Genomic challenge of human immunity

Human genome determines who we are in terms of species difference, although other vertibrate species such as mice, contain up to 99% of gene counterparts. One can argue that only 1% is needed to make such big difference. I don’t want to disagree.

What I really want to say is that our genome may also determine how our immune system works. It should not sound inconsistent with what I just said above. It’s been proven that our immunity can be compromised due to certain mutations that may be inheritable. PIK3CD varients caused immunodeficiency in patients is a good example. No one would deny the association between human genomic stability and human immunity efficiency. However, many would raise doubts that our genomic mutations are the sole factor for disruption or failure of our immunity against certain diseases.  I’d rather say that mutational changes in human genome are critical for causing our immunity compromise. There are more or less 20,000 protein coding genes and several thousand non-coding RNA genes in our genome. Yet we by far know very little about the biological functions of most of them.  We need a lot more research to provide scientific evidence as proof that the versatile capability of human immunity is largely determined by human genomic stability.

Dr. Gene Grantsman

SYK pairs with FLT3 to promote progression for AML disease

This year, approximately 14,600 Americans are expected to receive a diagnosis of AML. The cancer cells of some 20% of adult patients and 15% of pediatric patients harbor a genomic alteration called FLT3-ITD, in which segments of the FLT3 enzyme are duplicated and making the enzyme overactive.

A new findings which make me exciting were published in Cancer Cell  (2014; doi:10.1016/j.ccr.2014.01.022). The study raises hopes that treatment strategies could help bring molecularly targeted treatments to AML. In this paper, researchers report that a normal enzyme called SYK pairs with FLT3, to promote progression of the disease. This molecular partnership also promotes the resistance of AML cells to treatment with FLT3-blocking drugs. In an animal model of AML, treatment with a combination of FLT3- and SYK-inhibiting drugs were significantly more effective than treatment with either drug alone.

Through experiments in cell lines, the research team found that the interaction of SYK and FLT3-ITD is a key ingredient in the progression of myeloproliferative disorder into AML, and give patients a new hope for the disease.

Dr. Gene Grantsman

Gleevec makes a good marketing strategy

Imatinib, with a trade name “Gleevec”, is originally developed by Novartis. The drug was approved to the U.S.A. to treat Philadelphia chromosome-positive chronic myeloid leukemia (CML). Before imatinib was developed, average survival time of CML patients used to be 3 to 6 years. With much less side effects, imatinib is significantly safer than interferon, and became a first-line drug in CML treatment.

In 2002, imatinib gained accelerated approval from FDA to be the first-line drug in advanced or metastatic gastrointestinal stromal tumors (GIST) treatment. Imatinib acquired its first indication approval in 2001 and has since then acquired 10 indication approvals.

As an orphan drug approved to the market, imatinib becomes a blockbuster drug mainly due to the successful marketing strategy. As a specific drug to treat rare diseases (CML and GIST), Gleevec makes a marketing strategy to launch drug donation charity program. The program allows patients to take the drug for free after the donation so as to increase patients’ dependence on the drug. This strategy has not only solved patients’ problems but also brought excellent reputation for Gleevec, and making its global sales revenue surge. I hope more drugs could give patients a opportunity for treatment under this marketing strategy, especially in developing country.

Dr. Gene Grantsman

The trials of new drug for Down syndrome

Down syndrome is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. This syndrome is typically associated with  physical growth  delays, characteristic  facial features  and moderate  intellectual  disability.  In the last 5 years, the trials of new drugs were conducted to improve cognitive symptoms of Down syndrome.

Last week, I have read a paper concern the Down syndrome study which was published by Roche scientists. In this study, By blocking the chemical GABA in key regions of the brain, they were able to trigger major cognitive and behavioral improvements. Now, Roche is preparing for a human study to see if one of their GABA inhibitors can improve the IQ of young people with Down syndrome.

RG1662, a Phase II trial investigating experimental medicine, is a highly selective GABA-A a5 Negative Allosteric Modulator in individuals with Down syndrome. The trial will recruit individuals with Down syndrome across 10 countries. The ultimate goal is to enable individuals with Down syndrome live a more independent life.

The research in this field is still clearly at a very early stage, a stage with extraordinarily high risk and frequent failures. But in my view, new discoveries about how the brain works could one day lead to some revolutionary therapies for a disease, and the work could have implications for autism as well.

Dr. Gene Grantsman

A promising thinking for challenge our own immune system.

I read a good review about mammalian immunity selection authored by Dr. Owen M. Siggs from Cambridge.  He talked about the relationship between mutations and mammalian immune system. He highlighted in his article that not only are mutations the cause of creation of human immune system, it also can compromise and even diminish its defensive capability.

I totally agree with him on this. Our immune system is such a complex but fragile system. In the thousands of years of human history, we have survived a number of deadly infectious diseases.  Yet we still have no answers to HIV, hepatitis and etc.  I always wonder our immune defense mechanism proactively adjusts to variable attacks or negatively respond to them.

Good thing is that we at least have developed many great research tools to study our immune system. Our entire genome has been decoded. The sequences of each gene can be modified in any way of our desire to study the function of it. Dr. Siggs mentioned CRISPR/Cas9 mutagenesis technology as the most versatile mutagenesis platform to reveal gene function. We can challenge our own immune system by proactively mutating any gene we like. This is not just “some wishful thinking” any more, this is reality.  I can anticipate much more fascinating scientific progress that will be achieved to answer my question. Well, hopefully.

Dr. Gene Grantsman

BioLineRx’s investigational therapy BL-8040 for CML.

Chronic myeloid leukemia(CML) is characterized by production of too many white blood cells. Imatinib mesylate (Gleevec), a tyrosine kinase inhibitor, was used as the treatment for chronic myeloid leukemia. But some patients have dormant leukemic stem cells that are resistant to tyrosine kinase inhibitors, and need for new drugs to target these stem cells.

BioLineRx currently is studying the investigational drug in Phase II clinical trials for acute myeloid leukemia and hopes to begin Phase I trials for BL-8040 for stem cell mobilization in the second quarter of this year. BioLineRx has unveiled positive preclinical data for its experimental treatment for chronic myeloid leukemia. The results were published in Molecular Cancer Therapeutics and found that BioLineRx’s investigational therapy BL-8040 was effective on its own and in combination with imatinib at inhibiting human chronic myeloid leukemia cells. According to the findings, BL-8040 treatment induced programmed cell death of tumor cells in vitro and had a synergistic effect with imatinib. When combined with low-dose imatinib in mice engrafted with chronic myeloid leukemia tumors, BL-8040 significantly inhibited tumor growth. CXCR4 is overexpressed in more than 70% of human cancers and is often associated with disease severity.  BL-8040 acts as an antagonist for CXCR4, a chemokine receptor directly involved in tumor progression, growth of new blood vessels in the tumor, metastasis and cell survival. I hope that BL-8040 may give us a new opportunity for the treatment of CML.

Dr. Gene Grantsman

NewLink’s new vaccine in interim analysis.

    Currently, I have read some news about  immunotherapy for Pancreatic cancer,   which is a lethal disease and remains one of the most resistant cancers to traditional therapies.

    Algenpantucel-L is a pancreatic cancer vaccine and this immunotherapy is now in the midst of a Phase III study from NewLink Genetics. The company initiated a Phase-I/-II study  in November 2005.  Phase-II trial  evaluated the use of algenpantucel-L in combination with chemotherapy and chemoradiotherapy in pancreatic cancer patients in December 2007.

    Two weeks ago, the company’s independent data monitoring committee looked over the results under standard procedure for clinical trials. The committee found neither alarming safety issues nor exhilarating efficacy numbers from the trials. The group recommended NewLink stick to the script until the next planned interim analysis.

    The interim analysis does not mean the breaking down for the Phase III trial. Late-stage cancer vaccine trials from biotech companies had a very low success rate. Oncothyreon and Keryx all conducted phase III studies of cancer drugs that took longer than expected to reach the predefined time point for analysis, and all eventually failed in the clinic. As Chief Medical Officer Nicholas Vahanian from NewLink said, they will continue the study and to gathering additional data to provide improved treatment for patients. If it is possible, NewLink’s vaccine will be the first example of a successful and delayed cancer drug trial. I hope so.

    Dr. Gene Grantsman

Don’t underestimate food allergy and pay attention to your food.

Food allergy actually is not a small deal at all given how seriously it can turn into some fatal illness. Everyone may have food allergy at certain degree although the clinically proven cases are 5% for children and 4% for adults.

Food allergy involves two features of the human immune response. One is the release of immunoglobulin (IgE) and the other is the activation of mast cells. IgE is commonly known as antibodies that float through blood.  When allergen food is in-taken and digested, the specific IgE against this food is produced and released. It will then interact with mast cells to stimulate the release of certain chemicals such as histamine.  These chemicals will in turn cause food allergy symptoms, like itching and abdominal pain.  Certain severe cases could be breathing difficulties, diarrhea or even fever.

The entire process is complex in term of physiological and immunological interpretation.  What I just want to point out is that “Don’t  underestimate food allergy and pay attention to your food”. The common food allergies include:  peanuts, tree nuts such as walnuts , shellfish such as  shrimp, crab, and lobster, milk and eggs.  Please pay more attention to kid’s diet because their allergy pattern is somewhat different.

Dr. Gene Grantsman

A potential therapeutic solution to EoE.

Human health always deserves attention. I, as a research scientist specialized in immunological therapy, feel like sharing some of my readings with each one of you. I just hope it will be helpful in some way.
I read an article the other day about Eosinophilicesophagitis (EoE). It’s a chronic inflammatory disease that can be caused by food allergy. Many patients suffer form pain and have to rely on restricted diet. A research group from University of Cincinnati have published their exciting research progress, which suggests that a special type of immune cells called invariant natural killer T-cell (iNKTcells ) may be responsible for causing EoE. Their specific scientific approaches demonstrated that iNKT cells may induce EoE in mice, which is the most common animal model for this type of research. By neutralizing iNKTcells with specifically designed antibodies in the bodies of these mice, the chances of EoE occurrence can be lowered significantly in accordance with scientific measure. I know this is just some experimental conclusion which still needs more research to confirm their claimed scientific findings. What I am excited about this is that their hard work has offered a potential therapeutic solution to EoE, which is to neutralize iNKT cells in EoE patients.
Human immune system is probably the most complicated system ever created in this planet. Targeting this special group of iNKT cells without affecting the rest of the system can minimize any adverse effect on EoE patients. So it sounds like a promising option so far.

Dr. Gene Grantsman

Immunological Medicine Blog

Dr. Gene Grantsman’s blog is covering immunological medicine, human disease and clinical trials. Her goal is to provide news in immunological therapeutic solution and innovation, medical immunology and related research areas, as well as to share her professional opinions in biomedical science .