to use immunotherapeutic techniques to treat cancer. He found that infections could activate the immune system of the patient to attack the tumor cells. 

In 1918, G. L. Rohdenburg, MD, identified histologically confirmed cases of spontaneous cancer regression. In some patients, high fever (40-40.5 °C) occurred 3-5 days before regression, suggesting a potential link between immune activation and tumor disappearance.

Reports suggest that the use of antipyretics for fever may reduce their potential role in triggering tumor regression. 

Other regressions followed repeated infections or partial tumor removal. Rohdenburg also believed that external heat applications could help, similar to the hyperthermia used in modern cancer treatments.

Forty years later, Tilden C. Everson, MD, and Warren H. Cole, MD, from the Department of Surgery, University of Illinois College of Medicine, Chicago, defined spontaneous remission or regression as the partial or complete disappearance of malignant tumors without adequate conventional treatment.

Immune Activation and Tumor Regression

Generally, the immune system tolerates tumors despite recognizing them as foreign. According to the danger model, tumors rarely emit alarm signals unless they are damaged by infection or toxins. Once injured, tumor cells activate local antigen-presenting cells, triggering an immune response in the body. 

Coley’s experience supports this mechanism: His regimen involved administering the “toxin” daily or every other day until the tumor disappeared, followed by weekly doses for several months to prevent recurrence. If viable tumor cells remain, the immune response may fail, allowing the tumor to regrow unnoticed.

Favored Tumors

Both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) exhibit spontaneous remission; however, relapse is common in both. In a series of 50 AML and four ALL cases, 76% of remissions were associated with bacterial infection and 45% with blood transfusion. Relapses were frequent, with a median remission duration of approximately 5 months.

Viral infections can destroy malignant cells and trigger systemic immune responses. In 1904, George Dock, MD, a professor of internal medicine at the University of Michigan, Ann Arbor, reported spontaneous remission of undifferentiated acute leukemia after influenza. 

Attempts to treat malignancies with wild-type viruses have been unreliable, resulting in partial and short-lived remission. 

Currently, the genetically modified herpesvirus talimogene laherparepvec is approved in the United States for intratumoral injection in patients with advanced unresectable melanoma. 

Interestingly, smallpox vaccination has been associated with spontaneous remission of chronic lymphocytic leukemia, and diphtheria-tetanus-pertussis vaccination has been associated with remission of metastatic melanoma.

In rare cases, other primary tumors and metastases to multiple organs also show spontaneous regression. Among the 14 reported lung malignancies, six were linked to neurological diseases, suggesting that T lymphocytes may have cross-reacted with nervous tissue under the influence of onconeural antibodies.

The causes of spontaneous remission remain unclear. Contributing factors include misdiagnosis, hormonal changes, unusual responses to inappropriate radiotherapy, fever, infections, allergic reactions, altered tumor vascularization, removal of cancer-causing factors, alternative treatment methods, blood transfusions, biopsies, excisions, and nonspecific external interventions that induce cell death.

Intratumoral, intravenous, and preoperative adjuvant applications of oncolytic viruses are actively being researched. Understanding the underlying mechanisms or combinations of mechanisms responsible for spontaneous tumor regression can guide the development of targeted therapeutic strategies.

https://www.medscape.com/viewarticle/when-tumors-vanish-mystery-spontaneous-regression-2025a1000qty