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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Despite the impressive clinical success of the approved therapies, intense research is currently underway to increase the overall efficacy and persistence of infused cells, and to reduce toxicities. One potential way to achieve this is the use of alternative co-stimulatory domains, and lisocabtagene maraleucel (Liso-CelTM) has been developed by Bristol-Myer Squibb (BMS) based on this approach. This product is an anti-CD19 second-generation CAR construct with a 4-1BB co-stimulatory domain designed for treating patients with relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL), and a decision by FDA on approval is due later in 2020. Liso-CelTM has already achieved impressive responses in the clinic. In one clinical trial involving 250 patients, a CR of 53% was obtained, a superior result to that obtained for KymriahTM and YescartaTM in similar clinical trials. However, relapse remains a problem as with the other two products which may be due to the targeting of CD19 on the surface of healthy B cells which occurs irrespective of whether patients are CD19+ve or CD19-ve on their tumor cells. Therefore, relapse could be due to poor T-cell function or decreased persistence of the infused product. It has been suggested that the latter could be due to the murine components of the CAR constructs, specifically the scFv which may be immunogenic resulting in CAR-T elimination by the host immune response. Importantly, Liso-CelTM, KymriahTM, and YescartaTM all use the same murine-single chain Fv antibody, and so if a patient loses persistence to one of them, they are unlikely to respond to the others. Therefore, efforts are underway to reduce the immunogenicity of CAR-T therapies, for example, by utilizing versions of the scFv without murine components.
Regulatory and clinical development to support the approval of advanced therapies medicinal products in Japan
Published in Expert Opinion on Biological Therapy, 2022
Iglesias-Lopez Carolina, Agustí Antònia, Obach Mercè, Vallano Antonio
Axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, darvadstrocel and onasemnogene abeparvovec were not specifically developed in Japan but were approved in the three key regions: US and/or EU and Japan. Foreign data was used to support the MA of tisagenlecleucel and onasemnogene abeparvovec, along with data from the Japanese cohorts in these studies (n = 15 for tisagenlecleucel and n = 3 for onasemnogene abeparvovec). The approval of axicabtagene ciloleucel was based on data from the global pivotal trial (ZUMA-1) and the results of a phase 2, open-label, single-arm study conducted in Japan to assess efficacy and safety in 16 patients. For lisocabtagene maraleucel, the safety and efficacy data was based on a US Phase 1 trial and a Japan-included global Phase 2 study. The approval of darvadstrocel was supported by data from two clinical trials, a Phase 3, multicenter, open-label, uncontrolled study conducted in Japan that assessed the efficacy for 24 and 52 weeks, and safety for 156 weeks in 22 patients, and a pivotal study conducted in Europe and Israel.
Advances in therapeutic strategies for primary CNS B-cell lymphomas
Published in Expert Review of Hematology, 2022
Safaa Ramadan, Tommaso Radice, Ahmed Ismail, Stefano Fiori, Corrado Tarella
Chimeric antigen receptor (CAR) T-cell therapy has been shown to be effective for patients with CD19 B-cell malignancies and is currently approved as third-line systemic therapy for DLBCL [80–85]. In this context, the TRANSCEND study evaluated CAR T-cell lisocabtagene maraleucel (liso-cel; Breyanzi) as a third-line therapy in 256 evaluable DLBCL patients. The study included six patients with SCNS and CR was reported in three of them [82]. In a retrospective analysis of eight SCNSL patients who were treated with the CAR-T tisagenlecleucel (tisa-cel; Kymriah), two patients achieved CR and two PR. The treatment was tolerable with acceptable toxicity [83].
Lisocabtagene Maraleucel for the treatment of B-cell lymphoma
Published in Expert Opinion on Biological Therapy, 2021
Chaitanya Iragavarapu, Gerhard Hildebrandt
Lisocabtagene Maraleucel is a second generation CD19 directed CAR-T therapy that has been evaluated for the treatment of B-cell lymphoid malignancies. Pre-clinical work evaluating various T-cell subsets has shown maximum Th1 cytokine production with CD4+ Naïve T-cells (TN) while all CD8 + T-cell subsets show significant anti-tumor activity. However, CD8+ central memory T-cells (TCM) demonstrate the greatest proliferation and longest survival in-vivo. Lastly, there is synergistic effect between CD8+ TCM CAR-T cells & CD4+ CAR-T cell subsets with the greatest synergy noted with TN CAR-T cells.