Pharma and Health from Ingredients to Pills: Cancer Therapeutics Today(2)

CRISPR and Gene Editing

In 2015, the advantages of the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas)9-mediated genome modification enabled us to edit the genomes of a variety of organisms rapidly and efficiently for biological and therapeutic applications. (6)

Cas proteins are endonucleases that use a single guide RNA (sgRNA) to form complementary base pairs with target DNA and then cleave the DNA at specific sites. Among the different types of Cas proteins, Cas9 is the most widely used type because of its simplicity, high efficacy, and ease to use. One major concern about this system is its specificity, which has changed the field of gene editing by making it much simpler and faster to modify DNA sequences with high precision. (7) 

In 2016, a Chinese group initiated the first clinical study of CRISPR-Cas9 by injecting Cas9-engineered T cells to a patient with metastatic non-small cell lung cancer (NSCLC). (8) The result was promising. Another trial with a similar approach is currently running in the US. In addition, CRISPR technology could also be used to improve cancer therapies such as CAR-T.  

However, the CRISPR-Cas9 system  is still in its early stages. Similar as gene therapy, delivery of the CRISPR-Cas9 system to target tissues or cells in human body is the biggest challenge for its therapeutic applications. Development of safe and efficient delivery systems is therefore crucial for the success of CRISPR-Cas9 in humans.

Utilizing the Human Microbiome

Previous studies have shown that the risk of affecting colorectal cancer through diet is actually altered by the intestinal microbiome (the collection of microorganisms that live in our bodies). In the last decade, researchers have uncovered that the human microbiome plays an important role in many aspects of our health, including cancer.  Tumors have been known to be able to “hide” from the immune system, however, within the microbiome there exist peptides that mimic antigens on the surface of tumors.

A France-based company, Enterome has created a cancer vaccine based on these tumor-mimicking molecules, which generates strong immune responses against the tumor. (9) The goal is to reactivate the immune system and make  the tumor visible for the immune system to find and destroy the cancer cells. They aim to combine this technology with checkpoint inhibitors, a type of drug that blocks one of the mechanisms by which tumor cells hide from the immune system.

Immune Checkpoint Inhibitors (ICIs)

Immune Checkpoint Inhibitors (ICIs) are monoclonal autoantibodies that specifically target inhibitory receptors on T cells: cytotoxic T lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) and its ligand (PD-1L). It works by blocking checkpoint proteins from binding with their partner proteins and allows the T cells to kill tumor cells. This breakthrough discovery was recently rewarded by the Nobel Prize in 2018.(10)

Inhibition of these receptors by immune checkpoint inhibitors can successfully activate the immune system to fight cancer. Several ICIs are already approved by the regulatory authorities, and many more are currently used in studies of several solid tumors and hematologic malignancies. To date, positive studies have led to the US FDA and European Medicines Agency (EMA) approval of a number of these compounds. (11)

Epigenetic Therapeutics

Epigenetic therapy is a relatively new treatment that is related to gene therapy. It works to alter the DNA sequence and focuses on changes in DNA expression. The combination of immune-checkpoint inhibition with epigenetic therapy is one such strategy that is being tested in clinical trials, encompassing a variety of cancer types. (12)

Multiple studies have revealed key roles of epigenetic processes in regulating immune cell function and mediating antitumour immunity. These interactions make combined epigenetic therapy and immunotherapy an attractive approach to circumvent the limitations of immunotherapy alone.

Currently all the drugs bring huge breakthroughs in their targeted cancers, dramatically improving quality of life, survival rates, and even cure rates.

The Future of Novel Treatments

For the short term, two technologies appear to be driving the future of cancer research. As described above, further advancing immunotherapies which leverage the patient’s own immune system in the battle against the disease. This method still leaves much to be researched and the development of new techniques is occurring yearly. More robust capabilities to gene map and then design mRNA introduction systems are currently well funded and have plenty of traction from both industry and Tier I academia.   

The second technology slated for development in the future is the use of nanoparticle to deliver medicine to the cancerous cells.  For instance, lung tumors are often difficult to remove using current surgical techniques due to their location in the lung or the fact that there are multiple tumors which are too small to observe. Tumors also develop natural barriers to prevent drugs and immune cells from reaching the tumor cells.  

In order to overcome this challenge, scientists developed a novel surgical technique that introduces the nanoparticles only into the blood vessels of the lung to specifically target lung tumors.(13) Using this technology, nanoparticles reach the interior of dense tumors and are selectively taken up by lung cancer cells, which enable targeted drug delivery for lung cancer treatment with increased therapeutic efficiency and reduced systemic toxicity.(14)

At present, multiple clinical trials involving cancer vaccine, chemotherapy, targeted therapy, immunotherapy, plus immune-checkpoint inhibition are ongoing across a variety of cancers.

References:

1. The War on Cancer, 40 years later. (2013) https://blog.dana-farber.org/insight/2011/12/the-war-on-cancer-40-years-later/

2. Science 2018 Mar 23;359(6382):1355-1360.

3. Nat Rev Clin Oncol. (2016) 13(6): 370-383.)

4.  Maude SL et al. (2015) Blood 125: 4017-4023

5.  LabBioTech.eu. (2019) https://www.labiotech.eu/in-depth/cancer-treatments-immuno-oncology/

6.  Nature. 2011;471:602-+

7.  FEBS J. 2014 Dec;281(23):5186-93

8.  Nature. 2016 Nov 24; 539(7630):479

9.  Enterome. (2020). Immuno-Oncology. https://www.enterome.com/

10.  The Nobel Prize in Physiology or Medicine 2018 https://www.nobelprize.org/prizes/medicine/2018/summary/

11.  J Carcinog 2019 May 23;18:2.

12.  Nat Rev Clin Oncol 2020 Feb;17(2):75-90

13.  Lund University. Medical Express. (2020) https://medicalxpress.com/news/2020-07-treatment-smart-nanoparticles-lung-cancer.html

14.  Adv. Therap. (2020) July.

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Pharma and Health from Ingredients to Pills: Cancer Therapeutics Today (1)

About the Author:

Lin Zhang, M.D., senior director of a health care industry company in the United States. With the experience in clinical medicine, biotechnology, health industry and other fields, he is responsible for the research and development of plant medicine, functional food and health products. He was a clinician and worked for the National Cancer Institute, FDA and the National Cancer Center of Japan for many years.

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