Category Archives: Uncategorized

Bispecific Antibodies for Cancer Treatment

Bispecific antibodies are bioengineered proteins that can simultaneously bind to two different types of antigen (such as found on cancer cells). Bispecific antibodies appear to be destined to play an important role in immunotherapy-based cancer therapy together with checkpoint inhibitors, CAR-T cell therapy, and other types of immunotherapy. Cancer immunotherapy improves the functioning of the immune system to better seek out and destroy cancer cells. Research has uncovered ways to modify immune cells in ways to improve their functioning.

Bispecific antibodies have an advantage over other immunotherapies since they can bring cancer cells and immune cells in closer proximity, allowing immune cells greater opportunity to kill cancer cells. Bispecific antibodies can bind to antigens that are expressed relatively weakly, making them more toxic to cancer cells than other immunotherapies. Also, bispecific antibodies can be mass produced in advance, while CAR-T cells, for example, must be prepared for each cancer patient.

The basic structure of all antibody molecules consists of four protein chains shaped like a capital letter Y. Two chains are longer and are designated “heavy,” while the other two chains are shorter and designated “light.”  Antigen-binding sites are located on the outward tips of the four protein chains. Different regions of the antibody, designated “Fc” and “Fab,” can also serve as binding sites. These regions have significance in the development of bispecific antibodies.

Public Domain (work of the US Government-May 6, 2007)

The bispecific antibody, blinatumomab, was approved by the FDA in 2017 for the treatment of acute lymphoblastic anemia. Another bispecific antibody, catumaxomab, has orphan drug status from the FDA for gastric and ovarian cancers. However, this drug is no longer produced by the manufacturer. Clinical trials are currently underway, studying over fifty bispecific antibodies for various malignancies.

References

  1. Clift,I, “Bispecific, Multispecific Antibodies Grapple with Cancer,” Genetic Engineering & Biotechnology News. Feb. 7, 2019. https://www.genengnews.com/insights/bispecific-multispecific-antibodies-grapple-with-cancer/
  2. Jenks, Susan. “Bispecific Antibodies in Cancer.” Cancer Therapy Advisor. Aug. 22,2018. https://www.cancertherapyadvisor.com/home/cancer-topics/general-oncology/bispecific-antibodies-in-cancer/
  3. Kaiser, Jocelyn. “Designer antibodies fight cancer by tethering immune cells to tumor cells.” Science. May 28, 2020. https://www.sciencemag.org/news/2020/05/designer-antibodies-fight-cancer-tethering-immune-cells-tumor-cells
  4. Runcie, K., et al. “Bi-specific and tri-specific antibodies- the next big thing in solid tumor therapeutics.” Molecular Medicine. (2018) 24:50 https://pubmed.ncbi.nlm.nih.gov/30249178/
  5. “Bispecific monoclonal antibody.” https://en.wikipedia.org/wiki/Bispecific_monoclonal_antibody

 

CRISPR Illustration

Using CRISPR in cancer research and treatment

CRISPR is a gene editing tool that works by precisely removing short segments of DNA from genes. CRISPR technology has attracted interest from the cancer research community since cancer is a genetic disease.

CRISPR consists of two components: an RNA targeting device called guide RNA, and an enzyme, commonly Cas9. The precise location of the problematic DNA sequence of a gene is determined. The guide RNA is complementary in sequence to a target DNA of a gene and binds to it.  Cas9 then cuts the DNA at this location. This process is known as “knock-out” or removal of a gene. The cell’s normal DNA repair mechanism fixes the cut by joining the two cut sections of DNA. It is also possible to “knock-in” or insert a gene between the two DNA segments.

CRISPR has been used in studies to improve immunotherapy, harnessing the body’s defense mechanism to treat cancer. In particular, CRISPR has been shown to enhance the effectiveness of CAR-T therapy. T cells are an essential component of the immune system and can interact with cancer cells through receptors. Cancer cells can develop the ability to activate or disable receptors resulting in a loss of immune function.

Studies have been conducted using CRISPR to disable CTLA-4, PD-1, and other receptors that inhibit immune function. Although CRISPR could theoretically be used to “knock-in” genes that could activate receptors to attack cancer cells, this approach has been more challenging.

References

  1. Liu, J. et al. “ Building Potent Chimeric Antigen Receptor T Cells With CRISPR Genome Editing.” Frontiers in Immunology. March 19, 2019. https://www.frontiersin.org/articles/10.3389/fimmu.2019.00456/full
  2. National Cancer Institute. “How CRISPR Is Changing Cancer Research and Treatment.” July 27, 2020. https://www.cancer.gov/news-events/cancer-currents-blog/2020/crispr-cancer-research-treatment?cid=eb_govdel
  3. Stadtmauer, E., et al. “CRISPR-engineered T cells in patients with refractory cancer.” Science 367, 1001 (2020). https://science.sciencemag.org/content/sci/367/6481/eaba7365.full.pdf

Targeting cancer’s master regulators

Cancer is caused by genetic mutations. Although targeted therapy seeks to control cancer by targeting the proteins created by the genes, the vast number of mutated genes present in cancers could necessitate the development of thousands of drugs to effectively control all cancers.

Andrea Califano, a systems biologist at Columbia University has developed a new approach to the problem of cancer gene mutations. Drawing on his computer training, Andrea developed an algorithm to analyze the vast malfunctioning cancer gene networks. He was then able to identify specific transcription factors that act as bottlenecks in the cancer gene networks. Califano has called transcription factors as “master regulators.” Transcription factors are proteins that bind to DNA to activate transcription to proteins (aberrant proteins in the case of cancers). Targeting these transcription factors can minimize the number of drugs necessary to treat cancer.

Transcription factors have had the reputation of being hard to target and therefore undruggable, but recent advances have changed the situation. Califano, through his company, DarwinHealth, has begun a clinical trial at Columbia to test drugs involving 3000 patients. DarwinHealth is also licensing their tools to other researchers around the world to test against cancer.

References

  1. Jin Jing, et al. “Identification of Genetic Mutations in Cancer: Challenge and Opportunity in the New Era of Targeted Therapy,” Frontiers in Oncology, 16 April 2019 https://www.altmetric.com/details/60056433
  2. Khamsi, Roxanne. “Computing cancer’s weak spots.” Science 12 Jun 2020. Vol. 368, Issue 6496, pp. 1174-1177. https://science.sciencemag.org/content/368/6496/1174
  3. Lambert, Melanie, et al. “Targeting Transcription Factors for Cancer Treatment.” Molecules 2018, 23 (6), 1479. https://www.ncbi.nlm.nih.gov/pubmed/29921764
antibody binding

A New Type of Cancer Immunotherapy

A newly emerging type of cancer immunotherapy uses bispecific antibodies. These drugs attach to both immune cells and tumor cells thereby facilitating destruction of the tumor. They are called bispecific as they bind to a unique surface protein, CD3, on an immune T cell and to a antigen marker on a tumor.

Although bispecific antibodies have been studied for decades, the field was slow to develop due to difficulties in designing and producing the drugs. Those problems are now rapidly being overcome. The field continues to evolve with many new designs of bispecific antibodies being prepared. A major advantage of bispecific antibodies is that they can be mass produced in advance.

Bispecific antibody therapy joins other well-established methods of immunotherapy. CAR T cell therapy involves the use of bioengineered drugs. In this approach, T cells are separated from a patient’s blood, and a specialized receptor gene is inserted. The CAR T cells are then multiplied in the laboratory and reinserted into the patient. The CAR T cells have enhanced ability to hone onto cancer cells and destroy them.  CAR T cells, however, must be prepared for each patient, an expensive and slow process.

Another important immunotherapy treatment involves the use of checkpoint inhibitors.  Immune checkpoints are signals used by the immune system to control an immune response. After the immune response has completed its task, checkpoint inhibitor proteins shut down its activity to prevent the immune system from destroying normal tissue. Cancer cells can develop the means to stimulate these proteins to prevent the immune system from attacking the cancer. Checkpoint inhibitor drugs known as monoclonal antibodies can block this action.

All three immunotherapies have their limitations, so many researchers now believe that the most effective therapy could involve using them in combination.

Reference

http://science.sciencemag.org/content/368/6494/930

In a recent article in the New York Times, (https://www.nytimes.com/interactive/2020/04/30/opinion/coronavirus-covid-vaccine.html)

Stuart Thompson provided sobering information regarding a proposed timetable to develop a COVID-19 vaccine. Although the most optimistic estimate provided by top health officials is to develop a vaccine in 12-18 months, typically vaccine development requires at least a decade.

Why does vaccine development take so long? A vaccine must be proven to be safe and effective to be approved for use by the FDA. Achieving these high standards can take a long time. The development of a vaccine begins with academic research. After lab studies, clinical studies with a few humans begins to evaluate toxicity. Phases II and III follow with increasing numbers of patients. Finally, a New Drug Application is submitted to the FDA for approval. After approval, pharmaceutical companies face other major challenges, including scale-up for manufacturing, often requiring building a new factory to accommodate specific needs for the vaccine. Also, distributing the vaccine to millions of people would be a logistical challenge.

Fortunately, developmental research on COVID-19 can be shortened due to previous research on coronaviruses. The timeline could be advanced by starting up manufacturing capability even before approval of the vaccine, which could entail great risk for a pharmaceutical company. Most of the vaccine development on COVID-19 uses the new DNA and mRNA vaccines which provide many advantages over older technologies, including inherently better safety and more rapid production.

The article makes it clear that while waiting for a vaccine, the best immediate hope would be for the development of effective treatments. A vigorous search is underway evaluating current therapies for other conditions to see if they could be safe and effective against COVID-19. As of this writing, The FDA has approved the emergency use of remdesivir for treatment of patients who require a ventilator. Clinical studies have shown that remdesivir can reduce the recovery time by four days and can also reduce the mortality rate. These studies are promising but indicate that the search for effective treatments is far from over.

I will discuss DNA and mRNA vaccines in future articles and how they can be useful against cancer.

 

Better off Bald book cover

Review of Better off Bald

Better off Bald is an extraordinary book by Andrea Wilson Woods describing the journey she took with her younger sister Adrienne, who was diagnosed with liver cancer. The book serves as a profound statement on how cancer affects both patients and caregivers. Andrea carries on the legacy of Adrienne through nonprofit organizations she founded to provide awareness and education related to cancer.
Better off Bald is written as a journal, with each chapter representing a certain number of days after Adrienne’s diagnosis. Each chapter begins with a journal entry written by Adrienne. These entries provide insight into Adrienne’s character. Andrea brings the reader into her thought processes as she copes with the progression of Adrienne’s cancer. She writes in short sentences often with contradictory viewpoints reflecting a person in the panic of the moment. Interspersed within each chapter are remembrances of the lives together of the two sisters. Andrea obtained custody of her sister after her mother was no longer capable of taking care of Adrienne.
Andrea’s book is essential reading for anyone serving as a caregiver for a loved one. Beginning with the shocking and unexpected diagnosis of advanced cancer in Adrienne, Andrea has to navigate through the world of hospitals and doctors, keeping up with all the medications and daily crises in Adrienne’s condition. Although Adrienne’s condition appears hopeless, Andrea conducts extensive research on liver cancer and becomes very knowledgeable on the subject. However, doctors treating Adrienne do not find the alternate treatments found by Andrea to be viable alternatives.
The profile of Adrienne shows a spirited young woman who is a fighter. The diagnosis of cancer served as a wake-up call to develop strength of character and an overall positive approach to life. Instead of giving in to depression, Adrienne looks forward to new experiences and events.
The loss of Adrienne’s hair during treatment inspired the title, Better off Bald. In this way, Adrienne’s inner beauty can better come forth, not hidden by hairstyles as a means of self-expression.
The photos in the book very nicely complement the text; Adrienne is always smiling and in good spirits. Adrienne’s favorite photo sees herself as an elegant mannequin instead of wasting away from disease. Adrienne is beaming during her meeting with her idol, Dave Navarro. The “View from Adrienne’s grave” at the end of the book was particularly touching as Adrienne was fond of the Hollywood sign.

Molecular pathways in cancer

Treating Cancer with Immunotherapy and Targeted Therapy

Treating cancer has always been a major challenge. Although great strides in treatment have taken place in recent years, all too often current treatments are less than effective, or patients relapse. Newer methods of cancer treatment, namely targeted therapy and immunotherapy, have generated great excitement in the scientific community. These newer methods of cancer treatment hold promise for patients who otherwise may have few options. Also, in the case of immunotherapy, responses to treatment can be maintained even after a cycle of treatments is complete.

This book discusses all the basics of cancer for the general reader, including characteristics and development of cancer, diagnosis, and classification. Standard methods of cancer treatment are discussed, including surgery, radiation, chemotherapy, and hormone therapy. The rationale and development of targeted therapies are presented. The immune system as it relates to cancer is explained, followed by the presentation of the main categories of immunotherapy, including checkpoint inhibitors, adoptive cell therapy, and cancer vaccines.

Published by Mercury Learning and Information

Arcade Gaming

Is Video Game Addiction a True Mental Disorder?

Is Video Game Addiction a True Mental Disorder?

The World Health Organization has included the condition “gaming disorder” in the latest 11th edition of its International Classification of Diseases (ICD-11). This inclusion follows the classification by the American Psychiatric Association (APA) of “Internet Disorder” as a “condition for further study” in its latest Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The ICD and DSM are major diagnostic manuals for mental disorders. As a result of collaborations between the organizations, the classification systems described in the publications have converged strongly in their latest revisions.

The APA is hesitant to call Internet Disorder as an “official” disorder; as such a classification would have important implications for physician diagnosis and treatment as well as for insurance claims. The WHO classification is already official for that organization.

According to the WHO, gaming disorder can include: impaired control over gaming; 2) increasing priority given to gaming to the extent that gaming takes precedence over other life interests and daily activities; and 3) continuation or escalation of gaming despite the occurrence of negative consequences. For gaming disorder to be diagnosed, the behavior pattern must be of sufficient severity to result in significant impairment in personal, family, social, educational, occupational or other important areas of functioning and would normally have been evident for at least 12 months.

The WHO recognizes that gaming disorder affects only a small proportion of people who engage in digital- or video-gaming activities. However, the inclusion of gaming disorder in ICD-11 will result in the increased attention of health professionals to the risks of development of this disorder and, accordingly, to relevant prevention and treatment measures. Addiction is usually associated with the taking of drugs or other substances (substance abuse), but an understanding of the disorder has been expanded to include behaviors not involving substances, such as gambling addiction.

A group of scholars has taken issue with the WHO’s classification of gaming disorder. Their contention is that the WHO and the APA find a unique disorder in what is a normal recreational activity (video gaming). The scholars argue that the wrong criteria are used to diagnose gaming addiction (neglecting other activities in the gamer’s daily life). They feel that problems with video gaming could be the result of a preexisting mental health disorder.

This issue is related to larger problems of classifying mental disorders. Classification systems are often based on the assumption of assigning categories with distinctive characteristics. In the case of mental disorders, the characteristics shown in many categories can show overlap. In other words, it can be difficult to classify mental disorders as distinct entities. Mental disorders are largely based on observable signs and patient-reported symptoms rather than by their underlying causes.

Van Den Brink replied to the scholars’ paper agreeing that there is nothing inherently wrong with video gaming and that it can be just another recreational activity.  However, he notes that, just like other activities, gaming becomes a problem when the person loses control over it, and it replaces other important activities.

What should the gamer or concerned family and friends do?

Gamers, as well as concerned family and friends, should be alert to the extent that gaming activities could be impairing their daily activities. Only a small proportion of gamers develop a truly addictive behavior, so people around the gamer should not become unduly alarmed. Many gamers with disorders can overcome their problems without professional help. The ICD-11 and DSM-5 classifications of gaming addiction provide guidelines to professionals, but they still use their clinical jjudgmentfor diagnosis and treatment of the condition.

References

  1. Aarseth, Espen, et al. “Scholars’ open debate paper on the World Health Organization ICD-11 Gaming Disorder proposal.” Journal of Behavioral Addictions 6(3), pp. 267–270 (2017) https://akademiai.com/doi/pdf/10.1556/2006.5.2016.088
  2. Clark, Lee Anna, et al. “Three Approaches to Understanding and Classifying Mental Disorder: ICD-11, DSM-5, and the National Institute of Mental Health’s Research Domain Criteria (RDoC)” Psychological Science in the Public Interest, 18(2) pp.72–145 (2017) http://journals.sagepub.com/doi/pdf/10.1177/1529100617727266
  3. Sarkis, Stephanie. Internet Gaming Disorder in DSM-5. Psychology Today

https://www.psychologytoday.com/blog/here-there-and-everywhere/201407/internet-gaming-disorder-in-dsm-5

  1. Van den Brink, Wim. “ICD-11 Gaming Disorder: Needed and just in time or dangerous

and much too early?” Journal of Behavioral Addictions 6(3), pp. 290–292 (2017)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700715/

  1. World Health Organization. Gaming disorder.

http://www.who.int/features/qa/gaming-disorder/en

 

 

 

Video Game Addiction

Video game addiction is a term that should be used with care. When video gaming disrupts multiple areas of a gamer’s life, it may more properly be called a disorder or addiction. Although only a small percentage of video gamers experience addiction, in terms of total numbers it is significant.

Video Game Addiction addresses the question of clinical addiction as well as other topics; including the nature of video gaming, the treatment and recovery from video game addiction, and some beneficial effects of video gaming. The book can be obtained from Mercury Learning and Information.

 

Asthma

Asthma is a very serious, widespread, and growing problem in the U.S. Asthma affects over 24 million Americans, and its prevalence has increased 12% in the last decade. This book is designed to be a comprehensive background on asthma for the general public. The latest developments in the understanding of asthma and its relationships to allergies and other conditions are presented. A broad range of treatments for asthma are available or under development. The book is published by Mercury Learning and Information, and is available in paperback or as an e-book.