Anti-Cancer Vaccine with Embryonic Stem Cells
What if I told you a simple vaccine could prevent or cure cancer? Would you laugh at such a ridiculous idea ? You might be surprised to know that a group at Stanford reported a successful anti-cancer vaccine in a animal breast cancer xenograft model.(1)(6-7) Instead of embryonic cells, Dr Wu used adult cells induced to form pluri potent stem cells, which are very similar to embryonic stem cells.(1)(6,7) Others have created similar successful vaccines against colon, ovarian and lung cancer.(2-3)(8-9) Remarkably, these vaccines have no toxicity to the host animal.
Cancer Cells Are Remarkably Similar to Embryonic Stem cells
It was recognized all the way back in 1906 by Schöne that injection of embryonic/fetal tissue stimulates rejection of transplanted tumors in animals.(5) More recent work has shown that cancer cells share many features of embryonic stem cells, including genetic signature and surface protein markers called epitopes which can be recognized by the immune system. These protein markers these include HCG and CEA.(5) HCG (human chorionic gonadotropic is a pregnancy test, and also a cancer test. The carcinoembryonic antigen (CEA) is a well known test for cancer cells by virtue of detecting an embyronic antigen released by cancer cells.(5)
Similarities between trophoblast (placental) cell and cancer cell behavior has been reported for over 100 years. More recently, Dr. C. Ferretti in 2006 found similarities in the molecular circuits relating to the proliferative, invasive and migratory capacities of both types of cells.(10) So it is not surprising that they should share surface antigens.
Circumventing Ethical Issues with Fetal Cell Research
Because of ethical concerns, fetal stem cell research was halted a few years ago. To circumvent this issue, Dr Wu’s group has converted adult cells into plui-potent stem cells which can serve in place of embryonic stem cells.
Conclusion: Anti-cancer vaccines derives from pluri-potent stem cells in animal models are quite effective. It may take a few more years to iron out the wrinkles and translate to human use.
Jeffrey Dach MD
Links and References:
Header Image Embryonic Stem Cells Courtesy of Wikimedia Commons
Breast Cancer Xenograft animal model
1) Autologous iPSC-Based Vaccines Elicit Anti-tumor Responses In Vivo Kooreman, Nigel G. et al. Cell Stem Cell , Volume 0 , Issue 0 ,
our data show the feasibility of creating broad tumor immunity against multiple cancer types using an iPSC-based vaccine that presents the immune system with large quantities of tumor antigens. Compared to current immunotherapy strategies, our iPSC vaccine is capable of reactivating the immune system to target cancers without therapy-associated adverse effects and can be created within a few weeks after diagnosis. These beneficial properties make this iPSC vaccine a potential option for personalized adjuvant immunotherapy shortly after conventional primary treatment of cancer.
2) Int J Cancer. 2018 Apr 1;142(7):1453-1466. Vaccination with human amniotic epithelial cells confer effective protection in a murine model of Colon adenocarcinoma.
Tabatabaei M1, Mosaffa N1, Ghods R2,3, Nikoo S4, Kazemnejad S5, Khanmohammadi M5, Mirzadeghan E5, Mahmoudi AR4, Bolouri MR4, Falak R4, Keshavarzi B1, Ramezani M6, Zarnani AH4,7.
As a prophylactic cancer vaccine, human amniotic membrane epithelial cells (hAECs) conferred effective protection in a murine model of colon cancer. The immunized mice mounted strong cross-protective CTL and antibody responses. Tumor burden was significantly reduced in tumor-bearing mice after immunization with hAECs. Placental cancer immunotherapy could be a promising approach for primary prevention of cancer. In spite of being the star of therapeutic strategies for cancer treatment, the results of immunotherapeutic approaches are still far from expectations. In this regard, primary prevention of cancer using prophylactic cancer vaccines has gained considerable attention. The immunologic similarities between cancer development and placentation have helped researchers to unravel molecular mechanisms responsible for carcinogenesis and to take advantage of stem cells from reproductive organs to elicit robust anti-cancer immune responses. Here, we showed that vaccination of mice with human amniotic membrane epithelial cells (hAECs) conferred effective protection against colon cancer and led to expansion of systemic and splenic cytotoxic T cell population and induction of cross-protective cytotoxic responses against tumor cells. Vaccinated mice mounted tumor-specific Th1 responses and produced cross-reactive antibodies against cell surface markers of cancer cells. Tumor burden was also significantly reduced in tumor-bearing mice immunized with hAECs. Our findings pave the way for potential future application of hAECs as an effective prophylactic cancer vaccine.
3) Asian Pac J Cancer Prev. 2012;13(9):4295-300.
Human embryonic stem cells–a potential vaccine for ovarian cancer.
Zhang ZJ1, Chen XH, Chang XH, Ye X, Li Y, Cui H.
To investigate the therapeutic potential of human embryonic stem cells (hESCs) as a vaccine to induce an immune response and provide antitumor protection in a rat model.
METHODS: Cross-reactivity of antigens between hESCs and tumour cells was screened by immunohistochemistry. Fischer 344 rats were divided into 7 groups, with 6 rats in each, immunized with: Group 1, hESC; Group 2, pre-inactivated mitotic NuTu-19; Group 3 PBS; Group 4, hESC; Group 5, pre-inactivated mitotic NuTu-19; Group 6, PBS; Group 7, hESC only. At 1 (Groups 1-3) or 4 weeks (Groups 4-6) after the last vaccination, each rat was challenged intraperitoneally with NuTu-19. Tumor growth and animal survival were closely monitored. Rats immunized with H9 and NuTu- 19 were tested by Western blot analysis of rat orbital venous blood for cytokines produced by Th1 and Th2 cells.
RESULTS:hESCs presented tumour antigens, markers, and genes related to tumour growth, metastasis, and signal pathway interactions. The vaccine administered to rats in Group 1 led to significant antitumor responses and enhanced tumor rejection in rats with intraperitoneal inoculation of NuTu-19 cells compared to control groups. In contrast, rats in Group 4 did not display any elevation of antitumour responses. Western blot analysis found cross-reactivity among antibodies generated between H9 and NuTu-19. However, the cytokines did not show significant differences, and no side effects were detected.
CONCLUSION:hESC-based vaccination is a promising modality for immunotherapy of ovarian cancer.
4) Kwiatkowska-Borowczyk, Eliza P., et al. “Immunotargeting of cancer stem cells.” Contemporary Oncology 19.1A (2015): A52.
Cancer stem cells (CSCs) represent a distinctive population of tumour cells that control tumour initiation, progression, and maintenance. Their influence is great enough to risk the statement that successful therapeutic strategy must target CSCs in order to eradicate the disease. Because cancer stem cells are highly resistant to chemo- and radiotherapy, new tools to fight against cancer have to be developed. Expression of antigens such as ALDH, CD44, EpCAM, or CD133, which distinguish CSCs from normal cells, together with CSC immunogenicity and relatively low toxicity of immunotherapies, makes immune targeting of CSCs a promising approach for cancer treatment. This review will present immunotherapeutic approaches using dendritic cells, T cells, pluripotent stem cells, and monoclonal antibodies to target and eliminate CSCs.
5) Exp Mol Pathol. 2009 Jun;86(3):192-7. Embryonic vaccines against cancer: an early history. Brewer BG1, Mitchell RA, Harandi A, Eaton JW.
Almost 100 years have passed since the seminal observations of Schöne showing that vaccination of animals with fetal tissue would prevent the growth of transplantable tumors. Many subsequent reports have affirmed the general idea that immunologic rejection of transplantable tumors, as well as prevention of carcinogenesis, may be affected by vaccination with embryonic/fetal material. Following a decade of intense research on this phenomenon during approximately 1964-1974, interest appears to have waned. This earlier experimental work may be particularly pertinent in view of the rising interest in so-called cancer stem cells. We believe that further work – perhaps involving the use of embryonic stem cells as immunogens – is warranted and that the results reviewed herein support the concept that vaccination against the appearance of cancers of all kinds is a real possibility.
5) Vinnitsky, V. “The development of a malignant tumor is due to a desperate asexual self-cloning process in which cancer stem cells develop the ability to mimic the genetic program of germline cells” Intrinsically disordered proteins 2.1 (2014): e29997-e29997.
Immunization against cancer using embryonic material has a history of more than 100 years. Oncodevelopmental antigens were reported to have been identified by transplantation as early as 1906 when Schone148 SchöneG. Untersuchungen uber Kakzinomimmunitat bei Mausen. Munch Med Wochenschr1906; 53:2517 – 9 [Google Scholar] found that tumor transplants that would kill normal mice would be rejected by mice that had previously been immunized with fetal tissue; immunization with adult tissue was ineffective.149 SellS, BeckerFF, LeffertHL, WatabeL. Expression of an oncodevelopmental gene product (alpha-fetoprotein) during fetal development and adult oncogenesis. Cancer Res1976; 36:4239 – 49; PMID: 61804 [PubMed], [Web of Science ®], [Google Scholar] In the following decades, many reports affirmed the general idea that immunization of an individual with fetal tissue, including placental tissue, can result in immunologic rejection of transplantable tumors, as well as prevention of the development of chemically-induced tumors.150
We consider the development of effective cancer vaccines using tumor-embryo cross-reacting antigens for early-life immunization as a new research strategy aimed at creation of life-long immunity against cancer.
6) Induced pluripotent stem cells could serve as cancer vaccine
Date: February 15, 2018 Source: Stanford Medicine
Summary: Induced pluripotent stem cells, or iPS cells, are a keystone of regenerative medicine. Outside the body, they can be coaxed to become many different types of cells and tissues that can help repair damage due to trauma or disease. Now, a study in mice suggests another use for iPS cells: training the immune system to attack or even prevent tumors.
7) Induced pluripotent stem cells could serve as cancer vaccine Priming the immune system with induced pluripotent stem cells prevented or slowed the development of cancer in mice, Stanford researchers found. (Stanford News Release)
8) Dong, Wei, et al. “Administration of embryonic stem cells generates effective antitumor immunity in mice with minor and heavy tumor load.” Cancer immunology, immunotherapy 59.11 (2010): 1697-1705.
The history of immunizing animals with fetal tissues to generate an antitumor response dates back a century ago. Subsequent reports supported the idea that vaccination with embryonic materials could generate cancer-specific immunity and protect animals from transplantable and chemically induced tumors. In our study, we found C57 BL/6 mice vaccinated with embryonic stem cells (ESCs) received obvious antitumor immunity, which protected them from the formation and development of lung cancer. Furthermore, we investigated the antitumor effects of administration of ESCs in mice with minor and/or heavy tumor load. The tumor growth was monitored, the proliferation of lymphocytes and secretion of cytokines were examined, and finally the tissue sections were approached by immunohistochemical and apoptosis staining. The results suggested that mice injected with ESCs received obvious tumor inhibition and retardation due to significant lymphocyte proliferation and cytokine secretion, which help to rebuild the host’s immunity against cancer to some extent and comprise the main part of antitumor immunity. Moreover, mice with minor tumor load received stronger antitumor effect compared with mice with heavy tumor load, may be due to relatively intact immune system. Thus, besides their function as prophylactic vaccines, administration of ESCs could be a potential treatment for cancer, which obviously prevent and control the proliferation and development of malignant tumors.
9) Yaddanapudi, Kavitha, et al. “Vaccination with embryonic stem cells protects against lung cancer: is a broad-spectrum prophylactic vaccine against cancer possible?.” PloS one 7.7 (2012): e42289.
The antigenic similarity between tumors and embryos has been appreciated for many years and reflects the expression of embryonic gene products by cancer cells and/or cancer-initiating stem cells. Taking advantage of this similarity, we have tested a prophylactic lung cancer vaccine composed of allogeneic murine embryonic stem cells (ESC). Naïve C57BL/6 mice were vaccinated with ESC along with a source of granulocyte macrophage-colony stimulating factor (GM-CSF) in order to provide immunostimulatory adjuvant activity. Vaccinated mice were protected against subsequent challenge with implantable Lewis lung carcinoma (LLC). ESC-induced anti-tumor immunity was not due to a non-specific “allo-response” as vaccination with allogeneic murine embryonic fibroblasts did not protect against tumor outgrowth. Vaccine efficacy was associated with robust tumor-reactive primary and memory CD8(+) T effector responses, Th1 cytokine response, higher intratumoral CD8(+) T effector/CD4(+)CD25(+)Foxp3(+) T regulatory cell ratio, and reduced myeloid derived suppressor cells in the spleen. Prevention of tumorigenesis was found to require a CD8-mediated cytotoxic T lymphocyte (CTL) response because in vivo depletion of CD8(+) T lymphocytes completely abrogated the protective effect of vaccination. Importantly, this vaccination strategy also suppressed the development of lung cancer induced by the combination of carcinogen administration and chronic pulmonary inflammation. Further refinement of this novel vaccine strategy and identification of shared ESC/tumor antigens may lead to immunotherapeutic options for lung cancer patients and, perhaps more importantly, could represent a first step toward the development of prophylactic cancer vaccines.
10) Ferretti, C., et al. “Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts.” Human reproduction update 13.2 (2007): 121-141. Molecular circuits shared by placental and cancer cells implications in proliferative invasive migratory trophoblasts Ferretti C Human repro upd 2007
11) Erenpreisa, Jekaterina, et al. “The “virgin birth”, polyploidy, and the origin of cancer.” Oncoscience 2.1 (2015): 3.
Recently, it has become clear that the complexity of cancer biology cannot fully be explained by somatic mutation and clonal selection. Meanwhile, data have accumulated on how cancer stem cells or stemloids bestow immortality on tumour cells and how reversible polyploidy is involved. Most recently, single polyploid tumour cells were shown capable of forming spheroids, releasing EMT-like descendents and inducing tumours in vivo. These data refocus attention on the centuries-old embryological theory of cancer. This review attempts to reconcile seemingly conflicting data by viewing cancer as a pre-programmed phylogenetic life-cycle-like process. This cycle is apparently initiated by a meiosis-like process and driven as an alternative to accelerated senescence at the DNA damage checkpoint, followed by an asexual syngamy event and endopolyploid-type embryonal cleavage to provide germ-cell-like (EMT) cells. This cycle is augmented by genotoxic treatments, explaining why chemotherapy is rarely curative and drives resistance. The logical outcome of this viewpoint is that alternative treatments may be more efficacious – either those that suppress the endopolyploidy-associated ‘life cycle’ or, those that cause reversion of embryonal malignant cells into benign counterparts. Targets for these opposing strategies are components of the same molecular pathways and interact with regulators of accelerated senescence.
These observations and conclusions largely fit the embryonal theory of cancer. Its oncogerminative variant is proposed by Vladimir Vinnitsky
This consideration brings us to the c-myc protooncogene, whose overexpression uncouples DNA replication from mitosis, thus leading to endopolyploidy . C-myc is one of the most ancient genes of early Metazoans , linked during evolution to the Warburg effect . It is also the main oncogene imposing immortality to cancer cells and a master regulator of stemness . Importantly, c-myc is a gene, whose suppression in in vivo models eliminates “oncogene addiction” and cures experimental cancer [113, 114]. Therefore, the targets for interrupting the cancer cell ‘life-cycle’ at its evolutionary root should likely focus around c-myc.
The best known and widely applied example of this treatment strategy is the differentiation inducer all-trans-retinoic acid (RA). Intriguing this is an old Chinese medicine against cancer and capable of curing acute myeloid leukemia