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Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Remarkably, a CAR T-cell therapy, axicabtagene ciloleucel, following been tested in several studies and found to be associated with high response rates and durable complete remissions in patients with relapsed and/or refractory lymphomas, was licensed by the FDA in November 2017, and European Medicines Agency (EMA) in June 2018. A second CAR T-cell therapy, tisagenlecleucel, was licensed by the FDA and EMA, in June 2018 for adult patients with DLBCL, HGL and DLBCL arising from FL, who had failed two or more lines of therapy. Both products are associated with substantial risks of immune-related adverse effects, which are largely transient, but carry a treatment-related mortality of about 3%. These are discussed further in Chapter 13.
Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
CAR-T cells target the surface antigens of malignant cells in an MHC-independent manner, thus tumor antigen escape by down-regulation of MHC molecules is of no consequence. The majority of clinical trials that have been undertaken with CAR-T therapies have been in the hematological setting. For example, anti-CD19 CAR-T cells have been the most studied in the clinic as CD19 expression is restricted to healthy B cells, their precursors, and to malignant B cells. The most advanced clinical trials, including those completed for approved therapies, have evaluated anti-CD19 CAR-T cells for the treatment of relapsed and refractory B-cell malignancies, such as Chronic Lymphoblastic Leukemia (CLL). In one of the initial studies at the University of Pennsylvania (USA), it was reported that two of the three enrolled patients experienced rapid and complete remission during the first six months. Crucially, these patients had already exhausted all other treatment options. A follow-up study of these patients revealed that they maintained a continued CR (complete response) for over five years with B-cell aplasia, suggesting that infused CAR-T cells can persist are administration. This result, along with another success in clinical trials involving young adults, solidified the interest of pharmaceutical companies such as Novartis in commercializing CAR-T therapies, and led to the approval of tisagenlecleucel (KymriahTM) for the treatment of B-cell Acute Lymphoblastic Leukemia (ALL) in patients up to 25 years old with refractory or relapsed disease. Later, an objective response rate of 53.1% was observed in a clinical trial of adult patients with relapsed/refractory DLBCL. Based on these results, in 2017 tisagenlecleucel became the first FDA-approved treatment to include a gene therapy step. The same year, the FDA granted approval to a second CAR-T therapy, axicabtagene ciloleucel (YescartaTM), developed by Kite Pharma for the treatment of patients with relapsed/refractory DLBCL. The approval was based on clinical studies demonstrating an objective response rate for axicabtagene ciloleucel of 82%.
Outcomes after allogeneic hematopoietic stem cell transplantation for adults with primary mediastinal B cell lymphoma: a SFGM-TC and LYSA study
Published in Acta Oncologica, 2022
Baptiste Le Calvez, Benoit Tessoullin, Loïc Renaud, Carmen Botella-Garcia, Micha Srour, Steven Le Gouill, Gaelle Guillerm, Rémy Gressin, Stéphanie Nguyen Quoc, Sabine Furst, Adrien Chauchet, David Sibon, Philippe Lewalle, Xavier Poiré, Natacha Maillard, Alban Villate, Michael Loschi, Jérôme Paillassa, Yves Beguin, Rémy Dulery, Jean-Jacques Tudesq, Amandine Fayard, Marie C. Béné, Vincent Camus, Patrice Chevallier, Amandine Le Bourgeois
The therapeutic landscape of PMBCL has recently evolved with the growing importance of immunotherapy such as anti-PD1 alone or in association with brentuximab vedotin [16,32–34]. As well, the development of CAR T-cells appears to be an important paradigm shift in the management of B-cells malignancies [17,33,34]. Anti-CD19 CAR T-cells have been approved by the FDA for aggressive R/R non Hodgkin lymphomas (NHL), including PMBCL. However, only few patients with PMBCL were included in the pilot studies ZUMA-1 and TRANSCEND-NHL-001(17) [34,35]. Crombie et al recently reported the real-life results of 33 patients treated with axicabtagene ciloleucel for R/R PMBCL. The overall response rate was 78% with 69% of CR. The 24-month (intent-to-treat) PFS was 64% and 24-month OS 78% [19], which appears to be superior to the results reported in our cohort.
What are the key considerations for deciding on the use of CAR T-cell therapy for patients with follicular lymphoma?
Published in Expert Review of Anticancer Therapy, 2022
For the cellular therapist, considerations for the use of CAR T-cell therapy for follicular lymphoma patients include all of the above, with the addition of deciding which of the FDA approved agents to use. While cross-trial comparisons are difficult, there are multiple trials of axicabtagene ciloleucel [5,8–10] and tisagenlecleucel [7,11,12] for multiple B-cell malignancies to better allow for comparison of efficacy and toxicity. In general, while absolute response rates tend to be higher with axicabtagene ciloleucel, rates of grade 3+ neurologic toxicity and cytokine release syndrome have been lower in clinical trials to date with tisagenlecleucel. Many patients with follicular lymphoma are in the 8th or 9th decade of life – for patients with significant comorbidities (i.e. heart failure with reduced ejection fraction, chronic kidney disease, compromised pulmonary function, poor performance status), it may be in the patient’s best interest to utilize the CAR T-cell product with the most favorable toxicity profile rather than the product with the highest reported response rates. These decisions are nuanced and require detailed discussion between the patient and her cellular therapist.
Axicabtagene ciloleucel for the treatment of relapsed or refractory follicular lymphoma
Published in Expert Review of Anticancer Therapy, 2022
Axicabtagene ciloleucel is a second generation autologous anti-CD19 CAR T-cell developed by Kite Pharmaceuticals in collaboration with earlier work conducted by James Kochenderfer and Steven A. Rosenberg at the Surgery Branch of the National Cancer Institute. The CAR construct consists of (1) an extracellular antigen-binding domain that has a single chain variable fragment (scFv) containing a variable light and variable heavy region specific to CD19 connected by a pliable linker [34–36] (2) CD28 hinge and transmembrane domains that aid in immune synapse specificity and stability of the CAR T-cell [37,38] (3) a CD28 intracellular costimulatory domain, required for sufficient resting T-cell activation [39] and which associates with both rapid T-cell expansion and exhaustion [26,40] and (4) a CD3ζ activation domain.