Cancer is an uncontrolled proliferation of cells that have accumulated genetic mutations over time. Conventional cancer treatments are mainly based on surgery, chemotherapy, and radiotherapy. As for gene therapy, which for decades has been perceived as a method right out of science fiction, has recently established itself as one of the new pillars of cancer treatment. On the occasion of World Cancer Day, celebrated on February 4, Ici Beyrouth provides an update on this therapeutic approach which has revolutionized medical oncology. In the first part of a series of three articles, Professor Salima Hacein-Bey-Abina, pioneer in gene therapy, elaborates on this method.
With time, rewriting the code of life has progressively become achievable. In fact, the rise of molecular biology and the emergence of genetic engineering, -mostly due to the efforts of American biochemists Stanley Cohen and Herbert Boyer-, have widely opened the doors to the computerization of living organisms. The dazzling progress in gene editing technologies has thus shaped the cornerstone of a brand new therapeutic concept: gene therapy. This consists of introducing exogenous genetic material (a DNA sequence for example) into target cells, in order to supplement a deficient gene, eliminate or repair an altered gene in the aforementioned cells, modify the expression of a particular gene, or change the biological properties of these cells for therapeutic purposes.
Initially, this biotechnological strategy was developed to treat rare hereditary monogenic diseases (i.e., pathologies caused by a mutation or an alteration in the DNA sequence of a single gene). But a much wider range of genetic, neoplastic, degenerative diseases, and many more, has captured the attention of gene therapy. In this regard, scientists’ points of views seem to diverge. Some express cautious optimism, others wavering pessimism, regarding the ability of this therapy to provide a safe, effective and accessible treatment for patients suffering from monogenic or even polygenic diseases, also known to be complex genetic diseases.
The American registry of clinical trials, ClinicalTrial.gov, identified -as of February 1, 2023-, 2,058 clinical trials of ongoing gene therapy, 151 of which are in phase III, and 1,475 (i.e., 71.7% of the total cited above) are allocated to the field of oncological diseases.
First proof of concept
During the past three decades, biotechnological progress on the one hand, and the identification of more specific tumors molecular targets on the other, linked with promising clinical data, have made cancer one of the main diseases targeted by gene therapy. Several therapeutic strategies, based on genetic approaches, are currently implemented in the context of preclinical studies. The aim of these studies carried out in vitro on cancer cell lines, or in vivo on animals, as well as clinical trials, is to assess the efficacy and safety of this innovative treatment.
This enthusiasm for gene therapy dates back to April 28, 2000. Back then, a French team, led by Professors Alain Fischer, Salima Hacein-Bey Abina and Marina Cavazzana-Calvo, published in the American journal, Science, the primary positive results of gene therapy. This type of medical treatment had been carried out as part of a clinical trial on a disease known as “bubble babies”. Children with this disease suffer from a severe combined immunodeficiency linked to the X chromosome, characterized by the total absence of T and NK lymphocytes, cells of the immune system responsible (among other things) for the body’s defense against infections. This great therapeutic victory thus established the first proof of concept regarding the effectiveness of gene therapy.
A major milestone
Contacted by Ici Beyrouth, Professor Salima Hacein-Bey-Abina, one of the three French pioneers of this successful treatment, reviews the circumstances and results of this clinical trial: “The severe combined immune deficiency linked to chromosome X is a pathology due to a genetic anomaly characterized by an absence of T lymphocytes”, she says. “This disease is manifested by severe and recurrent infections that start in the first months of life. Without a bone marrow transplant from a matching donor, the “bubble babies” die within a few months.”
The French immunologist, who won numerous scientific prizes, including the prestigious Prix Galien, points out that gene therapy has been a “major milestone” in the history of medicine. “This genetic strategy consists of infecting ex vivo (outside the body) hematopoietic stem cells (precursors of blood cells, editor’s note) taken from patients, containing an abnormal version of the gene. This is done through a vector derived from a virus carrying a normal version of this gene or transgene. It will later on be inserted into the stem cells, explains Professor Hacein-Bey-Abina. Once modified, these cells are then re-injected into the babies.”
Cell immunotherapy
The results of the aforementioned clinical trial have shown the presence of functional T lymphocyte reconstitution in the ten children treated. However, cases of leukemia have been reported as a result of this therapy, but the development of new viral vectors has made it possible to solve this problem. “This has thereby led to the rise of gene therapy in various fields, including oncology”, notes Professor Hacein-Bey-Abina.
In fact, the transfer of therapeutic genes has become, recently, a new approach of anti-cancer treatment. This technique makes it possible to introduce new genes into cancer cells, surrounding tissue, even immune cells, to provoke cell death, slow cancer growth, and program specific killer cells for tumor antigens.
Undoubtedly, immunotherapy -which was awarded the Nobel Prize in 2018-, has become over the past two decades, one of the main cancer treatment options. The credits mainly go to the achievement of immune checkpoint inhibitors (antibodies that prevent the inhibition of immune cells, editor’s note). Furthermore, its success has spurred with the development of oncolytic viruses (viruses that kill cancer cells) and genetically modified T lymphocytes.
Immune cells engineering
The emergence of genetically modified T lymphocytes (or CAR-T cells, an acronym for Chimeric Antigen Receptor T cells) as a new cancer treatment strategy, marks the beginning of a new era in medical oncology. In fact, over the last decade, clinical trials using CAR-T lymphocytes have shown significant full remission rates, between 70% and 90%, for the treatment of certain forms of lymphomas and leukemia (particularly B-cell acute lymphoblastic leukemia) and, more recently, multiple myeloma. In that respect, Professor Hacein-Bey-Abina points out that the engineering of T cells with a chimeric antigen receptor has paved the way for the emergence of treatments of refractory or recurrent forms of cancer.
“While CAR-T cells have provided proof of concept for the success of this strategy in resistant hematological cancers, this treatment can currently measure up to second and even first-line treatments”, she says approvingly. She goes on to state that additional molecular modifications have reduced the potentially serious side effects of this therapy (such as cytokine shock and neurological toxicities). “The engineering of NK lymphocytes with a chimeric antigen receptor will later on make it possible to obtain satisfactory results with fewer side effects”, notes Professor Hacein-Bey-Abina. Finally, she underlines, that combinatorial therapies based on conventional drugs, therapeutic antibodies (especially immune checkpoint inhibitors, and bi-specific antibodies), as well as cellular immunotherapies, will constitute the basis for the future treatments of oncological diseases.
Cancer Gene Therapy: When Science Fiction Meets Medicine (2/3)