Novartis to launch World's First T-cell CAR Therapy

An innovative immuno-oncological treatment of acute lymphoblastic leukemia will appear very soon

Roman Dmitriev, Mosmedpreparations

The Advisory Committee to the US Food and Drug Administration (FDA) unanimously voted to approve tisagenlecleucel-T (tisagenlecleucel-T), or CTL019, – T-cell CAR therapy, which Novartis is engaged in.

At this stage, we are talking about its applicability in the treatment of recurrent and refractory B-cell acute lymphoblastic leukemia (ALL) among children and adolescents (3-25 years). The relevant verdict of the regulator should be made by the end of September: As a rule, the FDA listens to the conclusions of its experts.

According to industry experts, tisagenlekleysel-T, being a completely personalized therapy for the patient, proclaims the beginning of a new era in the management of oncological diseases. Current options for dealing with ALL are limited, despite the fact that the median overall survival lies within three to nine months. Acute lymphoblastic leukemia is diagnosed in a quarter of cancer cases in patients under the age of 15. The chances of survival within five years for those who have experienced multiple relapses or have not been able to reach remission are in the range of 10-30%.

The mechanism of action of CTL019 is transparent. Autologous T-cells of the patient are genetically reprogrammed by transfection with a lentiviral vector that causes the expression of chimeric antigenic receptors (CAR) that recognize and destroy CD19-positive cancer B-cells. The CAR construct is composed of three components (scFv-41BB-cd3ζ): intracellular T-cell receptor CD3-zeta domain of the signal chain, inducing activation of T cells; costimulating domain 4-1BB, enhancing T-cell-mediated responses; single-stranded variable fragment of anti-CD19 antibody, binding to CD19.

CTL019, developed in collaboration with the University of Pennsylvania, is characterized by high targeting. Phase II of the ELIANA clinical trials among 50 patients demonstrated complete remission or complete remission with partial restoration of the shaped blood elements in 82% of them after three months after a single administration of the drug.

As for safety, 48% of participants recorded cytokine release syndrome (CRS) level 3 or 4 – a known complication of such experimental therapy associated with the activation of modified immunological cells in the patient's body. There were no deaths due to complications of treatment.

However, some public figures believe that Novartis does not have enough data to substantiate the effectiveness and safety of tisagenlekleysel-T: the regulator, they say, should wait at least three more months to collect the necessary clinical information. Meanwhile, parents of children who have undergone an experimental course of treatment are literally begging the FDA to approve the novelty.

Taking into account both the peculiarities of drug pricing in the West and the innovative component of CAR-T therapy, the cost of the course of tisagenlekleysel-T will be simply prohibitive for many. So, in the UK, it may cost 649 thousand dollars. In general, Novartis will start from the existing prices for stem cell transplantation.

It is difficult to imagine the complexity of CAR-T therapy: it is enough to assess the scale of the production of lentiviral vectors, which is handled by the British Oxford BioMedica, a long-term partner of Novartis. Image: Molecular Therapy. Methods & Clinical Development.

In parallel, the Swiss pharmaceutical giant continues to study the applicability of tisagenlekleysel-T against recurrent or refractory B-large cell lymphoma (DLBCL).

Competition in this sector is just being formed, but it is already beginning to escalate. By the end of November, the FDA must make a decision regarding axicabtagene ciloleucel, or KTE-C19, which Kite Pharma has targeted DLBCL. This CAR-therapeutic drug is simultaneously tested on patients with ALL: the data obtained are impressive.

Juno Therapeutics and Bluebird Bio have also achieved some success, working separately, but each together with Celgene: the first boasts of the achievements of CAR therapy among patients with DLBCL, follicular lymphoma at stage 3B or mantle cell lymphoma (MCL), the second is pleased with the results of treatment of multiple myeloma.

The Chinese Nanjing Legend Biotech attracted unprecedented excitement: five patients with recurrent and/or refractory multiple myeloma, who were monitored for over a year, remain in the status of a strict complete response. And this is surprising, because the cells of the experimental CAR drug LCAR-B38M persist in the body for only a few months. It is generally recognized that long-term remission requires the constant presence of CAR cells. So the patients are most likely completely cured.

Portal "Eternal youth" http://vechnayamolodost.ru  18.07.2017