Presentation on theme: "James S. Welsh, MS, MD Northern Illinois University."— Presentation transcript:
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”
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???
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 proof a. 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 In immunologically compromised dogs the 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 devils E 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 molecules reduces 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 recipient 1.) The immune system must be keeping these cancer cells in check in the donor 2.) The recipient’s immunosuppression is NOT the only reason why the cancer can redevelop 3.) 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?
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?
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 moles Invasive moles Choriocarcinoma – 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-protein Increased during pregnancy in cases of spina bifida and other fetal malformations Lower than normal in Down syndrome Testicular cancer and Hepatocellular carcinoma Human chorionic gonadotropin The pregnancy test Germ 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?
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 size By 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- TNF 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 antigens Possesses a “memory” Antibodies from B-cells and T cell mediated immunity Estimated that gene rearrangements can yield ~5x10 13 different Ig molecules and 10 18 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 animals A 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 Proliferation The dark side of the synapse
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 IgG1 monoclonal antibody against CTLA-4 T 1/2 = 12-14 days Tremilimumab Fully human IgG2 monoclonal antibody against CTLA-4 T 1/2 = 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 cancers Transplanted cancers Normal, ectopic and surrogate pregnancies Molar 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 (?)