CAR-T Immunotherapy

To date, allogeneic HSCT is the oldest and most commonly used antileukemic immunotherapy. However, it does constitute a radical ( recipient's immune system is destroyed and replaced by the donor's immune system ), non-specific, non-targeted immunotherapy, which explains its major toxicities - particularly the risk of GVHD , there are ongoing effects on the patient's immune system months or years after interruption of cell transplantation. The development of chimeric antigen receptor ( CAR ) T cells has revolutionized cellular anti-tumor immunotherapy in an unprecedented manner [13, 14, 15, 16, 17, 18, 19] .

CAR is a conventional T cell that is genetically engineered to express a specific receptor that targets an antigen. This chimeric receptor consists of an extracellular single-chain variable fragment of immunoglobulin ( scFy ) capable of specifically recognizing antigens on target cells, a transmembrane domain, and an intracellular domain for signaling, composed of cytoplasmic CD3ζ Signaling components make CAR activation independent of pMHC ( first-generation CARs ), domains in which CD28 or 4-1BB co-stimulatory domains are injected to enhance mechanotransduction ( second-generation CARs ), or a combination of both ( third- generation CARs) generation CAR ) or a single costimulatory domain associated with another transgene to increase cytokine expression and thereby promote CAR-T cell effector capacity ( fourth generation ). EMA ( European Food and Drug Administration ) has approved the use of axicabtagene ciloleucel and tisagenlecleucel in R/R DLBCL [20] and tisagenlecleucel in young adults with B-ALL. Other autologous anti-CD19 or anti-BCMA CAR-T cells are available for early use in adult ALL, follicular NHL, and myeloma.

With these innovative new therapies, long-term responses are observed in 40-60% of patients , with median overall survival typically around 6 months, revolutionizing the treatment of these refractory relapsed hematologic malignancies. pattern [21, 22, 23] . However, the use of CAR-T therapy still faces many obstacles and practical problems [24] .

(1) CAR-T cells are developed from the patient’s own autologous cells. The quality of the T lymphocytes collected during the lymphatic blood collection process and the heterogeneity of the obtained products ( such as effector capacity, viability, and expansion capacity) , T cell senescence and exhaustion ), which are essentially caused by previous treatments and are also caused by the patient’s immune system status;

(2) These obstacles from collection to production make the manufacturing process laborious, lengthy, and very expensive ; today, the cost of CAR-T cell therapy for a single B-cell lymphoma patient in the United States averages $373,000. A new study by Prime Therapeutics using real-world data found that the total cost averaged more than $700,000, and in some cases, CAR-T transplant follow-up costs could exceed $1 million. In France, when social insurance covers the entire cost of CAR-T surgery, the price of CAR-T treatment is approximately 350,000 euros, excluding the price of hospitalization and auxiliary treatment. The delay between production and infusion of CAR-T cells can reach 2 months, which is too long for patients with refractory uncontrolled hematologic malignancies.

(3) In addition, injected anti-CD19 CAR-T cells have their own toxic side effects—the most common being inflammation and cytokine release syndrome ( CRS ) or nerve and blood damage ( e.g., cytopenias, sometimes may continue to exist). Finally, the loss of antigen targets after CAR-T treatment is an important cause of relapse, especially in CD19 B ALL [25] .

Other genetic modifications—such as TCR inhibition or introduction of suicide genes—are necessary; some researchers have even tried using double-negative CAR-T cells ( CD4-CD8- ) without rejection or GVHD [26] . Several clinical studies are ongoing to test these allogeneic CAR-T cells ( primarily for type B malignancies ) versus the usual fludarabine-cyclophosphamide ( FluCy) lymphodepletion to which alemtuzumab has been added to reduce the risk of immune rejection. This process increases the toxicity characteristics of CAR, but subsequently increases the risk of immunosuppression and even long-term hypoplasia. In a recent trial from the UCART19 group, genome-edited, donor-derived allogeneic anti-CD19 CAR-T cells were administered to patients with refractory B- ALL ADULTS AND CHILDREN. Only patients who received alemtuzumab showed expansion and antileukemic activity, with a CR rate of 67% 28 days after infusion, but the main cost was high toxicity [27] . Today, the most common use of allogeneic CAR-T cells is as a bridge to allogeneic HSCT—particularly in AML and myeloid tumors .