CAR-T immunotherapy against certain hematologic neoplasms

CAR-T une immunothérapie contre certaines tumeurs hématologiques

Cells CAR-T are T lymphocytes genetically modified used for the treatment of pediatric leukemias and certain lymphomas adults.

Strengthening the system immune

It is now well established that the immune system plays a vital role in the surveillance and elimination of cancer cells from the body. An anticancer approach very promising is therefore to identify drugs capable of activating the immune system fight cancer, a strategy known as immunotherapy. A concrete example of this approach is the recent development of antibodies against certain control points in the immune (immune checkpoints) that prevent the cancer cells look like normal cells and thus allow the immune system to eliminate them. Clinical studies have shown that this class of drugs has increased dramatically the survival of patients with certain types of cancers, especially metastatic melanomas(1).

Immunotherapy custom

The therapy CAR-T (pronounced to English-AS-Ti) represents another way of enhancing the immune response of the patient. This immunotherapy is very complex, is to take from the patient white blood cells specialized in the recognition and destruction of foreign cells (T-cells), and then to modify their genetic heritage with the help of a virus to produce on their surface a protein called a “receptor antigenic chimeric” (Chimeric Antigen Receptor or CAR) that makes them able to recognize and kill cancer cells.

These altered T lymphocyte are then multiplied and re-injected into the patient where they will attack the tumor cells and eliminate them. The AS-T are, therefore, mainly of T lymphocytes that have been engineered to express on their surface a molecule directed against the cancer being treated.

This procedure allowed us to obtain tumor regressions and dramatic remissions in 60% to 90% of patients with hematologic neoplasms such as follicular lymphomas in B and chronic lymphocytic leukemia (CLL) or acute (LAL)(2).

For example, a phase II clinical trial currently in progress with children with LAL, and who do not respond to standard treatments (including after bone marrow transplantation) showed that 83 % (52 patients out of 63) are in remission within three months following the initiation of treatment and do not show any residual disease detectable. This therapy (Kymriah) was approved in September 2018 by Health Canada and is now reimbursed by MEDICARE for certain eligible patients, children and young adults from 3 to 25 years of age with acute lymphoblastic leukemia relapsed or refractory to other treatments, as well as adult patients with lymphoma large B-cell relapsed or refractory to other treatments.

A few small caveats

The spectacular results of the therapy CAR-T in some patients with hematologic neoplasms, however, should not obscure the fact that it has certain limitations. First of all, this type of immunotherapy currently does not have therapeutic activity against solid tumors, which represent the vast majority of cancers diagnosed each year. The therapy CAR-T does not represent a universal treatment of cancer. Secondly, the treatment is often accompanied by toxic effects severe caused by overactivation of the immune and the massive release of cytokines (fever, tachycardia, renal failure), and toxicities neurological (tremors, convulsions) that require a medical surveillance supported. Finally, mention must be made of the cost-boggling these treatments, in the neighborhood of $ 500,000 per patient, a problem which is likely to increase in the coming years due to the large number of therapies AS-T that are in development. How these therapies are very costly will they be able to be included in the list of reimbursed drugs by public health systems ?

(1) Ribas A and JD Wolchok. Cancer immunotherapy using checkpoint blockade. Science 2018; 359: 1350-1355.

(2) Park JH et al. Long-term follow-up of CD19-CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 2018; 378: 449-459.

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