We have learned from a sneak preview on the American public radio station NPR news[1] that a cancer treatment trial using CRISPR received a positive safety report on Wednesday, November 5. A good opportunity to have another look at some of the current issues in oncology.
CRISPR: a game-changer for oncology?
Cancer is probably the biggest mystery in contemporary human biology. The extraordinary research efforts undertaken since Richard Nixon’s famous law, signed on December 23, 1971, which declared war on cancer, have reduced mortality. Having been disappointed on countless occasions by the cancer immunotherapy approach, despite how logical it would seem to be, doctors are nowadays often sceptical about new treatments, even if the evidence of their effectiveness has never been so indisputable. The 2018 Nobel Prize in Medicine, which recognized James P. Allison’s work, focused on the detailed relationship between cancer cells and immune cells. So what can we expect from CRISPR in the treatment of cancer?
CRISPR is a technique with almost limitless possibilities. The added value is obviously in the modification of the genome and not in the tool that enables it. However, this particular tool, CRISPR, is unimaginably valuable, due to its low cost and efficiency. Moreover, there is no contradiction between an approach which modifies the genome of tumours to re-differentiate them or make them less aggressive, and one which modifies the genome of immunocompetent cells to restore their ability to destroy tumour cells.
The use of CRISPR in cancer treatment is also an extremely sensitive subject, not just because of the implications for patients but also the possible disruptive effects for the pharmaceutical industry.
Over the past decade, immunotherapy using monoclonal antibodies against targets identified on tumour cells has led to the development of effective treatments. The new phase which researchers have been able to embark on thanks to CRISPR represents a complete departure. It is about creating real living drugs using sophisticated cellular engineering. Cells are trained and equipped ex vivo to destroy the cancer in question. CAR T-cells, for example (Chimeric antigen receptor T cells), are T lymphocytes, collected from the patient’s blood and then genetically modified in vitro to express an artificial receptor, known as a chimeric receptor. The extracellular part of this receptor can recognize a tumour antigen, as specifically as possible in order to avoid adverse effects on other cells. The intracellular part will be responsible for the activation of the lymphocyte after binding to the tumour cells.
In the current clinical trial in the USA
(https://clinicaltrials.gov/ct2/show/NCT03399448?term=Stadtmauer&cond=Cancer&cntry=US&draw=2&rank=7 ) the aim was to remove three “blocking” genes and add one that could make these T cells (white blood cells specialized in cancer defence) effective.
This approach appears relatively safe according to the results that have been reported recently.[2] Treatment efficacy data will be presented in December to the American Society of Hematology; of the first three patients treated with these cells modified using CRISPR, two have multiple myeloma and one has synovial sarcoma.
It is important to put this new step into perspective: in recent years, there have been three major transformations in cancer treatment.
Cancer is not a disease of an organ.
This is a change in the way we think about the nature of cancer. We no longer treat a stomach tumour, we treat a cancer that may have developed in the stomach but which has specific genetic, metabolic and survival characteristics which will determine the most effective treatment. Knowing the anatomical location of a cancer is increasingly secondary to the intrinsic characteristics of the cells of which it is comprised. So treating cancer in a hospital unit dedicated to a specific organ is becoming less and less relevant. Exceptionally, in France the development of cancer treatment centres anticipated this biological approach several decades ago.
The challenge of the last cells
Several oncologists have summed up the challenge of the last cell. In France we think of the work of Georges Mathé[3] and Lucien Israël.[4] Wherever it is in the tumour, in the dormant phase of cell division, protected from pharmacological missiles, or circulating and already dividing in an organ where its size enables it to escape detection, the last cell is inaccessible to conventional treatments. Moreover, cells are programmed to survive. Cancer cells are no exception to this observation. This is why allopathic cancer treatments (surgery, radiotherapy and chemotherapy) need the individual’s immune system to be able to aim for a cure. It is equally paradoxical to note that conventional treatments are also immunocompromising. Under these conditions, immunotherapy plays an essential part even if it has not yet made it possible to develop a generalized therapeutic strategy against cancer.
From idealized immunotherapy to cell engineering
Whether it is the spontaneous remission of cancers, cases of which have been authenticated, albeit in highly exceptional circumstances, or solid evidence that non-specific stimulation of the immune system helps to cure certain cancers such as superficial bladder cancer[5], immunotherapy has long remained no more than wishful thinking. A very precise knowledge of the mechanisms by which cancer cells escape the body’s immunosurveillance, the development of monoclonal antibodies against targets on the surface of cancer cells, and now the use of CRISPR to train and equip autologous immune cells are discoveries and innovations that are real game-changers. This brings us to the clinical stage where an individual’s immune cells have been modified and re-injected into the patient with the aim of reaching all cancer cells immediately or subsequently, depending on the development of the tumour.
It is a huge encouragement for cancer patients and for the doctors who care for them. Doctors have gradually transformed some cancers into chronic diseases as a result of the rapid development of new treatments, as new innovations succeed each other. There is everything to play for in this research but we also stand to lose everything from scientific denial, or failure to invest in new cancer treatments. This is a real test of political will.
[1] https://www.npr.org/sections/health-shots/2019/11/06/776169331/crispr-approach-to-fighting-cancer-called-promising-in-1st-safety-test )
[2] https://www.statnews.com/2019/11/06/first-use-of-crispr-against-cancer-in-patients-clears-early-safety-hurdles/
[3] “La dernière cellule” [“The last cell”], in: Presse méd, 75 (1967): 2591-2593
[4] https://academiesciencesmoralesetpolitiques.files.wordpress.com/2019/01/3israel.pdf
[5] https://www.ncbi.nlm.nih.gov/pubmed/820877 and https://www.ncbi.nlm.nih.gov/pubmed/350390
This post is also available in: FR (FR)