james s. welsh, ms, md northern illinois university
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James S. Welsh, MS, MD Northern Illinois University. the Abscopal Effect, Contagious Cancers, Transplanted Cancers and Pregnancy: Clues to a genuine Cure for cancer?. Curious clues. Contagious cancers – should not occur Transplanted cancers – should not thrive - PowerPoint PPT PresentationTRANSCRIPT
THE ABSCOPAL EFFECT, CONTAGIOUS CANCERS,
TRANSPLANTED CANCERS AND PREGNANCY:
CLUES TO A GENUINE CURE FOR CANCER?
James S. Welsh, MS, MD Northern Illinois University
Curious clues Contagious cancers – should not occur Transplanted cancers – should not thrive Surrogate pregnancies – should not be
possible Gestational trophoblastic neoplasia –
should not exist
Curious clues Contagious cancers – should not occur Transplanted cancers – should not thrive Surrogate pregnancies – should not be
possible Gestational trophoblastic neoplasia –
should not exist And one more thing that should not
happen…
A sad story Young male in his 30’s with widespread
metastatic melanoma Metastases to lung, liver, lymph node and
bone Life expectancy ~4 months(?) Severe pain in hip Hypofractionated course of photon-based
external beam radiotherapy
A sad story Young male in his 30’s with widespread
metastatic melanoma Metastases to lung, liver, lymph node and
bone Life expectancy ~4 months(?) Severe pain in hip Hypofractionated course of photon-based
external beam radiotherapy Within 4 months ALL evidence of cancer was
completely gone!
A man’s aggressive cancer mysteriously disappears as quickly as it arrived. Pick up the issue and enjoy the adventure”
“THE ABSCOPAL PHENOMENON: Anti-cancer action at a distance – Oncology’s equivalent to quantum entanglement”
“Disappearing Act”
The Abscopal Effect So why is this sad????
The Abscopal Effect So why is this sad???? One of only two encounters with this… Pursuit of the underlying mechanism
and the ability to do it again at will has become an obsession…
So where does one begin the search???
So where does one begin the search???
Devil Facial Tumor Disease
First observed in 1996 DFTD is a contagious cancer
Tumor cells directly transplanted from one animal to another
A xenograft Typically causes death within 6-18 months Species is threatened with extinction
Cytogenetic proofa. Normal karyotype (14 chromosomes,
including XY)b, Karyotype of cancer cells
Devil Facial Tumor Disease
But if it’s a “transplanted organ” shouldn’t it be rejected???
Devil Facial Tumor Disease
But if it’s a “transplanted organ” shouldn’t it be rejected???
Do I have to be extra careful in the clinic when doing procedures?
Are there any other examples of this in the animal kingdom?
Canine Transmissible Venereal Tumor(CTVT)
“Sticker’s sarcoma”
Canine Transmissible Venereal Tumor
In immunologically compromised dogsthe tumor progresses, ulcerates, metastasizes
and kills the dog But in most dogs the tumors spontaneously
regress after a period of logarithmic growth Immunity develops and prevents successive
occurrences
Molecular clock data suggest an ancient origin
How has CTVT survived for so long???
CTVT has a unique trick to fool the immune system – but eventually the immune system gets wise and awakens
Clonally transmissible cancers in dogs and Tasmanian devilsE P Murchison. Oncogene. 2008 Dec;27 Suppl 2:S19-30
Immunological mechanisms of escape in canine transmissible venereal tumor
CTVT cells initially reduce their expression of MHC Class I moleculesreduces visibility to the host's immune system
MHC Class I downregulation allows it to escape adaptive immunity (T-cell–mediated immunity)(which would occur if MHC I were fully expressed)
This trick also allows escape from innate immunity (natural killer cells)(which would eradicate any cells completely devoid of
MHC I)
Some have proposed that the primary reason DFTD exists is because of the lack of genetic diversity in the population
All Tasmanian devils are closely related and so organ transplants would not be readily rejected
Immunological mechanisms of escape in devil facial tumor disease
Some have proposed that the primary reason DFTD exists is because of the lack of genetic diversity in the population
All Tasmanian devils are closely related and so organ transplants would not be readily rejected
Well, I REJECT THIS HYPOTHESIS!
Immunological mechanisms of escape in devil facial tumor disease
Some have proposed that the primary reason DFTD exists is because of the lack of genetic diversity in the population
All Tasmanian devils are closely related and so organ transplants would not be readily rejected
Well, I REJECT THIS HYPOTHESIS! These tumors are grossly, histologically,
cytogenetically and molecularly VERY different from any living Tasmanian devil…There is something else going on
Immunological mechanisms of escape in devil facial tumor disease
The future of DFTD and the Tasmanian devil???
Will the devil (and the disease) go extinct?
Will natural selection (in the cancer) create a less virulent tumor that doesn’t kill all its hosts???This may be what happened with the dog tumor
Will natural selection (in the Tasmanian devil) create a kinder, gentler devil The “Tasmanian Angel”?
The Tasmanian Angel
Similarities and Differences: A biologist’s perspective
Both are rare (extremely rare) examples of a contagious cancer
Both can be thought of as transplanted parasites
DFTD emerged recently and is highly virulent CTVT probably arose thousands of years
ago but typically does NOT kill its host One is lethal, the other has evolved to survive
with its host
Similarities and Differences: A physician’s perspective
One is relentlessly progressive and uniformly fatal
The other spontaneously regresses Thus one behaves like most human
cancers while the other behaves like what we wish human cancers would do…
How can we force human cancers to behave like dogs rather than devils???Devil dog transition
Similarities and Differences: A physician’s perspective
Another line of reasoning…
Suppose an organ or tissue is intentionally or accidentally transferred to another person?
What usually happens in Man?
Organ transplants Organ transplantation requires a high
degree of genetic similarities (“a match”) Even with a good match, chronic
immunosupression is required Without immunosupression poor matches
(and even good ones) are vigorously rejected
So what about cancer?
What about an accidentally transplanted cancer?
Man Gets Woman's Cancer from Kidney Transplant - CBS News (May 2010) “... The scenario was unique…. A man had gotten a
transplanted kidney from a woman who had uterine cancer and didn't know it…”
He died of cancer only seven months after receiving the transplant
How can this happen??!?! One might expect cancer to be rejected Does the necessary immunosupression
impede the rejection process?
“Contaminated” vital organ transplants (heart , lung and liver) are almost always rapidly fatal
What about non-vital organs???
Renal transplants Kidneys are not completely indispensible Immunosupression could be halted Kidney (and cancer) should be rejected Kidney can be removed Patient could be put on dialysis and given
another kidney This is what often happens
Renal transplants Kidneys are not completely indispensible Immunosupression could be halted Kidney (and cancer) should be rejected Kidney can be removed Patient could be put on dialysis and given
another kidney This is what often happens But not always….
Example of kidney being rejected while the cancerous cargo is left
unmolested!!!
Strauss and Thomas. Lancet Oncol 2010; 11: 790–96
Melanoma has been transferred through organ donation up to 32 yrs after treatment!Suggests that cancer can remain dormant for
decades (maybe forever?)But can be reactivated upon transplantation into a
recipient1.) The immune system must be keeping these cancer
cells in check in the donor2.) The recipient’s immunosuppression is NOT the only
reason why the cancer can redevelop3.) The fact that a transplanted cancer can thrive
unmolested in the recipient suggests it has some form of “invisibility” to the immune system
Is there another example where something is completely untouched
by the immune system?
Is there another example where something is completely untouched
by the immune system? Yes of course For survival of the species…
Is there another example where something is completely untouched
by the immune system? Yes of course For survival of the species… Pregnancy is normally given complete
sanctuary from the immune system
How profound is the suppression of the immune response in pregnancy?
Extreme! First, mother and embryo/fetus are only
half-related (semiallogeneic)
Extreme! First, mother and embryo/fetus are only
half-related (semiallogeneic) Second, surrogate mothers who are not
related at all are possible - no genetic relationship at all to embryo
How profound is the suppression of the immune response in pregnancy?
Extreme! First, mother and embryo/fetus are only
half-related (semiallogeneic) Second, surrogate mothers who are not
related at all are possible - no genetic relationship at all to embryo
Finally, surrogate mothers of DIFFERENT SPECIES are sometimes possible!
How profound is the suppression of the immune response in pregnancy?
Fig. 1. River buffalo (2n = 50) calf born from swamp buffalo (2n = 48) surrogate mother after non-surgical transfer of vitrified in vitro-derived embryo.Danilda Hufana-Duran, Prudencio B. Pedro, Hernando V. Venturina, Peregrino G. Duran, Libertado C. Cruz. Full-term delivery of river buffalo calves (2n = 50) from in vitro-derived vitrified embryos by swamp buffalo recipients (2n = 48) Livestock Science, Volume 107, Issues 2–3, April 2007, Pages 213-219
Is the womb (uterus) the key to this immune sanctuary?
Is the womb (uterus) the key to this immune sanctuary?
Ectopic pregnancies occur outside the womb…
Is the womb (uterus) the key to this immune sanctuary?
Ectopic pregnancies occur outside the womb…
Therefore the uterine endometrium cannot be the answer!
A surgical emergency
So the embryo’s “immunity from immunity” is quite profound
Embryos are normal; cancer is not! Maybe this immune sanctuary is granted
only to normal embryos?
Gestational trophoblastic disease
Anything but normal…
Rather than the zygote developing into an embryo and fetus, it develops into a grape-like mass
Hydatidiform mole (molar pregnancy)
Gestational trophoblastic disease Three different degrees of severity:
Hydatidiform molesInvasive molesChoriocarcinoma – extremely rapidly growing
and potentially lethal cancer
Often the chromosomes are completely from the father – i.e. the cancer is strictly paternal (foreign) in origin
ABSOLUTELY should be rejected!!!
Cancer and pregnancy DO share features enabling them to evade the immune system
The analogies are more obvious when examining clinical tumor markers
Tumor markers Carcinoembryonic antigen
Colon/rectum cancer, pancreas, breast, ovary, or lung
Alpha Feto-proteinIncreased during pregnancy in cases of spina bifida
and other fetal malformationsLower than normal in Down syndromeTesticular cancer and Hepatocellular carcinoma
Human chorionic gonadotropinThe pregnancy testGerm cell tumors, testicular cancers,
neuroendocrine islet cell tumors
Cancer and pregnancy use the same ‘cloaking device'
Cancer evades the immune system ---- by masquerading as a baby!
But how can we expose the cancer for what it is?
Dr. William B. Coley (1862-1936) Developed Coley’s toxin in 1893
“… with a degree of success…”“…afforded some therapeutic successes…”
The curious case of Mr Stein… Recurrent sarcoma despite four operations Erysipelas (an infection with Streptococcus
pyogenes) But supposedly his cancer regressed during
the life-threatening infection…
Where did Coley get his idea?
Where did Coley get his idea?
The curious case of Mr Stein… Recurrent sarcoma despite four operations Erysipelas (an infection with Streptococcus
pyogenes) But supposedly his cancer regressed during
the life-threatening infection…
Found by Coley in the lower East Side ghetto six years later — in the best of health
Coley’s toxins Surmised that the infection had stimulated
Mr Stein’s immune system this immune reaction eradicated the cancer
Began to intentionally give patients infections to “awaken” their immune systems
Moved to a safer strategy of killed bacteria (Streptococcus pyogenes and Serratia marcescens)
Coley’s first patients January 1893 - John Ficken: bedridden, with a
massive, inoperable abdominal sarcoma Vaccine injected right into tumor every few days Dramatic fevers and chills Tumor gradually shrank
After 4 months the tumor was 1/5 its original sizeBy August, the tumor was barely perceptible
The patient was apparently cured Lived another 26 yrs
Immunotherapy’s Dark Ages
Coley died in 1936 and his treatment disappeared along with him
(Note entirely in the veterinary community however…)
Coley’s legacy and Immunotherapy’s Renaissance Bacterial lipopolysaccharide-induced
secretion of tumor necrosis factor-a (TNFa)
1.) Can we make vaccines to cancer?2.) Can we use other immune strategies such
as direct administration of TNF, interferons, interleukins, etc?
Two Branches of The Human Immune System
The Innate response - Non-specific, first line of defense Proteins (for example, complement) and Cells (for example, natural killer cells and neutrophils)
The Adaptive response Highly specific Capable of responding to new antigensPossesses a “memory” Antibodies from B-cells and T cell mediated immunity
Estimated that gene rearrangements can yield ~5x1013 different Ig molecules and 1018 different TCRs(!)
Cancer Immunotherapy I Interferon Interleukins Vaccines Adoptive T cell therapy
LAKs, TILs
Cancer Immunotherapy I Only modest success Toxic treatment WHY???
Cancer Immunotherapy I Only modest success Toxic treatment WHY???
To attempt to answer this, let’s return to the analogy with pregnancy
How is the placenta, embryo and fetus protected?
Regulatory T cells (Treg cells)CD4+/CD25+/FOXP3+
Increase during pregnancy Conversely, diminished numbers are associated
with spontaneous abortions i.e. immunological rejection of the fetus
Spontaneous abortions in mice can be prevented by transferring Tregs into abortion-prone animalsA possible explanation for infertility and A possible means of reducing miscarriage???
How is the placenta, embryo and fetus protected?
Treg cells prevent fetal rejection by creating a tolerant microenvironment characterized by high levels of:
TGF-β, IL-10, LIF, and HO-1
How is the placenta, embryo and fetus protected?
Treg cells prevent fetal rejection by creating a tolerant microenvironment characterized by high levels of:
TGF-β, IL-10, LIF, and HO-1
TGF-β is elaborated by tumors! And Tregs are abundant in tumors! A “bizarre tumor microenvironment” Is this why cancer immunotherapy failed in the
past?
Why previous immunotherapy approaches have failed
Maybe vaccines and cytokines turn on both a “tumor kill” pathway AND a “tumor protect” pathway
Both arms strengthened Thus, there is no net gain
Not enough of a good thing paradigm
(ineffective tumor-kill pathway)
Too much of a bad thing paradigm (too powerful “tumor-
protect” pathway)
TOLERANCE : How tumors escape immunity (i.e. what REALLY happens vs what we
thought was happening)
The tumor microenvironment
Lymphocytes infiltrating the tumor: Regulatory T cells Tumor associated macrophages: “M2 responses” Dendritic cells: Impaired/immature Myeloid-derived suppressor cells (MDSCs) Cancer associated fibroblasts: Secrete TGF-β and
VEGF, FGFs, PDGF to induce angiogenesis Elevated levels of neutrophils
Depress T-cells, stimulate tumor vasculature, promote tumor invasion
Rather than a half-life of <1day, in the tumor microenvironment they live much longer
Can modern tumor immunobiology translate into effective cancer
immunotherapy? Overcoming checkpoint interference Some steps have negative feedback loops
(“checkpoints”)tumors exploit checkpoints
Each exploited checkpoint might represent a therapeutic avenue
T-Cell Activation and Expansion
The “Immunological Synapse”
Inhibition of T-Cell Function and ProliferationThe dark side of the synapse
Immunological Checkpoints Negative feedback inhibitors Nature’s counterbalance to immune
activation pathwaysLAG-3TIM-3CTLA-4B7-H3PD-1
Needed to avoid autoimmune disease
Tumor cells themselves can inactivate T cells!!!
Checkpoint molecules Activating: CD28 OX40 GITR CD137 CD27 HVEM
Inhibiting: CTLA-4 PD-1 TIM-3 LAG-3 VISTA BTLA
Tumors seem pretty “smart”Can we outsmart them?
Anti-CTLA4 therapy idiosyncrasies
Delayed kinetics (compared to chemotherapy)
Responses (when they occur) are often quite durable
Immune-related adverse effects
Checkpoint agents currently approved or under
development Ipilimumab
Fully human IgG1k monoclonal antibody against CTLA-4
T1/2 = 12-14 days Tremilimumab
Fully human IgG2 monoclonal antibody against CTLA-4
T1/2 = 22 days Nivolumab – Fully human IgG4 monoclonal
antibody against PD-1 Monoclonal antibodies against PD-L1
Cancer Immunotherapy II Ipilimumab (Yervoy) – monoclonal antibody against
CTLA-4 Nivolumab – monoclonal antibody against PD-1 Monoclonal antibodies against PD-L1 Denileukin diftitox (Ontak) Sipuleucel-T (Provenge) - Dendritic cell-based
immunotherapy Cell-based autologous immune enhancement
therapy (AIET) Anti-CD25 mAbs: daclizumab and basiliximab Imiquimod topical cream
Conclusions The abscopal effect suggests that the immune system
can sometimes turn the tables on cancer and gain the upper hand
Astonishing observations in:Contagious cancersTransplanted cancersNormal, ectopic and surrogate pregnanciesMolar pregnancies and choriocarcinoma
Provide intriguing insights about interactions of the immune system and cancer.
Exploitation of our new understanding of tumor immunobiology might allow Science magazine’s “2013 Breakthrough of the Year” to fulfill its promise
Could low-dose total body irradiation be a means of overcoming the cancer’s
ability to evade the immune system?
Tumors escape from immune recognition in several ways…
But - the immune escape is not necessarily irreversible
Total body irradiation MIGHT selectively deplete Treg cells while boosting T effector cells, thereby shifting the balance of power in favor of the cancer-killing arm (?)
Tumor cells have several other tricks…
