World: Cured unexpectedly of cancer https://t.co/KoZwKpzfcy pic.twitter.com/KKaqmJvPwt
— Pulse Ghana (@PulseGhana) February 20, 2018
A fascinating article was published in the New York Times on February 20, 2018, about an inspiring story of the recovery of four women. These women were suffering from an extremely rare disease called hypercalcemic small cell ovarian cancer [1]. They received immunotherapy drugs and much to the surprise of the doctors it turned out to be beneficial as their condition went into remission. Since then, they have returned to their daily lives, living the dream which was once elusive. Bewildered by the outcome, researchers are now trying to come up with a possible explanation for this recovery. What makes this story even more fascinating is that a few years back Dr. Douglas Levine from NYU Langone had attributed the cause of this ovarian cancer to single gene mutations [2]. Thus, it was thought to be practically impossible for one’s immune system to recognize such modifications as a foreign entity and after that respond to immunotherapy drug treatment. A deviation from the usual and an almost miraculous recovery inspired us to write about immunotherapy.
Monoclonal antibody therapy is a kind of #immunotherapy that empowers the immune system to attack cancer cells. Monoclonal #antibodies are proteins created in a lab and designed to target a particular antigen, including those that live on cancer cells. https://t.co/GWTLH0buXF pic.twitter.com/Y2egrA2po6
— Dana-Farber (@DanaFarber) May 8, 2018
What is Immunotherapy?
The journal “Nature” defines immunotherapy as a way of treating cancer patients by using components of one’s immune system [3]. To explain it in simple terms, upon infection, the immune system attacks foreign entities to destroy them. In case of cancer though, the immune system does not always recognize it as a “foreign particle”. Some of them would happen by mutations which would be difficult to detect and treat. Thus, the extent of action varies based on the type of cancer, some of them being more responsive than the others. For example, immunotherapy drugs have been found to be more effective against massive mutation causing cancers such as lung, melanoma, etc. [1]. The effort was then to find out a reason for the recovery of the women suffering from hypercalcemic small cell ovarian cancer as theoretically it was not thought to be a target for immunotherapy drugs. In the process, some researchers from the Dana Faber Cancer Institute came up with a hypothesis according to which the immune system recognizes cells as foreign particles if they harbor genes undergoing erratic turning on and off and then destroys them [4]. Once identified, white blood cells are employed to attack as has been evident from samples from patient’s tumors. Dr. Pardoll at Johns Hopkins and Dr. Padmanee Sharma at M D Anderson Cancer Center are trying to use this concept to develop a new, fast and convenient assay for cancer detection and treatment [1]. The favorable method of treatment will be immunotherapy drug/drugs if white blood cells are detected in the tumor [5] [6] [7]. The development of this technology will help narrow down the cause of cancer. It will lead to faster and more targeted treatments, time being the most significant factor in this case.
10 questions about #immunotherapy, answered by our expert Dr. Padmanee Sharma: https://t.co/vRYGbOpf59 #CancerMoonshot #endcancer pic.twitter.com/cDKBmmkR2i
— MD Anderson Cancer Center (@MDAndersonNews) February 20, 2018
Types of Immunotherapy
Once the line of treatment is determined, the next mammoth task is to extend the use of immunotherapy to other forms of cancer. Different aspects of this therapy are already in use. There is one that includes the use of artificially synthesized antibodies against protein/antigens found on cancerous cells [8]. An example of one such targeted therapy uses trastuzumab (Herceptin) that binds specifically to the HER2 protein found in the breast and stomach cancer cells [9] [10]. There are over a dozen such mAbs that have been approved by FDA (Food and Drug Administration) to treat some forms of cancer [11]. The second type of immunotherapy used involves immune checkpoint inhibitors. Specific checkpoint proteins that are explicitly on T-cells (a form of white blood cells) put a brake on the attack by these cells on normal body ones. These inhibitors act against them to release and activate the T-cells to destroy the cancerous cells [12].
Drugs known as immune checkpoint inhibitors – a type of cancer #immunotherapy – have made one of the most impressive debuts of any type of #cancer therapy, but their success has not been uniform across all types of cancer. https://t.co/yVTjL03Fad pic.twitter.com/Xjb5KdqI4b
— Dana-Farber (@DanaFarber) March 30, 2018
The other form of immunotherapy which is gaining a lot of positive feedback is the CAR-T (Chimeric antigen receptor) therapy [13]. It is an advanced technique that involves modifying one’s T-cells by adding a CAR receptor that would enhance the ability of the T-cells to identify antigens on the cancer-causing ones. This property makes the CAR-T immunotherapy extremely specific and thus a target for further research [14]. FDA has already approved two of this therapy against acute lymphoblastic leukemia (ALL) in children and acute lymphomas in adults [15] [16]. An increasing effort is now being put in by researchers worldwide to improve this technique using gene editing tools like the CRISPR-Cas9 system. This would help obtain more precisely engineered T-cells [17].
FDA Approves First CAR-T Cell Therapy for Pediatric Acute Lymphoblastic Leukemia https://t.co/b1OnJWKWLK #FDA #Leukemia pic.twitter.com/ZGe4BBuHKo
— TrumpedCulture (@TrumpedCulture) September 2, 2017
Recent Industry Partnerships and Alliances on Immunotherapy
We shall now focus on some alliances and mergers in the healthcare market that have happened earlier this year. A lot of big pharmaceutical and biotech companies are taking an added interest in improving the CAR-T immunotherapy. A recent article in “Chemical and Engineering news” highlighted an initiative by Merck as it is trying to boost its already existing immunotherapy drugs with tumor-bursting viruses. They are in the process of acquiring an Australian biotech firm called Viralytics by paying close to $400 million. Once owned by the big pharma company, Viralytics will become a wholly-owned subsidiary of Merck and Merck will have access to the drug candidate CAVATAK. CAVATAK is a formulation of Coxsackievirus type21 that binds to certain receptors on cancer cells and cause their death by lysis. The idea is to combine this with the already existing Merck’s KEYTRUDA (which by itself is an approved checkpoint inhibitor) to improve the chances of treating certain cancers such as melanoma, prostate, lung and bladder cancer. The implementation date of this is June 2018, and once it happens it is expected to yield some useful results as stated by Dr. Malcolm McColl, MD, and CEO of Viralytics – “This proposed acquisition culminates years of dedicated work by the Viralytics team and represents an opportunity for significant value creation for our shareholders. Viralytics is proud to have progressed its lead investigational candidate CAVATAK to Phase 1 and Phase 2 clinical trials and, we believe that Merck, the leader in immuno-oncology, is best suited to advance CAVATAK for the benefit of patients globally, and to realize its potential” [18].
What’s behind @Merck‘s $400 million deal to acquire @Viralytics, the company that’s using a common cold virus to literally bust open cancer cells? It is a big deal for the oncolytic virotherapy field, and rationale I/O combos. My story for @cenmag here: https://t.co/jzm6xusHXS pic.twitter.com/FDoHJlsaFC
— Ryan Cross the Science Boss (@RLCscienceboss) February 21, 2018
Another major initiative on the part of Gilead Sciences has been to form an alliance with Sangamo therapeutics. The idea is to use its gene-editing technique to develop a range of next-generation cell therapies for cancer. Based on a press release of February 22, 2018, Kite, a Gilead company entered into a collaboration with Sangamo therapeutics to use a Zinc Finger Nuclease (ZFN) technology developed by the latter to advance next-generation ex-vivo cell therapies in cancer. The partnership will be initiated by an upfront payment of $150 million by Gilead to Sangamo. There will be further eligibility to generate $3.01 billion across 10 or more products utilizing Sangamo’s techniques which in turn would be dependent on milestones in research, regulatory, etc. [19]. This adds to the already existing Gilead’s endeavor of trying to improve the CAR-T therapy. Last December the company ended up giving $567 million for privately held Cell Design Labs working on the next generation CAR-T techniques [20]. They are in a constant battle with the other big pharmaceuticals like Celgene and Novartis who are actively pursuing mergers and alliances for bettering their cancer immunotherapy techniques.
The new @GileadSciences partnership with Sangamo Therapeutics shows that #CRISPR still has some competition. Many companies are using CRISPR gene editing to make off-the-shelf CAR-T cells, but Gilead chose to do it with Sangamo’s zinc fingers. @cenmag https://t.co/wEgX7UECr6 pic.twitter.com/Zuef2lUebP
— Ryan Cross the Science Boss (@RLCscienceboss) February 23, 2018
We are thus looking forward to an exciting era of academic and industrial accomplishments to find a faster and a more efficient way to cure cancer.
In an Infoshell…..
From Visually.
References:
[1] Cured Unexpectedly – Gina Kolata, New York Times, 2018 February 20.
[2] Recurrent SMARCA4 mutations in small cell carcinoma of the ovary – Jelinic P, Mueller JJ, Olvera N, Dao F, Scott SN, Shah R, Gao JJ, Schultz N, Gonen M, Soslow RA, Berger MF, and Levine DA, Nat Genet. 2014 May; 46(5): 424–426.
[3] Definition of cancer immunotherapy – Nature journal.
[4] Tumor mutational load and immune parameters across metastatic Renal Cell Carcinoma (mRCC) risk groups – De Velasco G, Miao D, Voss MH, Ari Hakimi A, Hsieh JJ, Tannir NM, Pheroze Tamboli, Appleman LJ, W. Rathmell K, Van Allen EM, and Choueiri TK, Cancer Immunol Res. 2016 October; 4(10): 820–822.
[5] New immunotherapy approaches to prostate cancer identified – Science Daily, 2017, March 27.
[6] VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer – Gao J, Ward JF, Pettaway CA, Shi LZ, Subudhi SK, Vence LM, Zhao H, Chen J, Chen H, Efstathiou E, Troncoso P, Allison JP, Logothetis CJ, Wistuba II, Sepulveda MA, Sun J, Wargo J, Blando J, Sharma P, Nat Med. 2017 May;23(5):551-555.
[7] Prediction of Response to Immune Checkpoint Inhibitor Therapy Using Early-Time-Point 18F-FDG PET/CT Imaging in Patients with Advanced Melanoma – Cho SY, Lipson EJ, Im HJ, Rowe SP, Gonzalez EM, Blackford A, Chirindel A, Pardoll DM, Topalian SL, Wahl RL, J Nucl Med. 2017 September;58(9):1421-1428.
[8] Monoclonal anitobodies to treat cancer – American Cancer Society, Web.
[9] Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2 – Cuello M, Ettenberg SA, Clark AS, Keane MM, Posner RH, Nau MM, Dennis PA, Lipkowitz S, Cancer Res. 2001 June 15; 61(12):4892-900.
[10] Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells – Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J, Cancer Res. 2001 June 15; 61(12):4744-9.
[11] From Monoclonal Antibodies to Chimeric Antigen Receptors for the Treatment of Human Malignancies – Caruana I, Diaconu L, and Dotti G, Semin Oncol. 2014 October; 41(5): 661–666.
[12] Immune checkpoint inhibitors to treat cancer – American Cancer Society, Web.
[13] CAR-T cell therapies – American Cancer Society, Web.
[14] CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers – National Cancer Institute, Web.
[15] FDA approval brings first gene therapy to the United States – USA Food and Drug Administration News release, 2017 August 30.
[16] FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma – USA Food and Drug Administration News release, 2017 October 18.
[17] Advancing chimeric antigen receptor T cell therapy with CRISPR/Cas9 – Ren J, Zhao Y, Protein Cell. 2017 September; 8(9):634-643.
[18] Merck and Viralytics Announce Acquisition Agreement, Expanding Merck’s Leading Immuno-Oncology Pipeline – Merck Press Release (Web), 2018 February 21.
[19] Kite, a Gilead Company, And Sangamo Therapeutics Announce Collaboration to Develop Next-Generation Engineered Cell Therapies for the treatment of Cancer – Sangamo Therapeutics Press Release (Web), 2018 February 22.
[20] Gilead Sciences and Kite to Acquire Cell Design Labs – Gilead Sciences Press Release (Web), 2017 December 17.
Cover image: Cell Image Library
About the Cover Image: Rapid extension of microvilli on the surface of a peritoneal macrophage (an immune cell), induced by treatment with a metabolic inhibitor, sodium azide, after 20 minutes at 22° C. Microvilli on neighboring lymphocytes in the upper left and right corners do not respond to this treatment. Image by Emma Shelton, Figure 36 from Chapter 2 (Specializations Of The Free Surface) of ‘The Cell, 2nd Ed.’ by Don W. Fawcett M.D. A PDF copy of the accompanying chapter is available on the ASCB’s BioEDUCATE website.
About the Author:
Esha Sehanobish
She is presently a Postdoctoral research fellow at Albert Einstein college of medicine, NY and works on characterization of enzymes that could act as potential therapeutic targets against tuberculosis. She is an enzymologist with a doctoral degree from the University of Central Florida in 2016. She loves using her communication skills to raise awareness about the importance of science in general by using social media. When she is not doing “science”, she loves designing and painting as a way of expressing ones thoughts through graphics and color.
Editor and Blog Design:
Abhi graduated from the Molecular Biophysics Unit of IISc (Bangalore, India) in 2011. As a Biomedical Scientist, he has worked with all three life-forms in his 13-year research career, viz., particulate, unicellular and multicellular. He is currently an Assistant Scientist at Emory University (Atlanta, GA) studying mechanisms of tumor recurrence in kids with brain tumors. As a postdoctoral fellow, he was the recipient of two Young Investigator Awards from Alex Lemonade Stand Foundation (Philadelphia, PA) and Rockland Immunochemicals. His current research has been funded by Northwestern Mutual Foundation (Milwaukee, WI), CURE Childhood Cancer Foundation (Atlanta, GA) and American Association for Cancer Research (AACR). When he is not on the bench you will find him spending time with his family or exploring the world through traveling and blogging.
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