As part of the article series on cancer gene therapy, Ici Beyrouth addresses, in this second part, the topic of genetically modified T lymphocytes as a new medical approach with Emmanuel Donnadieu, immunologist and researcher.
Over the last few decades, scientific research in the field of oncology has led to the development of a rich and complex accumulation of knowledge, which has revealed that cancer is a pathology involving, on the one hand, dynamic modifications of the genome, and on the other, specific characteristics that until now remain unknown. Accordingly, on January 7, 2000, the American biologists Douglas Hanahan and Robert Weinberg have thereby published in the American scientific journal, Cell, an article titled “The distinctive characteristics of cancer”. By February 1, 2023, this publication was quoted, 40,001 times, in numerous studies.
According to the researchers, cancer cells are characterized by growth autonomy, insensitivity to growth-inhibiting signals, resistance to apoptosis (i.e., programmed cell death), and limitless replications. In addition, those cells are also characterized by an activation of angiogenesis. The latter is a pathological process of growth of new blood vessels, which allows the vascularization of a cancerous tumor, and thus meet its nutrient needs, as well as an ability to form secondary tumors known as metastases.
In a new review paper “Distinctive characteristics of cancer: the next generation”, also published in Cell, on March 4, 2011, the two researchers put forward in addition to the aforementioned properties, two new characteristics, considered to be “emerging hallmarks”: dysfunction of energy metabolism and evasion immune destruction.
Anticancer immunosurveillance
In fact, through a range of biological mechanisms, cancer cells can circumvent immune surveillance and immunity destruction. In light of the identification of these circumventing immune mechanisms, and the development of cancer immunology and immunotherapy, a series of therapeutic approaches have been developed and clinically tested over the past fifty years. Unlike conventional cancer treatments, immunotherapy aims at stimulating immune cells, whether they are found inside or outside the tumor microenvironment, to identify and specifically attack cancer cells.
This approach has contributed to implement the paradigm according to which the host immune system constitutes, in itself, an effective “living drug” against malignant neoplasms. Cell therapy is amongst these immunotherapeutic treatments. It operates by the transfer of genetically modified T lymphocytes. These are CAR-T cells (acronym for Chimeric Antigen Receptor T cells). This cellular immunotherapy consists of collecting T lymphocytes from the patient or a donor, and modifying them genetically ex vivo (outside the body) to identify a specific tumor antigenic target. The next step includes expanding the genetically modified cells to large numbers in order to reach a certain titer, and then infusing them back to the patient.
Innovative gene therapy
As such, CAR-T cells belong to a new category of biological medications known, according to European regulation no.1394/2007, as “innovative therapy medicinal products”, and more precisely, to the sub-category of gene therapy medicinal products.
“This is a complicated process that depends on the genetic modification of T lymphocytes, previously isolated from the blood source. They will then be injected into a patient with cancer”, explains to Ici Beyrouth, Emmanuel Donnadieu, research director at the National Center for Scientific Research (CNRS) in France, and head of the Cancer and Immune Response team at the Cochin Institute in Paris. According to him, several steps are necessary for the implementation of this therapy. At first, T lymphocytes are isolated from the patients’ peripheral blood. The next step is to activate them and hence prompt their expansion. Thereafter, they are genetically modified with viral vectors so that they express a chimeric antigen receptor, namely a synthetic receptor capable of recognizing its target in a specific way. “This form of immunotherapy mainly concerns hematological malignancies, such as leukemia and lymphoma, and recently multiple myeloma, specifies Emmanuel Donnadieu. Unfortunately, CAR-T cells have so far proven to be ineffective against so-called solid tumors.”
Clinical trials and marketing authorization
A total of six CAR-T cell-based gene therapies have been approved by the US Federal Food and Drug Administration (FDA). The first marketing authorization (MA) has been granted, in 2017, to tisagenlecleucel, used for patients under the age of 25 with refractory or relapsed B-cell acute lymphoblastic leukemia (B-ALL). CAR-T lymphocytes targeting the CD19 antigen (present on most leukemic B cells) have thus been recommended for the treatment of certain refractory or recurrent hematological cancers (not as a first-line treatment), such as B-ALL, and certain types of lymphomas. Two other anti-BCMA CAR-T cells have been approved for refractory or relapsed multiple myeloma.
Although this therapeutic strategy has shown satisfactory results in clinical trials for the above-mentioned hematological malignancies, with total remission rates reaching more than 90%, its effectiveness remains much lower in other cancers, especially solid tumors. Moreover, the prohibitive costs of this treatment present a real challenge, if not a constraint, for a wide range of patients, especially those living in poor or developing countries.
Efficacy and toxicity
In that respect, Emmanuel Donnadieu points out that certain tumors, mostly solid tumors, are highly “hostile” to T cells function “For one thing, these tumors are not very tolerant to the inflow of CAR-T cells, he explains. Moreover, the blood vessels that vascularize these tumor masses are often abnormal. Plus, we find in these tumors so-called immunosuppressive factors and cells that can inhibit the correct functioning of genetically modified T lymphocytes.”
The choice of the targeted tumor is however crucial for one to obtain optimal effectiveness and acceptable toxicity. The ideal target should therefore be uniformly, extensively and selectively expressed solely on cancer cells. “However, it should be noted that, in solid tumors, it is relatively difficult to identify a target that is specifically expressed by all tumor cells and not by healthy ones”, underlines the expert. He reassures, however, that several leads are favored as a way to increase the efficiency of CAR-T cells in solid tumors. “We can, for example, target the suppressor elements of the tumor, explains Emmanuel Donnadieu. We can also reinforce the CAR-T cells to make them express molecules that can allow them to better proliferate or resist in a repressing environment.” And he adds that the identification of new targets specifically expressed by tumor cells remains an active field of research.
Second- and first-line treatments
“The techniques based on T cell gene therapies could complement conventional treatments and benefit patients who do not respond to these treatments, notes Emmanuel Donnadieu. Combinational methods associating CAR-T cells with chemotherapy treatments are also foreseen”.
It should be specified at this stage that this medical strategy is recommended as third-line treatments in patients with recurrent or refractory malignancies. However, following encouraging results from two large Phase III clinical trials, ZUMA-7 and TRANSFORM, the FDA has approved the use of two anti-CD19 CAR-T cell therapies (axi-cel on April 1, 2022, and liso- cel on June 24, 2022) as a second-line treatment in patients with diffuse large B-cell lymphoma (LDGBC). Further clinical trials are currently underway to assess the effectiveness and safety of these genetically modified cells as first-line treatment in high-risk LDGBC.
In an article published by Neelapu et al., in the British scientific journal, Nature, on March 21, 2022, the results obtained were satisfactory and very promising, with a complete response rate of 78% and an overall response rate of 89 %. Grade ≥3 adverse events (in 8% of patients) and neurological occurrences (in 23% of patients) were identified, but no grade 5 side effects were reported. It is recalled that the severity of the side effects, observed during a clinical trial, is evaluated according to a scale of 1 to 5: grade 1 corresponds to mild adverse events, grade 2 to moderate, grade 3 to serious, therefore severe, grade 4 to life-threatening, while finally, grade 5 corresponds to death due to side effects.
Anti-CD19 CAR-T cells could therefore be considered as safe and tolerable first-line treatment option for high-risk patients. This possibility, however, should be further investigated in a randomized trial, according to the authors of this study.