The spontaneous remission of cancer: Current insights and therapeutic significance

Abstract

Many diseases heal spontaneously. The common cold, for example, remedies itself within a few days in people with an uncompromised immune system. If a disease with a poor prognosis heals in the absence of a targeted therapeutic, many even call it a miracle cure. Such is the case with the spontaneous regression (SR) of malignant neoplasms, a rare but well-documented phenomenon that finds its first mention in the Ebers Papyrus of 1550 BCE. Given the challenges associated with current cancer treatment modalities such as rapidly evolving drug resistance mechanisms, dose-limiting side effects, and a failure to completely eliminate cancer cells, knowledge of how a tumour heals itself would be immensely helpful in developing more effective therapeutic modalities. Although the intricate mechanisms of SR have yet to be fully elucidated, it has been shown that infection-mediated immune system activation, biopsy procedures, and disruptions of the tumour microenvironment play pivotal roles in the self-healing of many tumours. Bacterial and viral infections are especially well-documented in instances of SR. Insights from these findings are paving the way for novel therapeutic strategies. Inspired by bacteria-mediated SR, Bacillus Calmette-Guérin (BCG) has been used as an approved treatment option for non-muscle-invasive bladder cancer (NMIBC). Similarly, Talimogene laherparepvec (T-VEC), the first engineered oncolytic herpes simplex virus (HSV), has been approved by the United States Food and Drug Administration for the treatment of some forms of advanced melanoma. Here we describe the current understanding of SR, explore its therapeutic significance, and offer perspectives on its future.

Full text

Translational Oncology 14 (2021) 101166
1936-5233/© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
The spontaneous remission of cancer: Current insights and
therapeutic signicance
Gudapureddy Radha , Manu Lopus
*
School of Biological Sciences, UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai, Vidyanagari, Mumbai, India
ARTICLE INFO
Keywords:
Spontaneous regression
Tumour immunology
Oncolytic virus
BCG
T-VEC
ABSTRACT
Many diseases heal spontaneously. The common cold, for example, remedies itself within a few days in people
with an uncompromised immune system. If a disease with a poor prognosis heals in the absence of a targeted
therapeutic, many even call it a miracle cure. Such is the case with the spontaneous regression (SR) of malignant
neoplasms, a rare but well-documented phenomenon that nds its rst mention in the Ebers Papyrus of 1550
BCE. Given the challenges associated with current cancer treatment modalities such as rapidly evolving drug
resistance mechanisms, dose-limiting side effects, and a failure to completely eliminate cancer cells, knowledge
of how a tumour heals itself would be immensely helpful in developing more effective therapeutic modalities.
Although the intricate mechanisms of SR have yet to be fully elucidated, it has been shown that infection-
mediated immune system activation, biopsy procedures, and disruptions of the tumour microenvironment
play pivotal roles in the self-healing of many tumours. Bacterial and viral infections are especially well-
documented in instances of SR. Insights from these ndings are paving the way for novel therapeutic strate-
gies. Inspired by bacteria-mediated SR, Bacillus Calmette-Gu´
erin (BCG) has been used as an approved treatment
option for non-muscle-invasive bladder cancer (NMIBC). Similarly, Talimogene laherparepvec (T-VEC), the rst
engineered oncolytic herpes simplex virus (HSV), has been approved by the United States Food and Drug
Administration for the treatment of some forms of advanced melanoma. Here we describe the current under-
standing of SR, explore its therapeutic signicance, and offer perspectives on its future.
Introduction
In 2020, 19.3 million new cancer cases and approximately 10 million
cancer deaths occurred worldwide, with breast cancer being the most
prevalent one and lung cancer, one with the highest mortality rate [1].
To effectively counter this surge, intense efforts have been focused on
developing novel drug molecules with enhanced efcacy and tolerable
side effects. From drugs conjugated to tumour-targeted antibodies [2]
and nanoparticles-based theranostics [3], the quests for developing
better therapeutics are underway with varying degrees and denitions
of success. Despite the lethal intensity of malignant tumours, at times, a
‘miraculous’ phenomenon occurs: a spontaneous remission of cancer.
The term spontaneous remission or spontaneous regression (SR) of cancer
translates into the recovery of a patient from cancer in the absence of a
disease-specic treatment or in the presence of inadequate therapy [4].
The recovery, therefore, does not involve conventional cancer treatment
modalities such as chemotherapy or radiotherapy. Given the current
prevalence of cancer cases, we believe that efforts must focus also on
unraveling the mechanisms of SR. A lucid comprehension of the inci-
dence patterns and the underlying mechanisms of SR could decipher
contiguous mechanisms of cancer progression and lead to the develop-
ment of efcacious treatment modalities. This review focuses on the
current understanding of spontaneous remission, its possible causes, and
clinical signicance.
SR and its therapeutic potential have been known for millennia.
Mention of indirect induction of SR as a treatment strategy is available in
Ebers papyrus, one of the oldest Egyptian medical documents written
during 1550 BCE that describes cures for various diseases. An Egyptian
physician, Imhotep, recommended the application of poultice on tu-
mours followed by an incision to induce an infection at the affected area
[5]. The infection, he reasoned, could promote tumour regression.
Perhaps, the most famous case of SR is the one reported from Italy in the
12
th
century. Peregrine Laziosi, a Catholic priest, had experienced re-
covery from a tumour that aficted one of his tibiae. Suffering from the
tumour, he also developed a severe infection on the skin, necessitating
an imminent amputation of his leg. Interestingly, before the surgery, he
* Corresponding auther.
E-mail address: manu.lopus@cbs.ac.in (M. Lopus).
Contents lists available at ScienceDirect
Translational Oncology
journal homepage: www.elsevier.com/locate/tranon
https://doi.org/10.1016/j.tranon.2021.101166
Received 13 May 2021; Received in revised form 26 June 2021; Accepted 29 June 2021

Translational Oncology 14 (2021) 101166
2
recovered from the tumour [6,7]. Due to this incident, tumours that
show spontaneous regression are also called “St. Peregrine tumour” [8].
So, how SR occurs? Despite notable exceptions, acute infections has
been a common denominator for a large number of SR cases. Although
the idea of infections triggering the immune system to eliminate tu-
mours was proven early on, two German physicians, Wilhelm Busch and
Friedrich Fehleisen, built the scientic basis for this concept (Fig. 1).
They independently discovered that erysipelas (Greek for “red skin”; an
infection caused by bacteria such as Streptococcus pyogenes) could lead to
tumour regression [9]. Further, their studies paved the way for indirect
interventions to regress many forms of aggressive tumours. Treatment
modalities thus evolved include the use of bacteria-based formulations
such as Coley’s Toxin, Bacillus Calmette-Guerin (BCG), and oncolytic
virus-mediated strategies.
Coley’s Toxin
The idea of inducing an infection to promote collateral regression of
tumours gained momentum with the advent of Coley’s Toxin. In 1891,
Dr. William Bradley Coley, an American bone surgeon and cancer
researcher, developed a formulation, the Coley’s Toxin. It consisted of
heat-inactivated Streptococcus pyogenes and Serratia marcescens. At New
York’s Memorial Hospital, Coley used the vaccine to treat a sarcoma
patient successfully [10]. After that, many cancer patients underwent
treatment with the Toxin with promising results. Even when adminis-
tered at the advanced stages of cancer, the Toxin brought forth
remarkable recoveries [10,11]. Nevertheless, for the formulation to be
effective, Coley maintained, a few conditions were to be met, including
induction of an acute infection that makes the patient feverish with
considerably elevated body temperature [12]. The inoculation should be
given daily or on every alternate day for a month or two with gradually
increasing dosage. The Toxin should be injected directly into the
tumour. Further, a six-month course of weekly injections is needed to
avoid relapse [12]. Coley’s Toxin was effective against many cases of
sarcoma, lymphoma, melanomas, and myelomas. Although it was a
breakthrough treatment strategy, with time, advanced treatment mo-
dalities, such as radiation therapy and chemotherapy, gained credence
and momentum. A lack of understanding of the exact mechanism of
action of the Toxin, the risks associated with infecting patients with
potentially pathogenic bacteria, and varied and often unpredictable
responses to the treatment led eventually to the relinquishment of this
treatment strategy in its original form. The infection-induced remission
of tumours nevertheless shed light on the vital roles of the immune
system in ghting cancer, as substantiated by prominent scientists of
that period, including Paul Ehrlich [9]. The last successful use of Coley’s
Toxin was reported in China in 1980 when a patient with terminal liver
cancer was given 68 injections of the Toxin for 34 weeks [11,13].
Coley’s efforts have laid the foundation for developing anticancer
immunotherapy regimens. He is deservedly considered as father of
cancer immunotherapy.
BCG (Bacillus Calmette-Guerin) and SR
During the 20
th
century, substantial progress in the eld of immu-
nology enabled researchers to revisit Coley’s treatment strategy with a
new perspective and deepened insight. Inspired by the ndings of Coley,
for instance, Lloyd Old and colleagues repurposed the well-known
antituberculosis bacterial formulation, Bacillus Calmette-Guerin
(BCG). It comprises an attenuated strain of Mycobacterium bovis [14]
(BCG was developed by two French Scientists, Albert Calmette and
Camille Guerin, in 1921). During the 1950s, Old studied the effect of
BCG on solid tumours and Ehrlich ascites cells implanted in mice [15].
The formulation regressed the tumours considerably.
Further evidence of BCG’s efcacy came in 1976 when many
recurrent supercial bladder tumours were treated successfully with it
[16]. A timeline of these and subsequent developments is available in
Fig. 1. Later studies attested the utility of BCG to induce tumour
remission via activating the immune system. Although the precise
anti-tumour mechanism of BCG is not clear, the internalization of BCG
by the tumour cells, the subsequent display of antigens on their surface
Fig. 1. Spontaneous remission of cancer as reported over time. From its earliest mention in Ebers Papyrus to the development of nanobodies-delivering designer
bacteria are shown.
G. Radha and M. Lopus

Translational Oncology 14 (2021) 101166
3
and the consequent release of cytokines, such as IL-2, TNF-
α
, INF-γ, IL-4,
and IL-6 from inltrating T-lymphocytes, are thought to induce the
remission (Fig. 2). Supporting this postulate, mice depleted of CD4+and
CD8+T-cells exhibited only a negligible response to BCG [17]. In
addition to the T-cells, granulocytes, macrophages, and dendritic cells
also play pivotal roles in the remission; the number of these cells in-
creases considerably during the treatment [18-20]. BCG therapy,
nevertheless, has its caveats. After the remission, the tumour returned in
nearly 30% of the patients. Nevertheless, by far, BCG is the only bac-
terial therapeutic used for the treatment of non-muscle invasive bladder
cancer (NMIBC) for the past 40 years [18].
Oncolytic viruses (OV)
One of the earliest examples of virus-orchestrated SR was reported in
1896 when inuenza cured a patient of leukaemia (Fig. 1) [21].
Measles-induced remission of Burkitt’s and Hodgkin lymphoma [22,23]
and several similar cases were reported subsequently [24]. SR after viral
infections thus paved the way for the development of a new mode of
cancer treatment- cancer virotherapy. Initially (between 1950–60),
wild-type viruses were used to induce the remission, which worked
successfully in some cases but proven to be dangerous to many patients
due to uncontrolled infection [25]. The risks associated with the use of
natural viruses led eventually to the dissolution of this treatment mo-
dality. However, by the end of the 20th century, the eld of cancer
virotherapy regained propulsion with the advent of genetically modied
viruses [9]. The inherent ability of viruses to enter specic host cells
(cellular tropism), to replicate therein and to subsequently lyse the host,
and to exert bystander toxicity to the neighboring cells make them po-
tential therapeutic agents (Fig. 3). Furthermore, upon exposure of the
viral PAMPs (Pathogen-associated molecular patterns), the immune
system primes the T-cells to effect contemporaneous elimination of
metastasized tumours (the so-called “abscopal effect”) [26] (Fig. 3).
Viral species such as adeno, herpes, vaccinia, polio, and measles are
design-optimized and evaluated in clinical settings as monotherapy or as
combination therapies [27]. Talimogene laherparevec (T-VEC) is the
rst engineered oncolytic herpes simplex virus (HSV) that received
United States Food and Drug Administration’s approval for the treat-
ment of advanced melanoma [28,29]. T-VEC is a double-edged weapon
that not only destroys the target tumour cells at the site of injection but
could also initiate localized as well as systemic immune response [30].
Locally, the lysed tumour cells release tumour-associated antigens.
These antigens attract members of the mononuclear phagocyte
system-especially the macrophages-promoting clearance of the dying
and dead tumour cells. The dendritic cells then present these viral an-
tigens to T-helper cells and cytotoxic T-cells and thereby mount a
formidable immune response at the systemic level [30]. Insights into the
mechanism of action of T-VEC have also led to the development of novel
combinatorial therapeutics. For example, T-VEC, in combination with
ipilimumab (an inhibitor of the immune-suppressor protein, CTLA-4),
has entered clinical trials for melanoma (https://clinicaltrials.gov/ct2/
show/NCT01740297). Similarly, the efcacy of T-VEC in combination
with pembrolizumab (a monoclonal antibody that blocks another im-
mune checkpoint protein PD-1) to improve the outcome of melanoma is
currently under investigation (https://clinicaltrials.gov/ct2/show/NC
T02263508).
SR of specic cancers
Interestingly, some forms of cancer seem to possess a peculiar pro-
pensity to regress spontaneously. There are several examples of such
remissions (Tables 1, 2). Among them, metastatic melanoma (MM),
Fig. 2. Postulated anti-tumour mechanism of BCG in non-muscle invasive bladder cancer. BCG gets internalized in the cancer cells of the urothelium and and in the
antigen-presenting cells (APCs). The urothelial cells and the activated APCs present the BCG antigens on their surface, leading to cytokine/chemokine release and
granuloma formation. These granulomas, comprising macrophages, dendritic cells (DCs), neutrophils, T cells, B cells, and broblasts, trigger innate and adaptive
immune responses and destroy the cancer cells.
G. Radha and M. Lopus

Translational Oncology 14 (2021) 101166
4
leukaemia, lung cancer, and Merkel cell carcinoma merit special
mention. MM is especially interesting as it can regress from end-stage
disease. In one such case, a patient was suffering from MM for nearly
ten years. When diagnosed, she was already at stage IV of the melanoma
with a poor prognosis. However, after episodes of fever, most of her
tumours disappeared, and the remaining ones stabilized (Table 1). The
frequency of SR of MM is 1 in 400 patients. Although it is often associ-
ated with immune response elicited by cytotoxic T cells [31], the SR in
MM can also occur in the absence of infection; Table 2. MM has also
shown regression in response to the DTP (for
diphtheria-tetanus-pertussis) vaccine [33].
Leukaemia, which accounts for 3.1% of global cancer deaths [1], is
another cancer that is prone to SR. Bradley and colleagues reviewed
several cases of SR of leukaemia that were reported from 1949 to 2019
[34]. Fifty cases were of acute myeloid leukaemia (AML), and four were
acute lymphocytic leukaemia (ALL). For leukaemia, out of the ve cases
reported in 2018, infection-driven remissions were seen in four cases
(Table 1). Unfortunately, many of the remissions of AML were not
long-lasting: a high relapse rate (<1Y) was reported among the patients
[34,35]. Nevertheless, design-optimized, infection-based therapies for
AML might yield a better prognosis. During the last leg of eradication of
smallpox, it has been observed that the smallpox vaccine could induce
remission of chronic lymphocytic leukaemia [36]. In another instance,
an acute are-up of hepatitis B virus healed a patient of splenic
marginal-zone lymphoma [37]. The virus build-up and consequent im-
mune response cleared atypical lymphocytes from the blood and bone
marrow of the patient. Concerning SR of lymphoma, three cases of
diffuse large B-cell lymphoma (DLBCL), one of follicular lymphoma (FL),
and one of Hodgkin lymphoma (HL) (Tables 1, 2) were reported in the
past three years. Some of these SRs-especially those associated with
FL-could be attributed to Helicobacter pylori infection, a known acti-
vating factor in the patient’s immune response against the lymphoma
cell [38]. DLBCL, on the other hand, is an aggressive cancer with a less
prognostic probability of SR. Nevertheless, such remissions do occur. For
example, Tanaka and colleagues presented a case of SR of DLBCL [39].
In the patient’s biopsy sample, rampant apoptosis of the cancer cells
were observed, suggesting that the regression could have occurred via
T-cell-mediated induction of apoptosis [39].
Lung cancer accounts for 18% of cancer deaths, making it the leading
cause of cancer death [1]. Zhang et al. reported 14 cases of remission of
lung cancer, barring patients who have received any chemotherapy and
radiotherapy [32]. Among cancers of the lung, SR of non-small cell lung
cancer (NSCLC) is very rare. Interestingly, among the reported SR cases
of lung cancer, none showed an association with concurrent or preced-
ing infections (Table 2). Instead, such regressions were associated with
postoperative trauma. Further, one of the patients attested using the
herbal extract of Rock pine (Orostachys japonicus) [40] as a potential
causative agent for the remission. Rock pine, widely grown on the rocks
in Korea, Japan, and China, has several anticancer compounds [41]. The
possibility that some of these compounds in the extract contributing to
the remission cannot be ruled out.
Merkel cell carcinoma (MCC) is an aggressive skin cancer with a
frequency of 0.7 out of one lakh population and shows a high rate of
metastasis [42]. Several cases of SR have been documented for MCC in
the past three years. Other less common cases of SR include the
regression of cancers of the liver, kidney, and colorectal areas (Table 2).
Fig. 3. Oncolytic viruses. Many OVs selectively replicate in cancer cells (cellular tropism) and lyse the cells. The resultant release of pathogen-associated molecular
patterns (PAMPs) and damage-associated molecular patterns (DAMPs) recruits and activates dendritic cells (DCs). DCs then migrate to lymph nodes and present the
antigens to the T cells. These activated cytotoxic T cells undergo clonal expansion. They induce apoptosis in target cells via the release of perforin and granzymes.
G. Radha and M. Lopus

Translational Oncology 14 (2021) 101166
5
Decoding SR with a therapeutic perspective
Different forms of cancer originate via a complex interplay among
signaling cascades induced by genomic, metabolomic, and proteomic
aberrations. Further, their often-counterintuitive modes of sustenance
and progression mean that the spontaneous remission of these cancers
could as well involve diverse inputs and mechanisms (Fig. 4). Febrile
infections are responsible for immune cell inltrations and cytokine
cascades, leading to SR in many cases. Nevertheless, as we have
mentioned before, not all cases of SR can be traced to bacterial or viral
infection (Table 2). In such scenarios, there must exist hitherto poorly
understood mechanisms that heal the tumour. Based on medical and
scientic observations, some possible whys and wherefores are as fol-
lows: Partial excision of a tumour impairs blood supply to the remaining
malignant tissue. Since tumour cells require an ample supply of blood
(so much so that the cells themselves promote angiogenesis to meet this
vampiric need), cutting it off could starve the cells to death [4]. Not
surprisingly, therefore, many SR cases have been attributed to biopsy
procedures [4]. Another interesting possibility lies in tumour ablation
procedures that could set forth an avalanche of tumour-derived antigens
in circulation. Studies have shown that the antigens thus released could
act as a therapeutic vaccine [64] (Fig. 4).
Techniques that use radiofrequency waves, high-intensity focused
ultrasound, or cryoablation are potential activators of immune cells
[64]. In addition to its hormetic effect, exposure to small doses of ra-
diation (such as those received during radiographic examinations) has
been shown to induce tumour remission [65]. Low-level radiation (≤0.1
Gy for acute irradiation, for example) is capable of pro-SR immuno-
modulation in experimental settings. Whole- or half-body exposures to
low dose radiations [66] as enablers of anticancer immune defense is
gaining considerable momentum. Blood transfusion procedures per-
formed in leukemic patients, and use of herbal extracts are also impli-
cated as potential triggers of SR [67,40]. Hormonal inuence in SR of
breast and prostate cancers and withdrawal of carcinogenic agents could
promote the remission [4]. Such non-targeted bystander inputs could
lead to processes such as telomerase inhibition, promoting cytostatic or
cytocidal outcomes in cancer cells [24] (Fig. 4). Concerning the latter,
not only apoptosis but non-apoptotic cell death pathways [68] could
also facilitate SR. Such pathways can be considered for future inter-
ventional or surrogate therapeutic strategies. Changes in the tumour
microenvironment (TME) due to presence of metalloproteinase in-
hibitors and anti-angiogenesis factors are also believed to play a role in
the regression [69] (Fig. 4).
Kwok et al. analyzed SR cases of chronic lymphocytic leukaemia
(CLL). They excluded patients with infections, second malignancies, or
are undergoing immunosuppressive therapies from their study [70] and
compared regressing and non-regressing CLL using ow-cytometry,
single nucleotide polymorphism (SNP) analysis, and exome
Table 1
Clinical characteristics of SR cases linked to infection reported during 2018–2020.
Patient
age and
gender
Cancer type
showing SR
Diagnostic methods Features of the remission Associated history or details Follow up
to conrm
the SR
Reference
41 Y F MM CT, chest X-ray, MRI SR was observed after episodes of fever
No sign of reoccurrence when tested
subsequently
The fever episodes were not tretaed with
any medication. It is a remarkable
recovery from stage IV melanoma with
dissappearance of the most of the tumours
and stabilization of the remaining ones.
>2.5 Y [31]
58 Y M AML Bone marrow biopsy,
blood counts, CT
Myeloblast counts signicantly reduced
(from a 25% increase) to normal levels after
two weeks of gastrointestinal infection (GI).
The patient suffered GI due to which
intravenous antibiotics were given.
Blood transfusions were performed.
>2 Y [34]
40 Y M AML Bone marrow biopsy,
blood counts, ow-
cytometric analysis,
CT
Blast cell percentage came down to normal
levels after three weeks since the diagnosis.
S. aureus growth was obsreved in blood
cultures, and antibiotics were given. The
patient had episodes of fever. Frequent
blood transfusions were required.
6 M [43]
42 Y F AML CT, blood counts,
bone marrow biopsy,
cytogenetics, ow
cytometry
Signicant decrease in blast cell count and
simultaneous recovery from pneumonia
after four weeks of detection in 2017. Blast
cell counts were normalized in the
subsequent four weeks.
The patient was previously diagnosed
with AML in 2000 and underwent
chemotherapy. Also, allogenic blood stem
cell transplantation was performed.
17 years later, the patient suffered severe
pneumonia and again developed AML
(relapse). Antibiotics were given to treat
pneumonia and the AML regressed
14 M [35]
31 Y F ALL Blood counts, ow-
cytometric analysis,
bone marrow biopsy
Blood samples came negative for ALL. CR
was observed in 42 days after the 1
st
diagnosis.
The patient experienced a relapse of ALL
twice. After each relapse, the patient
exhibited septic shock followed by SR.
The patient was pregnant when diagnosed
with ALL for the rst time. She
experienced fever, pancytopenia, and
inammation and delivered a healthy
preterm child.
Blood transfusions were on during the
treatment.
NA [44]
47 Y M Non-Hodgkin FL Blood counts, Bone
marrow and lymph
node biopsy, CT, PET
Three months after diagnosis, blood counts
were normal and the CT scan showed
regression in lymphadenopathy and
splenomegaly.
The patient had H. pylori infection during
this course and was given antibiotics.
2 Y [38]
76 Y M Myelodysplasia Blood count , CT The patient was diagnosed with transfusion-
dependent myelodysplasia in2011, followed
by urinary bladder cancer in 2014. During
the treatment of bladder cancer with BCG
(2015-2016), SR was observed for
myelodysplasia.
The patient suffered anemia since 2008
and developed myelodysplasia in 2011.
Blood transfusions were on.
The patient developed a bladder tumour,
for which tumour resection was
performed and an intravesical BCG course
was on . Bladder cancer showed no
reoccurrence.
NA [45]
(Y- years, M-months, F-female, M-male, CR- complete recovery, CT- computed tomography, MRI- magnetic resonance imaging, MM- metastatic melanoma, AML- acute
myeloid leukemia ALL- acute lymphoblastic leukemia, FL- follicular lymphoma, BCG- Bacillus Calmette-Guerin, NA- not available, PET- positron emission tomography,
NA- Not available)
G. Radha and M. Lopus

Translational Oncology 14 (2021) 101166
6
Table 2
Clinical characteristics of SR cases reported during 2018-2020 that are not associated with preceding infection.
Patient
age and
gender
Cancer type
showing SR
Diagnostic
methods
Features of the remission Associated history or details Follow up
to conrm
the SR
Reference
86 Y M Pulmonary
metastatic
melanoma (MM)
Biopsy, X-ray,
PET,CT
12-mm round lesion in the right lung
detected in 2014. It was not seen in 2015
while mediastinal metastasis was
progressive. Signicant shrinkage of
metastatic mediastinal mass was observed in
2017 with no relapse of pulmonary
metastasis.
MM was detected in 2012 on the left
forearm. In 2014, it metastasized to the
right lung and mediastinal lymph nodes.
NA [46]
75 Y M MM CT, MRI, Biopsy,
PET,CT
Tumour metastasized in the left mandibular
ramus, shrunk completely.
NA 2 Y [47]
72 Y M AML Blood counts,
bone-marrow
biopsy
Seven weeks afterthe diagnosis, the skin
lesion showed inltration of myeloblasts,
but blood counts showed no sign of AML.
The patient was suffereing from
comorbidities, such as ischemic and
valvular heart disease and chronic kidney
disease.
Blood transfusions were performed.
AML relapsed after one year; the patient
died in few days.
- [48]
73 Y M NSCLC CT/, PET, biopsy After 14 months of the biopsy procedure,
tumour mass in the lungs decreased
substantially.
Before the biopsy, the patient suffered non-
invasive bladder cancer, for which he had
completed a BCG instillation course of six-
weeks (one month before the lung biopsy).
NA [49]
74 Y F NSCLC X-ray, CT,
biopsy, PET, CT
After one year of discontinuation of
chemotherapy, the lung tumour showed SR
The patient received two cycles of
chemotherapy for advanced lung cancer.
She then developed drug-induced hepatitis
and took a short break from chemotherapy.
The therapy was then resumed and
continued for several months, and later
abandoned.
Few months before SR, the patient had been
taking herbal medicine of Orostachys
japonicus extract.
NA [40]
77 Y M NSCLC X-ray, CT, biopsy Near CR was observed within 24 months of
initial diagnosis.
It was andvanced-stage lung cancer that
regressed
>1 Y [50]
56 Y F NSCLC CT, PET, biopsy Six weeks after the diagnosis, tumour mass
on the right lower lobe decreased while the
size of swollen mediastinal lymph nodes
increased.
Advanced-stage lung cancer metastasized to
mediastinal lymph nodes while regressing at
its site of origin
NA [51]
57 Y M Lung cancer Biopsy, CT, PET Tumour mass on the lower lobe of the left
lung signicantly decreased in three months
and further reduced when examined after a
month.
The patient was a cigarette smoker. NA [52]
35 Y M DLBCL PET,CT, biopsy Three months after the biopsy, regression of
abnormal accumulation of cells in the small
intestine and lymph nodes was observed.
The patient did not take any medication or
had any infection.
3 Y [39]
88 Y F DLBCL Biopsy, PET,CT Lymphoma remission was observed three
months after the biopsy.
The patient died ~two yrs after remission
due to progressive respiratory insufciency.
NA [53]
66 Y M DLBCL Biopsy, CT Two months post-diagnosis, DLBCL-leg type
purple tumour in the left lower leg started to
regress.
No systremic therapy was used to initiate
the regression.
NA [54]
32 Y F Classical HL Biopsy, PET,CT Complete regression after two years of
diagnosis.
The patient also exhibited thyroid papillary
cancer at the time of diagnosis. However, SR
was not observed for the same.
3.5 Y [55]
74 Y M Hepatosplenic T-
cell lymphoma
PET,CT, surgical
biopsy
Complete disappearance of lesions in the
liver after one and a half months of
diagnosis.
Surgical biopsy was suspected as the trigger
of the SR.
NA [56]
96 Y F MCC Biopsy Regression of tumour mass after two weeks
of the biopsy. CR was observed
subsequently.
The patient used topical tea tree oil NA [57]
69 Y M MCC Biopsy Five weeks after diagnosis, the nodular
lesion on the head regressed.
NA 4 Y [58]
78 Y M MCC Biopsy, CT, PET After the biopsy, tumour nodules present on
the head gradually decreased. The patient died in 10 months after
developing tumour lesions in the rib
regions.
- [59]
83 Y F MCC and SCC Biopsy The nodule on the nose showed regression in
one month, after which surgical resection of
the tumour was performed.
No systemic therapy was used. >10 Y [60]
79 Y F HCC with
pulmonary
metastasis
CT Two months after the diagnosis, a signicant
decrease in liver tumour mass was observed
while nodules in the lung completely
disappeared. Tumour leison of the hepatic
lobe also showed signs of regression
~Five years after initial follow-ups, the
patient developed a solid mass on the liver
and several nodules in the lungs, and the
patient died within few weeks.
- [61]
78 Y M CRC NA 1 Y [62]
(continued on next page)
G. Radha and M. Lopus

Translational Oncology 14 (2021) 101166
7
sequencing. It was found that CLL clone in residual SR tumours gradu-
ally acquires a low-proliferation state with reduced expression of
migration-specic markers. Therefore, it is postulated that in specic
genomic backgrounds, changes in microenvironmental factors, such as
B-cell-receptor stimulation, can spontaneously regress CLL [70]. This is
the only major study published to date that had analyzed the tran-
scriptomic and genomic data to understand the intricacies of SR.
SR and immunity
Since immune response plays crucial roles in tumour regression,
many SR cases could also be considered as immunity-mediated tumour
remissions. In fact, SR linked to infections inuenced the discovery of
different anti-cancer therapies that work by boosting the immune system
to recognize and attack the cancer cells [71]. The eld of cancer
immunotherapy (CI) has evolved from clinically-induced infections
(Coley’s toxins) in the 19th century and cytokine therapy and cancer
vaccines in the 20th century to current approaches, such as immune
checkpoint inhibitors, oncolytic viruses and Chimeric antigen receptor
(CAR)-T cell therapy [72,9]. Different CIs-although they differ in their
mechanism of action-work to bolster a weakened immune system.
Immuno-onco therapies are broadly classied into active and passive
therapies [72]. Active immunotherapy involves triggering the host
immune response using cytokines or cancer-specic antigens leading to
immunological memory. Passive therapies include direct targeting of
tumours with monoclonal antibodies (mABs) or modied immune cells,
as in the case of adoptive cell transfer therapy (ACT), without inducing
immunological memory [73]. Establishing CI as the fourth pillar of
cancer treatment modality (along with chemotherapy, radiation and
surgery), the number of CI drugs has been on the rise and many mole-
cules are undergoing clinical trials [74]. CI nevertheless has its draw-
backs, such as immunological toxicity [75]. Studies showing that gut
microbiomes could inuence an individual’s anti-tumour response to
immunotherapeutic agents are quite intriguing [75–77]. It has been
reported that bacteria from the Bidobacteriaceae and Bacteroidaceae
family enhance the response to anti-PD-L1 (anti-programmed cell death
protein ligand- 1) and anti-CTL4 (anti-cytotoxic T-lymphocyte antigen
4S) therapies, respectively [78,79].
Future perspective
Occurrences of spontaneous regression have been reported for many
types of cancer. Despairingly, the frequency of SR is very low; one in
60,000–1,00,000 cancer cases [4,9,80]. Melanomas, lymphoma,
leukaemia, neuroblastoma, renal cell carcinoma, and germ cell cancers
have shown higher frequency of SR [81,8]. The reasons behind higher
Table 2 (continued )
Patient
age and
gender
Cancer type
showing SR
Diagnostic
methods
Features of the remission Associated history or details Follow up
to conrm
the SR
Reference
Colonoscopy,
biopsy, CT
Two months after the diagnosis, colectomy
was performed, which showed the absence
of cancer cells.
66 Y F RCC MRI, CT, biopsy SR observed after renal mass biopsy. It was a low-grade carcinoma with oncolytic
features.
NA [63]
(Y- years, M-months, F-female, M-male, CR- complete recovery, MM- metastatic melanoma, AML- acute myeloid leukemia, NSCLC- non-small cell lung cancer, DLBCL-
diffuse large B-cell lymphoma, HL-Hodgkin lymphoma, MCC-Merkel cell carcinoma, SCC-Squamous cell carcinoma, CRC-colorectal cancer, RCC-renal cell carcinoma,
PET, positron emission tomography, CT- computed tomography, MRI- magnetic resonance imaging, NA - not available)
Fig. 4. Possible mechanisms involved in SR of cancers. Factors that stimulate an immune response, including fever and infection, may promote SR. Similarly,
disruption in the tumour microenvironment, biopsy and ablation procedures and the induction of cell death by various means, may also induce SR.
G. Radha and M. Lopus

Translational Oncology 14 (2021) 101166
8
percentages of SR in certain types of cancer are poorly understood.
Understanding the mechanistic aspects of SR of cancer could pave the
way for innovative strategies to improve cancer outcomes.
Learning from the drawbacks of Coley’s toxin, the search for efca-
cious recombinant microbes as cancer therapeutic agents began in the
21st century [82]. The genetically engineered bacteria thus created
express cytotoxic proteins or toxins to elicit an anti-tumour immune
response. For example, programmable bacteria could grow into the core
of tumours and deliver anti-CD47 nanobodies into B-cell-lymphoma
[83]. A welcome addition to this targeted repertoire is a class of engi-
neered non-pathogenic bacteria that can prime cytotoxic T-cells to induce
tumour regression [84]. Anaerobic bacteria could be an apt choice to
enhance the targeted delivery into the deep interiors of solid tumours
due to their penchant for hypoxic environments [85,82].
Given that antibiotics are available for most bacterial strains, it
might be easier to regulate the possibility or severity of infection in such
treatment regimens. Interestingly, in addition to full-grown bacteria,
bacterial spores have been explored for their tumoricidal effect. When
the spores of certain bacterial species germinate, get metabolically
active, and grow under conducive conditions, they could promote
tumour regression. In this context, Clostridium novyi NT (non-toxic)
spores have been extensively studied. These spores have entered phase 1
clinical trials-alone or in combination with chemotherapeutic drugs-for
the treatment of solid tumours that are not responding to conventional
treatments [82]. When it comes to the fate of the tumour cells under
self-regression, apoptosis could be the prevalent mechanism. However,
exceptions do occur. During SR of some neuroblastoma, for example, the
tumour cells undergo a RAS-associated, caspase-independent,
non-apoptotic form of cell death [86]. Therefore, in addition to
apoptosis, regulated cell death (RCD) mechanisms, such as ferroptosis,
necroptosis, pyroptosis, parthanatos, etc. [68] may play a crucial role in
SR. Given that many tumour cells resist natural or drug-induced
apoptosis, exploring non-apoptotic RCD mechanisms involved during
the self-regression would provide valuable insights of therapeutic rele-
vance. As we have discussed earlier, understanding of infection-based
immune system activation against tumours has led to the development
of more efcacious treatment strategies of bacteriotherapy and viro-
therapy. However, research on the non-infection-based mechanisms of
SR is still in its infancy.
It is quite challenging to deduce all the factors responsible for
spontaneous or indirectly induced tumour regression. Bio-banking
tumour biopsy samples of those patients who experienced SR without
undergoing any cancer-specic treatments will allow retrospective
studies [44]. Investigating SR case reports in the light of diet and
microbiome composition of the recovered patient may aid in developing
novel therapies with reduced side effects. Further, insights from these
studies may help predispose and orient one’s lifestyle towards condi-
tions that are barren for cancer cells to ourish.
CRediT authorship contribution statement
Gudapureddy Radha: Writing – review & editing. Manu Lopus:
Writing – review & editing.
Declaration of Competing Interest
None to be declared
Acknowledgment
The authors thank UM-DAE Centre for Excellence in Basic Sciences
for nancial support. All gures used in this article were created using
BioRender Software
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