In part one of this series, we discussed strategies to eradicate cancer stem cells using Doxycycline and high dose Vitamin C. Unfortunately, a few cancer stem cells, however small in number, will always remain behind at the end of treatment. These will again grow into sizable tumor masses capable of metastasis to remote areas of the body. The new tumors may even be more treatment resistant and more aggressive than the original cell type. How can we avoid this scenario ? Above Left image: Killer T-Cell scanning electron micrograph courtesy of Science Magazine.
You might ask the question, why doesn’t the immune system recognize these cancer cells as “foreign invaders” and kill them as they do for other invaders? After all, the cancer cells are genetically different from the host cells. How do the cancer cells evade the immune system?
The answer lies in the observation made over a hundred years ago by John Beard (1858-1924), a Scottish embryologist, who recognized the similarity between embryo implantation and tumor metastasis.(1) See my article on the Trophoblastic theory of cancer.
Cancer cells invade and induce new blood vessels similar to trophoblast (placenta) growth into the endometrium during pregnancy, and both are governed by a protein called PIBF, progesterone inducing blocking factor. PIBF suppresses the activity of NK killer cells of the immune system, allowing the cancer cells to evade surveillance by the immune system.
Treatment of cancer cells with progesterone upregulates PIBF, while blocking progesterone receptors with a drug called Mifepristone, prevents secretion of PIBF, and renders the cancer cell vulnerable to attack by the immune system.
Dr Wan in his 2015 Oncotarget article suggested Mifepristone together with a platelet inhibitor and the antibiotic doxycycline could prevent metastatic disease.(1) Mifepristone inhibits adhesion of Circulating Tumor Cells to vascular endothelium.
Working with a Glioblastoma brain cancer cell model, Dr Gutiérrez-Rodríguez found that PIBF promotes proliferation, migration, and invasion of human glioblastoma cells.(2) Likewise for Leukemia cell types, Dr. Check in 2009 found that 100% of human leukemia cell lines express mRNA for the PIBF protein.(3) PIBF protein expression was inhibited by the progesterone receptor blocker, mifepristone.
Unfortunately the drug, mifepristone is restricted and unavailable for routine clinical use. Only licenses abortionists may use this drug. As luck would have it, elimination of PIBF may be accomplished with another drug which is widely available, the microtubule disrupting agent mebendazole which is similar to nocodazole used in the study.
Below Image is Figure 7 from Lachman (7) Notice the green dots in the untreated cells (Red Arrows) representing PIBF. Above Panel A- After treatment with the microtuble disrupting agent nocodazole, the green dots are gone, PIBF is not present.(Green arrows red box).
Below Panel B -PIBF associates with two centrosomes and tubulin in the mitotic spindle in actively dividing cell (red arrows)
Mebendazole for Disrupting Microtubules and Knocking Out PIBF
Margit Lachmann found “PIBF (progesterone induced blocking factor) is over-expressed in highly proliferating cells and associated with the centrosome” which is involved with the mitotic spindle and its microtubule system. (7) Nocodazole is a microtubule disrupting agent similar to mebendazole. Dr Lachman found that “treatment with nocodazole (at 5 μg/ml concentration for 4 hr), a microtubule-disrupting agent led to the time-dependent disappearance of the perinuclear PIBF dots, which paralleled with the disintegration of the Golgi apparatus (7a lower panel).”(7)
Beneficial effects on the immune system by microtubule disrupting agents such as mebendazole have been recognized previously. Dr Pan Pantziarka says in his 2014 article, Mebendazole as an anti-cancer agent:
“There is also increasing evidence that existing microtubule disrupting agents used at low or metronomic doses, including the taxanes and vinca alkaloids, exert a positive immunomodulatory action that may help to reverse the immunosuppressive effect of cancer [33–36]. We can speculate, mechanistically, that some of this immunomodulatory action is related to microtubule dynamics. Therefore, there may be a similar effect with MBZ and other benzimidazoles, and this may also be a factor in the anti-cancer effects of these drugs.”
Artemisinin and Microtubules
Artemisinin may also have an effect on the microtuble system of the cancer cell as discribed by Dr Anne Hamacher-Brady in her article “Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production J Biol Chem 2011 Hamacher Brady
When Artemisinin enters the cancer cell, it causes a peculiar re-arrangement of the lysosomes and mitochondria in a pattern typical for autophagy (the cell eats itself and dies) as reported by Dr Brady . This peri-nuclear clumping has also been observed in experiments which knock out KIF5B, the only microtubule motor protein associated with the lysosomes. Therefore it has been speculated that the effect of Artemisinin in the lysosome is to impair the microtubule motor proteins. This perinuclear clustering of organelles is a prelude to programmed cell death. One might speculate on possible downregulation of PIBF. Although artemisinin are known to down regulate immune functions, the effect of artemisinin on PIBF has not yet been studied. Further research would be useful here.
New Drugs- Immune Check Point Inhibitors
The new anti-cancer drugs are the Immune Checkpoint Inhibitors. The FDA has approved a number of these drugs: ipilumimab, nivolumab and pembrolizumab as inhibitors of CTLA-4 and PD-1. Ipilimumab is an anti-CTLA-4 monoclonal antibody which activates Killer T-Cells by preventing tumor inhibition. Clinical trials for relapsed B cell lymphoma after allogeneic stem cell transplant have shown promising results. (43-45) The drug upregulates the “graft vs. lymphoma effect” .(43-45) The drugs may also be injected directly into the tumor mass after cryoablation using image guided techniques.(45) PD-1 inhibitors are: atezolizumab and avelumab.
Unfortunately, Graft vs. Host disease is an adverse effect of Checkpoint Inhibitors after failed Allogeneic stem cell transplant. . Dr Bradly Haverkos says in Blood 2017, “PD-1 blockade in relapsed cHL allo-HCT patients appears to be highly efficacious but frequently complicated by rapid onset of severe and treatment refractory GVHD. “(49) Treatment refractory Graft vs. Host Disease carries a high mortality rate.
This article provides a nice overview of Immune checkpoint Inhibitors:
Ok, Chi Young, and Ken H. Young. “Checkpoint inhibitors in hematological malignancies.” (2017).J Hematol Oncol. 2017; 10: 103.
Bi-Directional Antibodies- Next Generation Immunotherapy
The anti-CD20 mono-clonal antibody, Rituximab revolutionized lymphoma treatment 20 years ago by targeting surface markers on Malignant B-cells. The next generation version of Rituximab is a bidirectional antibody called Blinatumomab.(51-57)
“Blinatumomab is a bispecific T-cell engager (BiTE) molecule that recruits cytotoxic T cells to target tumor B cells by linking the CD3 and CD19 antigens.” (55)
“Blinatumomab is a bispecific T cell engager (BiTE) antibody construct that binds to both CD3 on T cells and CD19 on B cells by 2 linked single-chain variable antibody fragments. T cells and B cells are brought together, allowing T cells to recognize and target malignant B cells, resulting in tumor cell apoptosis.”(52)
Blinatumomab (Blincyto) was FDA approved in Dec 2014 for treatment of B-cell acute lymphoblastic leukemia.(53) Use in other types of B-Cell malignancies (B-cell lymphoma etc) is considered off-label use.
ADC – Antibody Drug Conjugates -Adding Chemo to Rituximab
Left Image Figure 8 A) Schematic diagram of the PBD dimer SJG‐136 forming an interstrand cross‐link with the DNA sequence 5′‐AGATCT‐3′. Its sequence‐selectivity is due in part to a) covalent bonds formed. from (67) Zammarchi, Francesca, et al. “Pre-clinical development of Adct-402, a novel pyrrolobenzodiazepine (PBD)-based antibody drug conjugate (ADC) targeting CD19-expressing B-cell malignancies.” (2015): 1564-1564.
The ADC ( Antibody Drug Conjugate) is another next generation version of Rituximab. The ADCT-402 drug combines a highly toxic PBD dimer to the antibody which targets the CD19 marker on the B-Cell.(63-67) (see above image)
In the ADCT-402 drug, the toxic warhead is PBD (pyrrolobenzodiazepine), a highly toxic natural product derived from actinomycetes bacteria, an agent which binds and crosslinks DNA which of course, kills the B-Cells. (see above image)
PBD is “significantly more potent than systemic chemotherapeutic drugs”. PBD will “typically demonstrate IC50 values in the low to mid picomolar range in a variety of cell types, and unlike the anti-tubulin agents, they can induce cell death in both dividing and non-dividing cells.” ADCT-402 has shown promising results in early clinical trials in refractory B cell Lymphomas with 40% complete remission and 70% overall response.(63-67) Adverse events were not life threatening and generally manageable.
Mebendazole and other microtubule disrupting agents (Vinca Alkaloids, Taxol, Vincristin etc) reverse the immunosuppressive effect of cancer by downregulating or eliminating PIBF in the cancer cells. PIBF is intimately associated with the microtuble complex. This removes their cloak of protection, and cancers are now vulnerable to the Killer T-Cells which destroy the cancer. This topic would be a fertile area for further NIH funded research.
An explosion of new immunotherapy drugs under development include CAR T cells, Bidirectional Antibodies, ADC (Antibody Drug Conjugates) , Immune Checkpoint Inhibitors, etc. Will these new drugs make the older cytotoxic chemotherapy obsolete? I sure hope so. This is a fast moving field with high stakes for the biotech industry. So, stay tuned.
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Fl 33314
Articles with related Interest:
Links and References
Wan, Liyuan et al. “Aspirin, Lysine, Mifepristone and Doxycycline Combined Can Effectively and Safely Prevent and Treat Cancer Metastasis: Prevent Seeds from Gemmating on Soil.” Oncotarget 6.34 (2015): 35157–35172.
Recent scientific advances have increased our understanding of the cancer metastatic complexities and provided further impetus for new combination therapies to prevent cancer metastasis. Here, we demonstrated that a combination (HAMPT) of aspirin, lysine, mifepristone and doxycycline can effectively and safely prevent cancer metastasis. The pharmaceutically-formulated HAMPT inhibited adhesion of cancer cells to either endothelial cells or extracellular matrix via down-regulating cell adhesion molecules ICAM-1 and a4-integrin. HAMPT inhibited the cloak effect by activated platelets on cancer cells, thereby interfering adhesion and invasion of cancer cells to the underlying stroma. At the effective concentration, HAMPT induced cancer cells into dormancy with minor inhibition on cell viability. Four-day pretreatment followed by 30-day oral administration of HAMPT (33.5-134 mg/kg) to the mice inoculated with cancer cells produced significant inhibition on cancer metastasis dose-dependently without marked side effects. Fifty-day rat toxicity study with HAMPT at doses (335-1340 mg/kg) 20-fold higher than its therapeutic dose produced no significant toxicity. Interestingly, the acute toxic death could not be reached at the maximum administrable dose (5 g/kg). This proof-of-concept study provides the first conceptual evidence that cancer metastasis can be controlled by using affordable old drugs to restrain circulating tumor cells from gemmating on the metastatic soil without the need for cytotoxicity.
metapristone (the active mifepristone metabolite) has a safe and effective profile as a cancer metastasis chemopreventive agent by inhibiting adhesion of CTCs to vascular endothelium
We proposed that the initiation of CTC adhesion to the local vascular endothelium is the first and important step for CTCs to start the metastatic cascade.HAMPT prevents cancer cells from cloaked or aggregated by platelets
As the molecular understanding of the biological functions necessary for metastasis increases, it becomes important to develop a comprehensive cancer metastasis chemoprevention strategy that targets not only the intrinsic growth of disseminated CTCs, but also their necessary adhesion and invasion to endothelial layer in the distant metastatic organs, including the bone marrow. Most of CTCs die in the circulation, presumably due to the loss of matrix-derived survival signals, circulatory shear stress, or anoikis . Mifepristone, aspirin, lysine and doxycycline hyclate work differently at distinct metastatic targets and pathways.
Interestingly, it seems like that there are some similarity between embryo implantation and tumor metastasis , which constructs the base for the abortifacient mifepristone to act as a metastatic chemopreventive. Patients already took mifepristone for as long as 14 years . The safety profile of mifepristone makes it well-suited for a safe metastatic chemopreventive candidate.
Gutiérrez-Rodríguez, Araceli, Valeria Hansberg-Pastor, and Ignacio Camacho-Arroyo. “Proliferative and Invasive Effects of Progesterone-Induced Blocking Factor in Human Glioblastoma Cells.” BioMed research international 2017 (2017).
These data suggest that PIBF promotes proliferation, migration, and invasion of human glioblastoma cells.
Med Hypotheses. 2009 Jan;72(1):87-90. doi: 10.1016/j.mehy.2008.05.042. Epub 2008 Oct 7.
Support for the hypothesis that successful immunotherapy of various cancers can be achieved by inhibiting a progesterone associated immunomodulatory protein.Check JH1, Dix E, Sansoucie L.
A hypothesis was proposed that cancer cells may utilize a pre-existing mechanism that pregnant mammals use to avoid natural killer cell immune surveillance of the fetus. The hypothesis suggested that those cancer cells that are able to proliferate may have found a way to cause the expression of the immunomodulatory protein known as the progesterone induced blocking factor (PIBF). The cancer cells could find an alternate pathway to make this protein that does not require progesterone secretion, or the cancer cells may actually utilize progesterone and thus make PIBF in a similar fashion to normal pregnancy. If the former mechanism was operational, then one could develop monoclonal antibody type therapy directed to this unique protein not needed for normal body functions. However, if the latter pathway involving progesterone secretion is operational, then there would be drugs already on the market, e.g., the progesterone receptor antagonist mifepristone that could be used to treat these cancers. In vitro data has shown that 100% of human leukemia cell lines express mRNA for the PIBF protein. Some leukemia cell lines have been found that actually express the PIBF protein. In fact adding progesterone to the culture media upregulated PIBF protein expression and mifepristone inhibited it. Controlled studies in various murine spontaneous cancers not known to be associated with progesterone receptors showed increased length and quality of life following mifepristone therapy. Anecdotal improvement in advanced widely metastatic human cancers has also been found. Thus there is now experimental data to support this hypothesis and a new door to a completely different type of cancer therapy has been opened.
4) Szekeres-Bartho, Julia, and Beata Polgar. “PIBF: the double edged sword. Pregnancy and tumor.” American Journal of Reproductive Immunology 64.2 (2010): 77-86. PIBF the double edged sword Pregnancy and tumor Szekeres-Bartho Julia Beata Polgar A J Reproductive Immunology 2010
Check, Jerome H., et al. “Mifepristone treatment improves length and quality of survival of mice with spontaneous leukemia.” Anticancer research 29.8 (2009): 2977-2980.
Mifepristone was found to suppress expression of the progesterone-induced blocking factor (PIBF). Progesterone-induced blocking factor suppresses natural killer cell activity.
The objective of the present study was to determine if treatment of mice with spontaneous murine lymphocyte leukemia with the progesterone receptor antagonist mifepristone could improve length and quality of life. Materials and Methods: Sixty-one mice were gavaged with mifepristone and 33 controls with olive oil. Quality of life was determined by body conditioning score (BCS). Treatment was initiated when the mice were 6 months old. Results: Within 2 weeks of therapy only 11.4% of the mifepristone treated mice died vs. about 50% of controls. The BCS was 5 (highest quality) in 82% of treated mice vs. 11% of controls after 2 weeks of therapy. Conclusion: Mifepristone therapy should be further evaluated for treating leukemia and lymphoma.
Check, Jerome H., et al. “Mifepristone Causing Complete Remission of Rapidly Advancing Leukemia with Measurement of Progesterone-induced Blocking Factor.” Anticancer research 34.5 (2014): 2413-2416.
one of the theories of how PIBF can aid malignant tumors to escape immune surveillance is that the tumor influences gamma/delta T-cells in the tumor microenvironment to secrete PIBF, which in turn inhibits NK cell cytolytic activity in the tumor microenvironment
see Figure 7: PIBF is sensitive to nocodazole (similar to mebendazole) and colocalizes with the centrosomal protein ?-tubulin.
Lachmann, Margit, et al. “PIBF (progesterone induced blocking factor) is overexpressed in highly proliferating cells and associated with the centrosome.” International journal of cancer 112.1 (2004): 51-60.
PIBF (Progesterone Induced Blocking Factor) was discovered in the context of reproductive immunology as a secreted product of human pregnancy lymphocytes and described as an immunomodulatory molecule relevant for the maintenance of pregnancy
The disappearance of the PIBF signal upon nocodazole treatment and the appearance of two PIBF signals on opposite sides of the nuclei in dividing cells suggested that PIBF might associate with the microtubule organizing center (MTOC) or centrosome.
In CMAP, the MBZ-induced gene expression profile correlated strongly with nocodazole a well-known tubulin inhibitor with chemical structure similarity to MBZ (mebendazole)
Association of PIBF with the centrosomes is clearly demonstrated in the present study. The nocodazole-sensitivity of the PIBF-centrosome interaction suggests that PIBF is not an integral component of the centrosome but rather a microtubule-associated protein. This is supported by preliminary copurification studies with ?-tubulin, where no direct interaction of PIBF with ?-tubulin was detected (data not shown).
nocodazole Progesterone Induced Blocking Factor
Anticancer Res. 2016 Dec;36(12):6511-6513.
Long-term High-quality Survival with Single-agent Mifepristone Treatment Despite Advanced Cancer. Check JH1,2, Check D2, Wilson C2, Lofberg P2.
We show long-term high-quality survival following single-agent treatment with a progesterone receptor antagonist in two cases of advanced metastatic cancer. Because no biopsy was performed (patient refused) the exact type of lung cancer was not determined but the majority of oncologists who evaluated the patient thought that the rapid onset and syndrome of inappropriate anti-diuretic hormone was more consistent with small-cell lung cancer. The US Food and Drug Association granted a compassionate-use investigational new drug approval for use of single-agent 200 mg mifepristone orally/day to a moribund woman with never-treated metastatic lung cancer and a male with bilateral renal cell carcinoma who had undergone only a unilateral hemi-nephrectomy. Both had long-term high-quality survival (5 years for the patient with lung cancer with complete remission of all lung lesions, and 12 years for the male patient with kidney cancer). Neither patient had any side-effects from mifepristone therapy.
CONCLUSION:These cases helped influence the US Food and Drug Association in granting an investigator-initiated investigational new drug study on advanced non-small cell lung cancer.
Check, Jerome H. “The role of progesterone and the progesterone receptor in cancer.” Expert Review of Endocrinology & Metabolism 12.3 (2017): 187-197.
There is an abundance of accumulating data strongly suggesting there is a key role for the progesterone receptor in the molecular events effecting the growth or containment of a variety of cancers. This knowledge should lead to novel new strategies to combat various cancers, including drugs classified as progesterone receptor modulators or monoclonal antibodies against some of the key proteins needed for cancer proliferation by suppressing immune surveillance.
Expert commentary: Discussion is made about a unique immunomodulatory protein called the progesterone induced blocking factor (PIBF). The role of this protein, that is unique to rapidly growing cells, may hold a key to how the cancer cells escape immune surveillance. Thus, techniques to suppress the intracytoplasmic isoforms of PIBF may play a significant role in the fight against all cancers, not just the ones with the classic nuclear progesterone receptors.
Clin Exp Obstet Gynecol. 2007;34(4):207-11.
Evidence that progesterone receptor antagonists may help in the treatment of a variety of cancers by locally suppressing natural killer cell activity.Check JH, Sansoucie L, Chern J, Amadi N, Srivastava M, Larece K.
To propose a novel concept that progesterone receptor antagonists, e.g., mifepristone, may prove effective in treating a variety of cancers–even those not shown to be hormonally dependent or possessing progesterone receptors.
METHODS:Multiple human leukemia cell lines were evaluated for mRNA expression of an immunomodulatory protein called the progesterone-induced blocking factor (PIBF) that suppresses natural killer (NK) cell activity during normal pregnancy. Furthermore, we evaluated the effects of progesterone (P) and mifepristone in PIBF protein expression. Finally, the effect of mifepristone treatment of mice with advanced leukemia was evaluated.
RESULTS:All tumor cell lines evaluated were found to express mRNA for PIBF and some were found to even express the PIBF protein. The addition of PROGESTERONE to the media increased the expression of PIBF and mifepristone downregulated its expression. Treatment of mice with spontaneous leukemia when they already had extensive disease seemed to increase the length and quality of their life.
CONCLUSIONS:These data and other experience with mice with lung cancer and some anecdotal human cancer experience suggest that various cancers may utilize similar mechanisms used by the fetus to escape NK cell surveillance. Mifepristone and other progesterone receptor antagonists may deserve a clinical trial in human cancer even where there is no knowledge of the presence of progesterone receptors.
Check, Jerome H., et al. “Evidence that mifepristone, a progesterone receptor antagonist, can cross the blood brain barrier and provide palliative benefits for glioblastoma multiforme grade IV.” Anticancer research 34.5 (2014): 2385-2388.
It has been hypothesized that an immunomodality protein expressed by gamma delta thymic (T) cells with up-regulation of progesterone receptors will be produced after these cells have been exposed to a high concentration of progesterone. It has been hypothesized that this protein, known as the progesterone-induced blocking factor (PIBF) suppresses natural killer cell activity in the tumor microenvironment and thus provides one mechanism allowing cancer cells to escape immune surveillance, similar to the immunosuppressant effect that this protein has on natural killer cells during normal pregnancy
This hypothesis was supported by the demonstration of PIBF mRNA expression in all human leukemia cell lines tested in one study, including T-cell leukemia, seven myeloid leukemia and 10 B-cell leukemia cell lines (7). In that same study, 4 out of 10 leukemia cell lines tested for expression of this PIBF protein exhibited up-regulation of PIBF expression when extra progesterone was added to the culture medium, and down-regulation of PIBF expression was found with use of the progesterone receptor antagonist mifepristone
Leuk Lymphoma. 2007 Aug;48(8):1610-7.
Expression and modulation of progesterone induced blocking factor (PIBF) and innate immune factors in human leukemia cell lines by progesterone and mifepristone.
Srivastava MD1, Thomas A, Srivastava BI, Check JH.
Progesterone (P), required for successful pregnancy, influences autoimmune, infectious, and malignant diseases via adaptive and innate immune effects. P induces NK inhibitor progesterone induced blocking factor (PIBF) in CD8+ T cells. PIBF isoforms could permit solid tumor immune escape. Expression and modulation of PIBF and innate immune proteins by P in leukemia cells and leukocyte subpopulations have not been reported. Ten T, seven myeloid, six B, five epithelial, fibroblast BG9, G-CSF mobilized CD34+ stem cells, and peripheral blood mononuclear cells were screened for PIBF mRNA by RT-PCR, and protein by immunohistochemistry in SRIK-NKL, MOT, U937, HL60, R-CLL, MD-E, 729pH6neo, SRIH-B(ATL), SRIK-B(T-PLL), and MeWo. Cell lines expressing PIBF and exemplifying myeloid/monoblast, natural killer/T, and B lineages were cultured with and without 0.5 – 5 microM P or 0.5 – 0.05 microM mifepristone (RU486) for 24 h. Subsequently they were examined for changes in the expression of mRNA by RT-PCR and protein by immunohistochemistry for PIBF and some innate immune factors. All cells expressed PIBF mRNA; protein only in four (SRIK-NKL, U937, SRIK-B(T-PLL) and HL60) out of 10 cell lines tested. P increased and RU486 decreased PIBF in U937, SRIK-B(T-PLL) and SRIK-NKL. P upregulated TLR-4 in U937, and HNP1 – 3, LL-37, IRAK-2, and IRAK-4 in multiple lines and RU486 down regulated these. PIBF may be used by some leukemias to evade immune surveillance and is a potential therapeutic target. P may impact infection and autoimmunity via effects on LPS receptor, TLR signaling, and antimicrobial peptides.
Brandhagen, BreeAnn N., et al. “Cytostasis and morphological changes induced by mifepristone in human metastatic cancer cells involve cytoskeletal filamentous actin reorganization and impairment of cell adhesion dynamics.” BMC cancer 13.1 (2013): 35.
Cytostatic concentrations of mifepristone induced alterations in the cellular structure of a panel of aggressive, highly metastatic cancer cells of different tissues of origin. Such changes were associated with re-distribution of actin fibers that mainly form non-adhesive membrane ruffles, leading to dysregulated cellular adhesion capacity.
Progesterone Receptor Blocker for Uterine Fibroids
Ulipristal Acetate: a novel medical therapy for uterine fibroids
Vikram Sinai Talaulikar MD, MRCOG
Clinical Fellow in Reproductive Endocrinology and Assisted Reproduction, University College London Hospital, London, UK
Uterine fibroids – current management options and the need for an effective medical therapy
Platelets and Metastases
Nat Rev Cancer. 2011 Feb;11(2):123-34. doi: 10.1038/nrc3004.
Contribution of platelets to tumour metastasis.
Gay LJ1, Felding-Habermann B.
Extensive experimental evidence shows that platelets support tumour metastasis. The activation of platelets and the coagulation system have a crucial role in the progression of cancer. Within the circulatory system, platelets guard tumour cells from immune elimination and promote their arrest at the endothelium, supporting the establishment of secondary lesions. These contributions of platelets to tumour cell survival and spread suggest platelets as a new avenue for therapy.
Anti-Cancer Effect of Dipyridamole
dipyridamole daily orally (75 mg)
Dipyridamole 75 mg was administered orally three times daily during the FU administration.
Mantle Cell Lymphoma
Am J Clin Pathol. 2001 Apr;115(4):567-70.
Platelet satellitism as presenting finding in mantle cell lymphoma. A case report.
Cesca C1, Ben-Ezra J, Riley RS.
Platelet satellitism surrounding polymorphonuclear neutrophils has been observed almost exclusively in EDTA-treated blood at room temperature. The mechanism underlying this phenomenon is not understood fully. We report a case of platelet rosetting around atypical lymphocytes in peripheral blood smears made from EDTA-treated and untreated blood. Flow cytometry of the peripheral blood sample and immunohistochemical stains of the subsequent bone marrow biopsy specimen revealed a monoclonal B-cell population positive for CD5, CD20, and cyclin D1 and negative for CD3 and CD23; cytogenetic findings revealed a complex karyotype that included t(11;14). These findings were consistent with mantle cell lymphoma. To our knowledge, the finding of platelet satellitism involving mantle cell lymphoma cells in peripheral blood has not been reported previously.
20) Rhodes, E. L., et al. “Dipyridamole for treatment of melanoma.” The Lancet 325.8430 (1985): 693.
21) Spano, Daniela, et al. “Dipyridamole prevents triple-negative breast-cancer progression.” Clinical & experimental metastasis 30.1 (2013): 47-68.
Wang, Chunmei, et al. “Chemoprevention activity of dipyridamole in the MMTV-PyMT transgenic mouse model of breast cancer.” Cancer Prevention Research 6.5 (2013): 437-447. Cancer Prev Res (Phila).in PMC 2014 May 1.
Dipyridamole (DPM) is widely used to prevent strokes and vascular thrombosis. Combination therapy of DPM and antimetabolites has shown synergistic anticancer activity. This study investigated the chemopreventive effects of DPM in the mouse mammary tumor virus promoter driven polyoma middle T oncoprotein (MMTV-PyMT) metastatic breast cancer model. We also investigated the effects of DPM on gene and miRNA expression. Chemopreventive activity was assessed by comparing the time to onset of palpable lesions, primary tumor growth kinetics and the number of lung metastases in transgenic mice treated with DPM or vehicle. Gene expression and microRNA (miRNA) expression profiles of mammary tumor tissues were then analyzed using the Affymetrix GeneChip® or miRNA 2.0 arrays. Real-time quantitative PCR (qPCR) was used to confirm changes in gene expression. Treatment with DPM beginning at the age of four weeks delayed the onset of palpable lesions, delayed tumor progression and suppressed lung metastasis. Microarray gene expression analysis identified 253 genes differentially expressed between DPM-treated and control mammary tumors. miRNA expression analysis revealed that 53 miRNAs were altered by DPM treatment. The results indicate that DPM has chemoprevention activity against breast cancer tumorigenesis and metastasis in mice. The array analyses provide insights into potential mechanisms of DPM’s chemopreventive effects, involving upregulation of several genes and miRNAs known to suppress cancer growth and/or metastasis and downregulation of genes known to promote cancer. Some of these genes have not been previously studied in breast cancer and may serve as novel molecular targets for breast cancer chemoprevention.
Ge, Shu-Min, et al. “Reverse screening approach to identify potential anti-cancer targets of dipyridamole.” American journal of translational research 8.12 (2016): 5187.
Leblanc, Raphael, and Olivier Peyruchaud. “Metastasis: new functional implications of platelets and megakaryocytes.” Blood 128.1 (2016): 24-31.
Cancer Metastasis Rev. 2014 Mar; 33(1): 231–269.
Platelets and cancer: a casual or causal relationship: revisited
David G. Menter, Stephanie C. Tucker, Scott Kopetz, Anil K. Sood, John D. Crissman, and Kenneth V. Honn
Front Oncol. 2014; 4: 245. Published online 2014 Sep 11.
Involvement of Platelet–Tumor Cell Interaction in Immune Evasion. Potential Role of Podocalyxin-Like Protein 1. Laura Amo,1,† Estíbaliz Tamayo-Orbegozo,1,† Natalia Maruri,1 Cristina Eguizabal,2 Olatz Zenarruzabeitia,3 Marta Riñón,1 Arantza Arrieta,1 Silvia Santos,2 Jorge Monge,2 Miguel Angel Vesga,2 Francisco Borrego,3,4 and Susana Larrucea1,*
1Regulation of the Immune System Group, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain
[CANCER RESEARCH 59, 1295–1300, March 15, 1999]
Lysis of Tumor Cells by Natural Killer Cells in Mice Is Impeded by Platelets1
Bernhard Nieswandt, Michael Hafner, Bernd Echtenacher, and Daniela N. Ma ¨ nnel2
Department of Pathology, Tumor Immunology, University of Regensburg, 93042 Regensburg, Germany
Cimetidine Histamine receptor Blocker
28) Saxena, Satya P., et al. “Histamine is an intracellular messenger mediating platelet aggregation.” Science 243.4898 (1989): 1596-1600.
Inflamm Res. 1998 May;47(5):211-20.
The role of histamine in platelet aggregation by physiological and immunological stimuli.
Masini E1, Di Bello MG, Raspanti S, Ndisang JF, Baronti R, Cappugi P, Mannaioni PF.
Platelets participate in allergic and inflammatory processes beside their role in haemostasis and thrombosis. This paper reports the level, the uptake, the metabolism and the release of histamine in human platelets. The effects of exogenous histamine, as well as the receptor and signal transduction of these effects, are also described.
METHODS: Purified suspensions of platelets, prepared from healthy volunteers and from atopic patients, were exposed in vitro to physiological and immunological stimuli. Platelet aggregation was measured by the increase in light transmission; histamine content and release, as well as cytosolic free Ca2+ concentration, were measured fluorimetrically. Platelet histamine forming capacity, and the uptake of exogenous histamine, were measured with a radioisotopic method.
RESULTS: Human platelets contain 72.5 +/- 9.6pmoles of histamine x 10(9) platelets, and their capacity to form histamine is 18.7 +/- 3.5pmoles h(-1)g(-1) protein, which is reduced by alpha-fluoromethylhistidine (10(-5) M) a selective inhibitor of the specific histidine decarboxylase. Human platelets take up the preformed amine by a calcium and energy-dependent process, and the uptake of histamine is reduced by mepyramine, an H1-receptor antagonist, and N,N-diethyl-2-[4-(
CONCLUSIONS: The synergistic effect between histamine and other monoamines on platelet aggregation may explain some aspects of allergic vasculitis in which platelet aggregation is present.
Histamine and platelets
Science. 1989 Mar 24;243(4898):1596-9.
Histamine is an intracellular messenger mediating platelet aggregation.
Saxena SP1, Brandes LJ, Becker AB, Simons KJ, LaBella FS, Gerrard JM.
Author information Department of Pediatrics, University of Manitoba, Winnipeg, Canada.
Inhibition of human platelet aggregation by N,N-diethyl-2-[4-(
The results indicate a role for histamine as an intracellular messenger, which in platelets promotes aggregation.
Inflamm Allergy Drug Targets. 2010 Jul;9(3):146-57.
Histamine and histamine receptor antagonists in cancer biology.
Blaya B1, Nicolau-Galmés F, Jangi SM, Ortega-Martínez I, Alonso-Tejerina E, Burgos-Bretones J, Pérez-Yarza G, Asumendi A, Boyano MD.
Histamine has been demonstrated to be involved in cell proliferation, embryonic development, and tumour growth. These various biological effects are mediated through the activation of specific histamine receptors (H1, H2, H3, and H4) that differ in their tissue expression patterns and functions. Although many in vitro and in vivo studies of the modulatory roles of histamine in tumour development and metastasis have been reported, the effect of histamine in the progression of some types of tumours remains controversial; however, recent findings on the role of histamine in the immune system have shed new light on this question. This review focuses on the recent advances in understanding the roles of histamine and its receptors in tumour biology. We report our recent observations of the anti-tumoural effect of H1 histamine antagonists on experimental and human melanomas. We have found that in spite of exogenous histamine stimulated human melanoma cell proliferation, clonogenic ability and migration activity in a dose-dependent manner, the melanoma tumour growth was not modulated by in vivo histamine treatment. On the contrary, terfenadine-treatment in vitro induced melanoma cell death by apoptosis and in vivo terfenadine treatment significantly inhibited tumour growth in murine models. These observations increase our understanding of cancer biology and may inspire novel anticancer therapeutic strategies.
Semin Cancer Biol. 2000 Feb;10(1):15-23.
Histamine as an autocrine growth factor: an unusual role for a widespread mediator.
Rivera ES1, Cricco GP, Engel NI, Fitzsimons CP, Martín GA, Bergoc RM.
The involvement of histamine in cancer growth represents an old controversy and direct experimental evidence proving this hypothesis is not still available. In this paper we review the most relevant mechanisms referring to the role of histamine receptors, histidine decarboxylase and histamine release in the onset of an autocrine loop, that enables histamine to act as an autocrine growth factor. We postulate that this autocrine loop, that has been studied in an experimental mammary carcinoma model induced in rats, may be present in different human neoplasias. Therefore, the better understanding of this novel regulatory pathway that is controlled by histamine may contribute to identifying new therapeutic targets.
Agents Actions. 1994 Nov;43(1-2):17-20.
Histamine as an autocrine growth factor in experimental mammary carcinomas.
Cricco GP1, Davio CA, Martin G, Engel N, Fitzsimons CP, Bergoc RM, Rivera ES.
In order to determine the role of endogenous histamine in the regulation of cell growth, the in vitro action of fluoromethyl-histidine (MFMH) was studied in experimental mammary carcinomas induced in rats. Tumor cells were cultured in soft agar using the clonogenic agar technique. The MFMH was added in different concentrations (0.01-100 microM). The effect observed was a 60% inhibition on colony formation with a maximal effect at concentrations over 10 microM. This action was completely reverted by the H2 agonists dimaprit and arpromidine with an IC50 value of 1 microM. The action of the H2 agonists when added alone was a significant increase in cell proliferation (135%), while the H1 agonist produced a dose-dependent inhibition on cell growth. In these experimental carcinomas endogenous histamine is critical for cell proliferation and one of its major effects may be the stimulation of cell growth by acting on specific H2 membrane receptors.
Biochem Pharmacol. 1995 Jun 29;50(1):91-6.
H1 and H2 histamine receptors in N-nitroso-N-methylurea (NMU)-induced carcinomas with atypical coupling to signal transducers.
Davio CA1, Cricco GP, Bergoc RM, Rivera ES.
Two specific binding sites for histamine were characterized in the cell membrane of N-nitroso-N-methylurea (NMU)-induced tumors. The first one, with higher affinity (Kd = 4 +/- 2 nM), was further identified as an H2 type, while the lower affinity one (35 +/- 10 nM) corresponded to an H1 receptor. Histamine concentrations up to 50 nM, as well as H2 agonists, significantly enhanced the phosphoinositide turnover by acting through higher affinity H2 receptors. On the other hand, histamine at concentrations over 50 nM and H1 agonists produced a 100% increase in cAMP levels in a response specifically blocked by mepyramine. These H1 and H2 histamine receptors that exhibit different linkages to second messenger systems may prove to be a characteristic of cells with a high proliferating capacity, such as undifferentiated or transformed cells.
Br J Pharmacol. 2010 Oct; 161(4): 755–767.
Histamine receptors and cancer pharmacology
Vanina A Medina1,2 and Elena S Rivera1
PIBF and trophoblast invasiveness
37) J Reprod Immunol. 2011 Jun;90(1):50-7.
Progesterone-induced blocking factor (PIBF) and trophoblast invasiveness.
Miko E1, Halasz M, Jericevic-Mulac B, Wicherek L, Arck P, Arató G, Skret Magierlo J, Rukavina D, Szekeres-Bartho J.
Controlled trophoblast invasion is a key process during human placentation and a prerequisite for successful pregnancy. Progesterone is one of the factors to regulate trophoblast invasiveness. Progesterone-induced blocking factor (PIBF) is a progesterone-induced molecule expressed by the trophoblast, and also by tumors. The distribution of PIBF within the first-trimester decidua coincides with sites of trophoblast invasion. Another molecule that has been implicated in the control of trophoblast invasiveness is placental leptin. Leptin inhibits the secretion of progesterone by cytotrophoblast. The aim of this work was to investigate the possible interaction of PIBF and leptins in regulating trophoblast invasion. Paraffin-embedded sections from normal first-trimester placentae, partial moles, complete moles, and choriocarcinomas were reacted with PIBF, leptin, and leptin receptor specific antibodies. PIBF-deficient trophoblast cells were generated using siRNA and leptin receptor was detected on Western blot analysis. The lysates of PIBF-treated cells were used for detecting leptin expression in a protein array. PIBF was expressed in both normal first-trimester villous trophoblast and in partial mole. Compared with this, PIBF expression was markedly decreased in complete mole and absent in choriocarcinoma. Neither leptinR nor leptin were detected in partial mole, whereas both of these molecules were present in complete mole and choriocarcinoma. Leptin receptor expression was upregulated in PIBF-deficient cells, while leptin expression was decreased in PIBF-treated cells. These data suggest that PIBF affects the expression of leptin and its receptor, and that PIBF expression is inversely related to trophoblast invasiveness.
Jerome Check MD
38) Study of Oral Mifepristone as Salvage Therapy in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer Check, Jerome H., M.D., Ph.D.
Collaborator: Corcept Therapeutics
mifepristone 300 mg capsule per day, orally in 28-day cycles
39) Check, Jerome H., et al. “Efficacy of the progesterone receptor antagonist mifepristone for palliative therapy of patients with a variety of advanced cancer types.” Anticancer research 30.2 (2010): 623-628.
Mifepristone has been demonstrated to improve longevity and quality of life in mice with spontaneous murine cancer without progesterone receptors and in human colon cancer. The present study evaluated the palliative effect of mifepristone in a variety of different types of human cancer. Patients and Methods: Mifepristone was given at 200 mg daily orally with permission from the Food and Drug Administration to people with widely metastatic human cancer no longer responsive to other chemotherapy regimens. Results: Improvement in pain and energy and/or length of life was found in thymic epithelial cell carcinoma, transitional cell carcinoma of the renal pelvis, leiomyosarcoma, pancreatic carcinoma, malignant fibrous histiocytoma and another case of adenocarcinoma of the colon. Conclusion: Our data demonstrate a palliative role for the use of mifepristone in cancer therapy. Progesterone receptor antagonists should be given a therapeutic trial in larger controlled studies of various malignancies in humans.
All patients reported significant decrease in pain and improved energy within 2 weeks of starting the medication. No one reported any side-effects.
In the United States mifepristone is a restricted drug. It can only be used by licensed abortionists. One needs special permission from the Food and Drug Administration to use it off-label. Approval can only be obtained for cases where no known approved therapy exists or the patient has proven resistant at this time to standard therapy.
40) Check, Jerome H., et al. “Mifepristone may halt progression of extensively metastatic human adenocarcinoma of the colon-case report.” Anticancer research 29.5 (2009): 1611-1613.
41) Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent
Pan Pantziarka Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent Ecancermedicalscience. 2014; 8: 443
Paclitaxel – Microtuble Disrupting Chemotherapy Agent
42) Sevko A, et al. Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model. J Immunol . 2013;190(5):2464–71. doi: 10.4049/jimmunol.1202781.
Using here the ret transgenic murine melanoma model, which mimics human cutaneous melanoma, we tested effects of ultra-low non-cytotoxic dose paclitaxel on functions of myeloid-derived suppressor cells (MDSCs), chronic inflammatory mediators, and T cell activities in the tumor microenvironment in vivo. Administration of paclitaxel significantly decreased accumulation and immunosuppressive activities of tumor-infiltrating MDSCs without alterations of the bone marrow hematopoiesis. This was associated with the inhibition of p38 MAPK activity, TNF-α and production and S100A9 expression in MDSCs. The production of mediators of chronic inflammation in the tumor milieu was also diminished. Importantly, reduced tumor burden and increased animal survival upon paclitaxel application was mediated by the restoration of CD8 T cell effector (Killer T Cell) functions. We suggest that the ability of paclitaxel in non-cytotoxic dose to block the immunosuppressive potential of MDSCs in vivo represents a new therapeutic strategy to down-regulate immunosuppression and chronic inflammation in the tumor microenvironment for enhancing the efficacy of concomitant anti-cancer therapies.
Ipilumab Yervoy anti-CTLA-4 monoclonal antibody
43) Davids, Matthew S., et al. “Ipilimumab for patients with relapse after allogeneic transplantation.” New England Journal of Medicine 375.2 (2016): 143-153.
Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte–associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect.
Among 22 patients who received a dose of 10 mg per kilogram, 5 (23%) had a complete response, 2 (9%) had a partial response, and 6 (27%) had decreased tumor burden. Complete responses occurred in 4 patients with extramedullary acute myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into acute myeloid leukemia. Four patients had a durable response for more than 1 year. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood.
In summary, CTLA-4 blockade was a feasible approach for the treatment of patients with relapsed hematologic cancer after transplantation. Complete remissions with some durability were observed, even in patients with refractory myeloid cancers.
44) Clin Cancer Res. 2009 Oct 15;15(20):6446-53. .
Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma.
Ansell SM1, Hurvitz SA, Koenig PA, LaPlant BR, Kabat BF, Fernando D, Habermann TM, Inwards DJ, Verma M, Yamada R, Erlichman C, Lowy I, Timmerman JM.
Author information 1 Division of Hematology and Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
The growth of non-Hodgkin lymphomas can be influenced by tumor-immune system interactions. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of T-cell activation that serves to dampen antitumor immune responses. Blocking anti-CTLA-4 monoclonal antibodies improves host resistance to immunogenic tumors, and the anti-CTLA-4 antibody ipilimumab (MDX-010) has clinical activity against melanoma, prostate, and ovarian cancers.
We did a phase I trial of ipilimumab in patients with relapsed/refractory B-cell lymphoma to evaluate safety, immunologic activity, and potential clinical efficacy. Treatment consisted of ipilimumab at 3 mg/kg and then monthly at 1 mg/kg x 3 months (dose level 1), with subsequent escalation to 3 mg/kg monthly x 4 months (dose level 2).
Eighteen patients were treated, 12 at the lower dose level and 6 at the higher dose level. Ipilimumab was generally well tolerated, with common adverse events attributed to it, including diarrhea, headache, abdominal pain, anorexia, fatigue, neutropenia, and thrombocytopenia. Two patients had clinical responses; one patient with diffuse large B-cell lymphoma had an ongoing complete response (>31 months), and one with follicular lymphoma had a partial response lasting 19 months. In 5 of 16 cases tested (31%), T-cell proliferation to recall antigens was significantly increased (>2-fold) after ipilimumab therapy.
Blockade of CTLA-4 signaling with the use of ipilimumab is well tolerated at the doses used and has antitumor activity in patients with B-cell lymphoma. Further evaluation of ipilimumab alone or in combination with other agents in B-cell lymphoma patients is therefore warranted.
45) Rosenberg, Mark A., and Jason Williams. “Image guided cryoablation of cancer with intra-tumoral injection of anti-CTLA-4 and PD-1 immune check-point inhibitors.” Journal for immunotherapy of cancer 3.2 (2015): P142.
46) Yared, J. A., et al. “Major clinical response to nivolumab in relapsed/refractory Hodgkin lymphoma after allogeneic stem cell transplantation.” Bone marrow transplantation (2016).
47) Lesokhin, Alexander M., et al. “Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study.” Journal of Clinical Oncology 34.23 (2016): 2698-2704.
J Clin Oncol. 2016 Aug 10;34(23):2698-704. doi: 10.1200/JCO.2015.65.9789. Epub 2016 Jun 6.
Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study.
Lesokhin AM1, Ansell SM2, Armand P2, Scott EC2, Halwani A2, Gutierrez M2, Millenson MM2, Cohen AD2, Schuster SJ2, Lebovic D2, Dhodapkar M2, Avigan D2, Chapuy B2, Ligon AH2, Freeman GJ2, Rodig SJ2, Cattry D2, Zhu L2, Grosso JF2, Bradley Garelik MB2, Shipp MA2, Borrello I2, Timmerman J2.
Cancer cells can exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity. In part, this may occur through overexpression of PD-1 and PD-1 pathway ligands (PD-L1 and PD-L2) in the tumor microenvironment. PD-1 blockade has produced significant antitumor activity in solid tumors, and similar evidence has emerged in hematologic malignancies.
In this phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma, T-cell lymphoma, and multiple myeloma received the anti-PD-1 monoclonal antibody nivolumab at doses of 1 or 3 mg/kg every 2 weeks. This study aimed to evaluate the safety and efficacy of nivolumab and to assess PD-L1/PD-L2 locus integrity and protein expression.
Eighty-one patients were treated (follicular lymphoma, n = 10; diffuse large B-cell lymphoma, n = 11; other B-cell lymphomas, n = 10; mycosis fungoides, n = 13; peripheral T-cell lymphoma, n = 5; other T-cell lymphomas, n = 5; multiple myeloma, n = 27). Patients had received a median of three (range, one to 12) prior systemic treatments. Drug-related adverse events occurred in 51 (63%) patients, and most were grade 1 or 2. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma, diffuse large B-cell lymphoma, mycosis fungoides, and peripheral T-cell lymphoma, respectively. Median time of follow-up observation was 66.6 weeks (range, 1.6 to 132.0+ weeks). Durations of response in individual patients ranged from 6.0 to 81.6+ weeks.
Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.
48) McDuffee, E., et al. “Tumor regression concomitant with steroid-refractory GvHD highlights the pitfalls of PD-1 blockade following allogeneic hematopoietic stem cell transplantation.” Bone marrow transplantation (2017).
For Hodgkin lymphoma (HL) patients who fail front-line therapy, salvage regimens including autologous and allogeneic hematopoietic stem cell transplant (alloHSCT) may cure select patients, although relapse remains a significant cause of transplant failure. Treatment strategies aimed at bolstering post-transplant immunity to both prevent and treat relapse following alloHSCT are of significant interest, especially immune checkpoint inhibitors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) monoclonal Abs.
49) Haverkos, Bradley M., et al. “PD-1 blockade for relapsed lymphoma post allogeneic hematopoietic cell transplant: high response rate but frequent GVHD.” Blood (2017): blood-2017.
PD-1 blockade in relapsed cHL allo-HCT patients appears to be highly efficacious but frequently complicated by rapid onset of severe and treatment refractory GVHD. PD-1
50) Hude, Ida, et al. “The emerging role of immune checkpoint inhibition in malignant lymphoma.” haematologica 102.1 (2017): 30-42.
To evade elimination by the host immune system, tumor cells commonly exploit physiological immune checkpoint pathways, restraining efficient anti-tumor immune cell function. Growing understanding of the complex dialog between tumor cells and their microenvironment contributed to the development of immune checkpoint inhibitors. This innovative strategy has demonstrated paradigm-shifting clinical activity in various malignancies. Antibodies targeting programmed death 1 and cytotoxic T-lymphocyte-associated protein-4 are also being investigated in lymphoid malignancies with varying levels of activity and a favorable toxicity profile. To date, evaluated only in the setting of relapsed or refractory disease, anti-programmed death 1 antibodies such as nivolumab and pembrolizumab show encouraging response rates particularly in classical Hodgkin lymphoma but also in follicular lymphoma and diffuse-large B-cell lymphoma. As the first immune checkpoint inhibitor in lymphoma, nivolumab was approved for the treatment of relapsed or refractory classical Hodgkin lymphoma by the Food and Drug Administration in May 2016. In this review, we assess the role of the pathways involved and potential rationale of checkpoint inhibition in various lymphoid malignancies. In addition to data from current clinical trials, immune-related side effects, potential limitations and future perspectives including promising combinatory approaches with immune checkpoint inhibition are discussed.
51) Int. J. Mol. Sci. 2017, 18(1), 48; doi:10.3390/ijms18010048
Review Bispecific Antibodies as a Development Platform for New Concepts and Treatment Strategies
Fa Yang 1, Weihong Wen 2,* and Weijun Qin 1,*1
Department of Urology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi’an 710032, China2
Department of Immunology, Fourth Military Medical University, 169 Changle West Road, Xi’an 710032, China
The single-chain-based bispecific antibodies usually bridge tumor cells with immune cells and form an immunological synapse because of their relatively small size.
52) Andrea S. Blevins Primeau, PhD, MBA June 27, 2017
In Focus: Blinatumomab for Non-Hodgkin Lymphoma
Jeffrey Barnes, MD, PhD, of the Center for Lymphoma at Massachusetts General Hospital Cancer Center in Boston,
Barnes Jeffrey A MD
Internist in Boston, Massachusetts
Address: 55 Fruit St # 148, Boston, MA 02114
Phone: (617) 724-4000
Mechanism of Action: Blinatumomab is a bispecific T cell engager (BiTE) antibody construct that binds to both CD3 on T cells and CD19 on B cells by 2 linked single-chain variable antibody fragments. T cells and B cells are brought together, allowing T cells to recognize and target malignant B cells, resulting in tumor cell apoptosis.
CD19 is expressed by malignant B cells and all developmental stages of B cells, except plasma cells and pluripotent stem cells of the bone marrow.
“BiTEs have an advantage over other T cell technologies, including chimeric antigen receptor T [CAR-T] cell programs in that they are ready right off the shelf for use, with no delay in initiating therapy,” Dr Barnes said. He noted that they have similar toxicities, but that BiTEs “can be discontinued where, currently, CAR T cells do not have an ‘off switch.’”
Blinatumomab is administered as a continuous infusion via an ambulatory pump for 4 to 8 weeks. “The drug is stable for only 48 hours requiring bag changes every 2 days…this has, however, been shown in previous phase 1 studies to be well-tolerated in the outpatient setting,” Dr Barnes said.
By The ASCO Post Posted: 12/3/2014 The U.S. Food and Drug Administration (FDA) today granted accelerated approval to blinatumomab (Blincyto) for the treatment of patients with Philadelphia chromosome–negative, relapsed or refractory precursor B-cell acute lymphoblastic leukemia (B-cell ALL). Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that activates endogenous T cells when bound to the CD19-expressing target cell.
54) Ther Adv Hematol. 2016 Jun; 7(3): 142–156.
Published online 2016 Apr 4. The role of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukemia
Jonathan E. Benjamin and Anthony S. Stein
Blinatumomab in Treating Patients with Relapsed or Refractory Non-Hodgkin Lymphoma
Trial Lead Organizations / Sponsors / Collaborators
Dana-Farber Harvard Cancer Center National Cancer Institute
Jeffrey A. Barnes, Principal Investigator
55) Expert Opin Investig Drugs. 2015 May;24(5):715-24. doi: 10.1517/13543784.2015.1021415. Epub 2015 Mar 4.
Blinatumomab for the treatment of B-cell lymphoma.
Oak E1, Bartlett NL.
Blinatumomab is a bispecific T-cell engager (BiTE) molecule that recruits cytotoxic T cells to target tumor B cells by linking the CD3 and CD19 antigens. Among the various formats of bispecific antibodies developed in the past 50 years, the BiTE class is remarkable for its low effector-to-target ratio, high tissue penetration and singular ability to activate T cells independent of MHC class I presentation or costimulation. Blinatumomab has been studied in patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL) and B-precursor acute lymphoblastic leukemia (B-ALL).
AREAS COVERED: This article reviews the current literature on blinatumomab including its pharmacology, preclinical findings, clinical trials in B-cell NHL and, to a lesser extent, Phase II studies in B-ALL. The authors discuss the potential future directions in light of other new competing therapies for NHL and unmet clinical needs in the market.
EXPERT OPINION: The recent approval of blinatumomab for B-ALL symbolizes a breakthrough for BiTE technology with prospective application in the targeted therapy of other cancers. Although blinatumomab seems an unlikely option for treating indolent lymphoma due to toxicity, the need for long-term continuous infusion therapy and multiple promising well-tolerated oral agents, it holds promise for aggressive NHL patients whose diseases are refractory to current standard approaches. Larger trials are needed to demonstrate blinatumomab’s curative potential in aggressive histologies.
56) Ku, Matthew, Geoff Chong, and Eliza A. Hawkes. “Tumour cell surface antigen targeted therapies in B-cell lymphomas: Beyond rituximab.” Blood reviews 31.1 (2017): 23-35.
Recent proliferation of novel targeted therapies in lymphoma has been substantial. B-cell receptor pathway inhibitors and immune checkpoint inhibitors have been a major focus, however significant advances in monoclonal antibodies (MoAbs) which directly target malignant cells have also occurred. These MoAbs continue to make significant impact in lymphoma management. Novel dosing schedules of anti-CD20 MoAb rituximab potentially optimise efficacy in specific lymphoma subgroups, as certain populations may be receiving suboptimal doses using current schedules. Next-generation anti-CD20 MoAbs may surpass rituximab in terms of efficacy. MoAbs targeting other B-cell surface antigens and antibody-drug conjugates (ADCs) have yielded promising data. Bispecific antibodies that can recruit T-lymphocytes to lymphoma cells have also shown efficacy. To further improve outcomes for patients with lymphoma using MoAbs, scrupulous trial design incorporating translational research, and synergistic drug combinations will be required. This review discusses the mechanisms of action, current data and future directions involving MoAbs.
57) Cambridge Healthtech Institute’s Third Annual
Engineering Next-Generation Cancer Immunotherapies
New Science and Technologies for Protein Engineers and Discovery Scientists to Support Development of Novel Immunotherapeutics and Treatment Combinations January 9-10, 2017 | Hilton San Diego Bayfront | San Diego, CA (Next meeting Jan 2018 San Fran)
Mechanisms of Action for the Application of BiTE Antibodies in Immunotherapy Combinations. Tara Arvedson, Ph.D., Director, Oncology Research, Amgen
Recent clinical data have demonstrated the potency and significance of T-cells in anti-tumor activity. For example, the CD19/CD3 bispecific T-cell engager (BiTE®) blinatumomab is now a proven means of harnessing T-cells for the treatment of cancer, and a CD33/CD3 BiTE is currently in clinical development.
Bispecific Antibodies for T-Cell Redirection and Dual Checkpoint Blockade, John Desjarlais, Ph.D., CSO, Xencor
We have optimized a plug-and-play, Fc-containing bispecific antibody platform with high stability, efficient production, and antibody-like pharmacokinetics. This optimized bispecific format resembles a standard monoclonal antibody, with one of the Fab arms replaced by a stability-optimized single-chain Fv (scFv) (scFv-Fab-Fc). We will present application of the platform to create a pipeline of CD3 bispecifics for T-cell redirection, and dual checkpoint blockade bispecifics for T-cell activation.
Combination Therapy of CAR T-Cells and Checkpoint Blockade
Prasad S. Adusumilli, M.D., FACS, Deputy Chief, Thoracic Service, Memorial Sloan Kettering Cancer Center
Adaptive resistance developed by the solid tumors following immune attack poses a hurdle for achieving durable responses by both CAR T-cell therapy and checkpoint blockade. We have shown that the effector function of CAR T-cells was restored through PD-1 antibody checkpoint blockade or with cell-intrinsic PD-1 blockade mediated by shRNAs or a dominant negative receptor. These findings provide a translatable strategy for combining CAR therapy and PD-1/PD-L1 blockade.
Bi-Directional Antibodies (BITE)
58) Lenalidomide and Blinatumomab in Treating Patients With Relapsed Non-Hodgkin Lymphoma
National Cancer Institute (NCI)- Principal Investigator: Joseph Tuscano City of Hope Comprehensive Cancer Center LAO
Smilow Cancer Center/Yale-New Haven Hospital Recruiting
New Haven, Connecticut, United States, 06510
Contact: Gottfried von Keudell 203-785-5702
Principal Investigator: Gottfried von Keudell MF/PhD
Yale University Recruiting
New Haven, Connecticut, United States, 06520
Contact: Gottfried von Keudell 203-785-5702
Principal Investigator: Gottfried von Keudell
59) Blinatumomab Nears 70% Response Rate in Non-Hodgkin Lymphoma
Jason M. Broderick Published Online: Thursday, Feb 18, 2016
Blinatumomab Nears 70% Response Rate in Non-Hodgkin Lymphoma Jason M. Broderick @jasoncology Published Online: Thursday, Feb 18, 2016
phase I study published in the Journal of Clinical Oncology.
24 patients with mantle cell lymphoma (MCL)
60) Goebeler, Maria-Elisabeth, et al. “Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: final results from a phase I study.” Journal of Clinical Oncology 34.10 (2016): 1104-1111.BiTE blinatumomab for relapsed non-Hodgkin lymphoma phase I J Clin Onc 2016
61) Viardot, Andreas, et al. “Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma.” Blood 127.11 (2016): 1410-1416.
62) Lancet Oncol. 2015 Jun;16(6):704-15. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.
Palanca-Wessels MC1, Czuczman M2, Salles G3, Assouline S4, Sehn LH5, Flinn I6, Patel MR7, Sangha R8, Hagenbeek A9, Advani R10, Tilly H11, Casasnovas O12, Press OW13, Yalamanchili S14, Kahn R14, Dere RC14, Lu D14, Jones S14, Jones C14, Chu YW14, Morschhauser F15.
Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL).
In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549.
Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL.
Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL.
Few patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) achieve prolonged disease-free survival. Blinatumomab, a bispecific T-cell engaging antibody construct, transiently links CD3-positive T cells to CD19-positive B cells. This phase 2 study evaluated stepwise (9-28-112 μg/d with weekly dose increases; n = 23) or flat (112 μg/d; n = 2) dosing of blinatumomab by continuous infusion, with dexamethasone prophylaxis, in patients with relapsed/refractory DLBCL. Patients received a median of 3 prior lines of therapy. Median time since last regimen was 1.5 months. Seventeen patients ended treatment in cycle 1 (induction), 7 in cycle 2 (consolidation), and 1 in retreatment. Among 21 evaluable patients, the overall response rate after 1 blinatumomab cycle was 43%, including complete responses (CRs) in 19%. Three patients had late CR in follow-up without other treatment. The most common adverse events with stepwise dosing were tremor (48%), pyrexia (44%), fatigue (26%), and edema (26%). Grade 3 neurologic events with stepwise dosing were encephalopathy and aphasia (each 9%) and tremor, speech disorder, dizziness, somnolence, and disorientation (each 4%). Of 5 (22%) patients who discontinued stepwise dosing because of adverse events, 4 (17%) had neurologic events. Most neurologic events resolved. The flat-dose cohort was stopped because of grade 3 neurologic events in both patients. Blinatumomab monotherapy appears effective in patients with relapsed/refractory DLBCL, a heavily pretreated patient population with a high unmet medical need. Further studies need to define the optimal approach to achieve the target dose without early dropout. The study was registered at www.clinicaltrials.gov as #NCT01741792.
ADCT-402 B cell lymphoma
63) Video on You Tube- Brad S. Kahl, MD, professor, Department of Medicine, Oncology Division, Washington University School of Medicine, discusses ADCT-402 for patients with relapsed/refractory B-cell lineage non-Hodgkin lymphoma.
64) A Phase 1 Dose-escalation Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and Antitumor Activity of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL)
This study evaluates ADCT-402 in patients with Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL). Patients will participate in a dose-escalation phase (Part 1) and dose expansion (Part 2). In Part 2, patients will receive the dose level identified in Part 1.
Study ADCT-402-101 is the first clinical study with ADCT-402 in patients with B-cell non-Hodgkin Lymphoma (NHL).
antibody-drug conjugates (ADCs)
ADCT-402 is an antibody drug conjugate (ADC) composed of a humanized antibody directed against human cluster of differentiation 19 (CD19), stochastically conjugated via a valine-alanine cleavable, maleimide linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin.
Columbia University Medical Center Herbert Irving Pavilion Recruiting
New York, New York, United States, 10032
Principal Investigator: Owen O’Connor, M.D., PhD.
Tremendous advances have been made in the treatment of non-Hodgkin Lymphoma in the past 20 years. However, a significant portion of the patient population still fail to respond to currently available therapies. Having seen the effects of other ADCs in various tumour types in recent years, we eagerly anticipate the results of this study,” explained Owen O’Connor, MD, Principal Investigator for the study and Professor of Medicine and Experimental Therapeutics, and the Director of the Center for Lymphoid Malignancies at the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center,
By The ASCO Post 6/21/2017 Key Points:
The overall response rate with doses ≥ 120 µg/kg was 61% in the total patient population (42% complete response, 19% partial response).
In patients with relapsing or refractory diffuse large B-cell lymphoma, the overall response rate was 57% (43% complete response, 14% partial response). ADCT-402 treatment has been reasonably well-tolerated, with the most common emergent adverse events being fatigue, neutropenia, and thrombocytopenia.
About ADC Therapeutics
Founded in 2012, ADC Therapeutics SA (ADCT) is an oncology drug development company that specializes in the development of proprietary antibody drug conjugates (ADCs) targeting major types of hematological malignancies and solid tumors. The Company’s ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with a novel class of highly potent pyrrolobenzodiazepine (PBD) based warheads via a chemical linker. Its three lead programs, ADCT-301, ADCT-402, and ADCT-502 are in five Phase I clinical trials in the USA and in Europe. ADCT enjoys strong relationships with world class partners, including AstraZeneca and its global biologics research and development arm, MedImmune.
pyrrolobenzodiazepine (PBD) dimer toxin
67) Zammarchi, Francesca, et al. “Pre-clinical development of Adct-402, a novel pyrrolobenzodiazepine (PBD)-based antibody drug conjugate (ADC) targeting CD19-expressing B-cell malignancies.” (2015): 1564-1564.
68) Mantaj, Julia, et al. “From Anthramycin to Pyrrolobenzodiazepine (PBD)‐Containing Antibody–Drug Conjugates (ADCs).” Angewandte Chemie International Edition (2016).
69) POSTER pdf
A phase 1 dose-escalation study to evaluate the tolerability, safety, pharmacokinetics, and antitumor activity of ADCT-402 in patients with relapsed or refractory B-cell lineage non-Hodgkin lymphoma (B-NHL) Owen A. O’Connor. ASCO Annual Meeting, Chicago, Illinois, USA, June 3–7th 2016 . Part 1 Dose escalation 1 hour intravenous infusion (15–300 μg/kg) on Day 1 every 3 weeks* ADCT-402 B-cell non-Hodgkin lymphoma B-NHL Poster 2016 ASCO Owen A OConnor
70) Grandad battling deadly cancer trials new drug – and the results are astonishing- Michael Prestidge – who suffers from an aggressive form of non-Hodgkin Lymphoma – has seen his tumours shrink dramatically in just five weeks By Katherine Bainbridge 20:40, 3 JUL 2017
link to this article: http://wp.me/p3gFbV-58n
Jeffrey Dach MD
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