Jayant Radhakrishnan
Chicago, Illinois, United States

Unexplainable events have always intrigued people. At the top of this list of the uncommon and perplexing is spontaneous cure or regression of cancer. A cure requires that the lesion disappear completely, never to return, letting the person live for a substantial period, and to later succumb from some other entity. Unfortunately, in most cancer cases, lifetime follow-up is not available; therefore, regression is the usually reported endpoint.

G.L. Rohdenburg (1918) should receive credit for being the first to try and systematically identify histologically proven cases of cancer that demonstrated spontaneous regression (SR). Others reported the phenomenon before him but some of those patients had no histologic diagnoses, while in others the diagnosis was unclear or suspect. Rohdenburg made the important observation that some patients developed a fever of 104–105°F for three to five days before the cancer regressed, and that in others it regressed following partial resection or after attacks of various infections. He also believed that externally applied heat was beneficial.¹

About forty years later, Tilden Everson and Warren Cole at the University of Illinois carried out the next rigorous study of this rare phenomenon. They defined SR as “partial or complete disappearance of a malignant tumor in the absence of all treatment or in the presence of therapy which is considered inadequate to exert a significant influence on neoplastic disease.” While they could not pinpoint a reason, they suggested numerous possible mechanisms that could be the basis for SR.²

The first widely believed record of a spontaneous cure of cancer appears to be that of the ulcerating, foul-smelling growth on St. Peregrine’s leg, which resolved upon his praying before the crucifix the night before his leg was to be amputated. St. Peregrine was cured, and he continued his work among the sick until he died at eighty years of age.³ Non-believers could assert that if it was in fact a tumor, it resolved because it was infected. Rohdenburg observed SR occurring overnight in a patient with lymphosarcoma, but his patient was not as fortunate as St. Peregrine. The patient’s tumor returned a week later, and he died.¹

Spontaneous cure of a recurrent sarcoma was also observed by William Coley in 1891 in a patient who had been operated upon five times in three years for a recurrent round cell sarcoma of the neck. On the last occasion, the tumor was felt to be inoperable, and the incision was left open to heal by granulation. Within a couple of weeks of the operation, the patient suffered from two episodes of erysipelas, after which the tumor disappeared, the granulations resolved, and the wound scarred over. The patient was recurrence-free seven years later. Realizing that infection played a role in SR, he proceeded to create bacterial “Coley’s toxins” to produce a high fever. He had acceptable results with sarcomas, less so with carcinomas. Radiation therapy had just been introduced and was demonstrating good results, while the toxins constituted a risky modality. In addition, leading oncologists of the time such as James Ewing, Ernest Codman, and Joseph Bloodgood did not believe his data. The toxins fell out of favor by the 1960s, and the modality was all but forgotten until recently. Coley now receives credit for being the first to treat cancer with immunotherapy.⁴ A significant local or systemic infection appears to upregulate the patient’s immune system to attack the antigens on the surface of tumor cells. A substantial febrile reaction is essential for this process to unfold, and the use of antipyretics appears to blunt the effect on the immune system.

To understand what induces the immune system to initiate SR, one first has to try and understand why the immune system does not attack the overwhelming majority of cancers even though it recognizes them as being nonself cells. The self-nonself (SNS) model has been modified over time, as new information has become available, to rectify its failures in explaining certain situations. However, the danger model seems to afford a more straightforward answer than does the SNS model. The danger model postulates that “the immune system is more concerned with damage than with foreignness, and it is called into action by alarm signals from injured tissues, rather than by the recognition of nonself.”⁵ In other words, tumors do not send out alarm signals and the immune system is not activated when they consist of healthy growing cells or the cells die by normal programmed processes and are scavenged before they disintegrate. However, if tumor cells are injured by toxins or infections occurring either spontaneously or upon intervention, the distressed or necrotic cells send out danger signals which stimulate the local Antigen-Presenting Cells (APCs), previously known as “stimulator” cells, into action. This results in a reaction until the danger signal is eliminated.

A tumor vaccine that stimulates immunity would achieve the same effect provided vaccinations are repeated until all tumor cells have been destroyed. If tumor cells are not destroyed completely, any remaining healthy tumor cells will not emit danger signals, the immune response will cease, and the tumor will grow back.⁵ Coley’s clinical observations led him to a similar conclusion. He instructed that his “toxins” be injected daily or on alternate days until the tumor disappeared completely and then weekly for a few months to prevent it from recurring.⁴

One malignancy that unquestionably fulfills the criterion of spontaneous cure is neuroblastoma. In older children with high grade malignancy, even with intensive treatment, the five-year survival rate is only about 40–50%. On the other hand, neuroblastoma is known to differentiate into benign ganglioneuromas and even to disappear completely in infants with stage IVS disease in whom the primary tumor is localized but metastatic lesions are present in the liver, skin, and/or bone marrow without involving the bone itself.⁶ Since there is no explanation for why such extensive disease resolves spontaneously in infants, the S indicating “special” has been added to such stage IV lesions.⁷ Spontaneous resolution of neuroblastomas could be the result of “(1) neurotrophin deprivation, (2) loss of telomerase activity, (3) humoral or cellular immunity and (4) alterations in epigenetic regulation and possibly other mechanisms.”⁸

Some cancers such as Acute Myeloid (AML) and Acute Lymphocytic (ALL) leukemias have a proclivity to SR. Bradley et al reported on spontaneous remission occurring in fifty AML and four ALL cases. Seventy-six percent had an associated bacterial infection and 45% were transfused with blood products. In their study, the relapse rate was extremely high, with a median time to relapse of five months.⁹

In 1904, before viruses had been visualized, George Dock reported on SR of mixed cell leukemia after a patient suffered from influenza.¹⁰ Subsequently, SR of various malignancies following other viral infections were reported. That viruses can destroy the cells that they infect, and are also able to prompt the body to generate an intense systemic immune response against cancers, resulted in the use of wild-type viruses to treat malignancies. However, their actions were erratic, unsafe, and lacked efficacy. Furthermore, the SRs were incomplete and short-lived. Therefore, the next step was genetic engineering of viruses to increase efficacy and safety.¹¹ To date, only one genetically modified oncolytic virus has been approved for clinical trials in the US. The herpes virus talimogene laherparepvec (lmlygic or T-VEC) has been approved for intra-tumor injection in advanced inoperable melanomas. The virus has been modified to reduce the risk of it causing herpes. It kills the cells and results in the release of danger signals that help generate an immune response.¹²

It is interesting that even vaccination for viral diseases such as smallpox may result in SR of chronic lymphocytic leukemia¹³ and vaccination for diphtheria-pertussis-tetanus in that of metastatic melanoma.¹⁴ Investigations are in the works to determine if other viruses could be used and whether it would be feasible to administer them intravenously rather than by intra-tumor injections, the problem being that, if administered intravenously, the virus would first have to survive its interaction with neutralizing antibodies and blood components. Investigators are also trying to determine whether treatment with an oncolytic virus prior to surgical extirpation would be beneficial in the treatment of some cancers.

On rare occasions, other tumors have demonstrated SR. In a series of fourteen lung cancer SR cases, six had associated neurologic disorders, suggesting that T lymphocytes were inadvertently attacking the nervous system as they were under the influence of onco-neural antibodies.¹⁵ Over the years, occasional SR has been reported to occur in primary tumors in almost every organ and also in metastatic lesions. It has been seventy years since Everson and Cole postulated possible causes for SR, but we are no closer to the answer. When concomitant or preceding infections have not been identified in a case, it is unclear what precipitates the series of events that result in SR. Everson and Cole speculated that unrecognized complete excision with misidentification of surrounding inflammatory tissues as residual tumor, misdiagnosis of malignancy, endocrine influences, unusual sensitivity to inadequate radiation or other therapy, fever and/or infection, allergic reactions, interference with nutrition (vascularity) of the tumor, and removal of the carcinogenic agent could result in SR.² To that list have now been added the use of alternative medicines, blood transfusions, biopsy or partial excision, and non-targeted external inputs that stimulate apoptotic and non-apoptotic cell death pathways as possible reasons. Any of the above mechanisms or others not yet identified could work individually or in combination to produce SR and the processes may differ for different cancers.

Identification of the mechanism or mechanisms that induce SR, whether acting individually or in combination, could help develop techniques to activate them. This knowledge would result in a sea change in the management of cancer. It could result in less aggressive surgical extirpation and a shift from adjuvant therapy that damages normal tissues along with cancer cells, to one where malignant cells are selectively targeted while normal ones remain untouched.

References

1. Rohdenburg GL (1918): Fluctuations in the growth energy of malignant tumors in man, with especial reference to spontaneous recession. J Cancer Research 3(2):193-225. https://doi.org/10.1158/jcr.1918.193.
2. Everson TC, Cole WH (1956): Spontaneous regression of cancer: Preliminary report. Ann Surg 144(3):366-383. doi: 10.1097/00000658-195609000-00007.
3. Pack, G.T. (1967): St. Peregrine, O.S.M.—The patron saint of cancer patients. CA: A Cancer Journal for Clinicians, 17: 183-184. https://doi.org/10.3322/canjclin.17.4.183.
4. Radhakrishnan J (2024): William Bradley Coley: Visionary or snake oil salesman? Hektoen International Surgery Summer 2024. https://hekint.org/2024/09/26/william-bradley-coley-visionary-or-snake-oil-salesman/
5. Matzinger P (2002): The danger model: A renewed sense of self. Science 296(5566):301-305. doi: 10.1126/science.1071059.
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7. Randolph JG (1977): Personal communication.
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13. Yettra M (1979): Letter to the editor: Remission of chronic lymphocytic leukemia after smallpox vaccination. Arch Intern Med 139(5):603 with reply by Richa M. Hansen. doi:10.1001/archinte.1979.03630420089031.
14. Tran T, Burt D, Eapen L, Keller OR (2013): Spontaneous regression of metastatic melanoma after inoculation with tetanus-diphtheria-pertussis vaccine. Curr Oncol 20(3):e270-e273. doi: http://dx.doi.org/10.3747/co.20.1212.
15. Zhang J, Wang H, Li C, Qian H (2020): Chance to rein in a cancer-spontaneous regression of lung carcinoma (1988-2018): a 30-year perspective. Int J Clin Exp Pathol 13(5):1190-1196. PMID: 32509094 PMCID: PMC7270659.