The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the Treatment of Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma

Abstract

Chimeric antigen receptor (CAR)–engineered T‐cell therapy is becoming one of the most promising approaches in the treatment of cancer. On June 28, 2018, the Committee for Advanced Therapies (CAT) and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kymriah for pediatric and young adult patients up to 25 years of age with B‐cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse after transplant, or in second or later relapse and for adult patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL) after two or more lines of systemic therapy. Kymriah became one of the first European Union–approved CAR T therapies. The active substance of Kymriah is tisagenlecleucel, an autologous, immunocellular cancer therapy that involves reprogramming the patient's own T cells to identify and eliminate CD19‐expressing cells. This is achieved by addition of a transgene encoding a CAR. The benefit of Kymriah was its ability to achieve remission with a significant duration in patients with ALL and an objective response with a significant duration in patients with DLBCL. The most common hematological toxicity was cytopenia in both patients with ALL and those with DLBCL. Nonhematological side effects in patients with ALL were cytokine release syndrome (CRS), infections, secondary hypogammaglobulinemia due to B‐cell aplasia, pyrexia, and decreased appetite. The most common nonhematological side effects in patients with DLBCL were CRS, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. Kymriah also received an orphan designation on April 29, 2014, following a positive recommendation by the Committee for Orphan Medicinal Products (COMP). Maintenance of the orphan designation was recommended at the time of marketing authorization as the COMP considered the product was of significant benefit for patients with both conditions. Implications for Practice Chimeric antigen receptor (CAR)–engineered T‐cell therapy is becoming the most promising approach in cancer treatment, involving reprogramming the patient's own T cells with a CAR‐encoding transgene to identify and eliminate cancer‐specific surface antigen–expressing cells. On June 28, 2018, Kymriah became one of the first EMA approved CAR T therapies. CAR T technology seems highly promising for diseases with single genetic/protein alterations; however, for more complex diseases there will be challenges to target clonal variability within the tumor type or clonal evolution during disease progression. Products with a lesser toxicity profile or more risk‐minimization tools are also anticipated.

Adaptor CAR Platforms—Next Generation of T Cell-Based Cancer Immunotherapy

“…To date, over 520 clinical trials have emerged worldwide, redirecting CAR T cells against 64 different tumor targets [2]. Among them, two CD19-specific CAR T cell products are approved for the treatment of acute lymphoblastic leukemia (ALL) and large B cell lymphoma [3][4][5]. Except for CD19 CARs, the most promising results have currently been achieved for the targeting of CD22 [6] and B cell maturation antigen (BCMA) [7,8] in ALL and multiple myeloma, respectively.…”

Nucleic Acid-Based Approaches for Tumor Therapy

“…One major limit has been the lack of appropriate delivery systems required to prevent degradation of pDNA/mRNA, and to enable cell type-specific delivery [ 125 , 126 ]. Insofar, it is not surprising that by now virus-based gene therapies including oncolytic viruses [ 471 , 474 , 475 , 477 , 478 ], and cell-based immunotherapeutics, namely CAR-T cell therapies [ 28 , 277 , 562 , 563 , 564 ], demonstrated more successful for tumor therapy, and have been approved for clinical treatment. However, in the last years, the development of biocompatible, cell targeting NPs, especially of liposomal carriers [ 565 ], has strongly improved the efficacy of e.g., mRNA-based anti-tumor vaccines [ 71 , 72 ].…”

Successful treatment of acute B lymphoblastic leukemia relapse in the skin and testicle by anti-CD19 CAR-T with IL-6 knocking down: a case report

“…CAR-T therapy is a novel therapeutic strategy for r/r B-ALL patients [8][9][10]. CAR-T cells can migrate into the leukemia cell sanctuary, such as cerebrospinal fluid by overcoming the blood-brain barrier (BBB), which might be an important approach for solving the sanctuary leukemia problems with traditional chemical agents [11].…”