Current Challenges in Providing Good Leukapheresis Products for Manufacturing of CAR-T Cells for Patients with Relapsed/Refractory NHL or ALL

Korell, Felix; Laier, Sascha; Sauer, Sandra; Veelken, Kaya; Hennemann, Hannah; Schubert, Maria‐Luisa; Sauer, Tim; Pavel, Petra; Müller-Tidow, Carsten; Dreger, Peter; Schmitt, Michael; Schmitt, Anita

doi:10.3390/cells9051225

Cited by 42 publications

(42 citation statements)

References 33 publications

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“…Since many of the included studies simultaneously reported more than one tumor type as listed in Table 2, therefore, we divided them into different groups based on the type of tumor for analysis. For studies that did not report efficacy and safety results by type of tumor, we grouped them by their major tumor type (19,26,27,(43)(44)(45)(46)(47)50). Case series that involved fewer than four patients after regrouping were excluded from analysis (Table 3).…”

Section: Subgroup Analysis Based On the Type Of Tumormentioning

confidence: 99%

Efficacy and Safety of CAR-T Cell Products Axicabtagene Ciloleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel for the Treatment of Hematologic Malignancies: A Systematic Review and Meta-Analysis

Meng

Wu²,

Sun³

et al. 2021

Front. Oncol.

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BackgroundCurrently, three chimeric antigen receptor (CAR)-T cell products axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel have been approved by the U.S. Food and Drug Administration for the treatment of large B cell lymphoma, which provide a novel and promising choice for patients with relapsed or refractory to traditional anti-tumor treatments. Thus, it is pertinent to describe the efficacy and safety profile of the three products available by summarizing the current evidence.MethodsTwo reviewers independently searched the Embase, PubMed, Web of Science, and Cochrane Library, to identify studies related to the use of the three CAR-T cell products for treating hematologic malignancies published up to October 5, 2020. We pooled the overall response rate, complete response rate, cytokine release syndrome, and immune effector cell-associated neurotoxicity syndrome of three products, and then performed subgroup analysis based on the type of product and type of tumor.ResultsThirty-three studies involving 2,172 patients were included in the analysis. All three products showed promising results in patients with different pathological subtypes and clinical characteristics that included those who did not meet the eligibility criteria of licensing trials, with overall response rates of nearly 70% or above and complete response rates of more than 50%. However, high rates of severe immune effector cell-associated neurotoxicity syndrome in patients undergoing axicabtagene ciloleucel treatment and life-threatening cytokine release syndrome in patients with leukemia undergoing tisagenlecleucel treatment required special attention in practice (31%; 95% CI: 0.27–0.35 and 55%; 95% CI: 0.45–0.64, respectively). Moreover, lisocabtagene maraleucel that showed a favorable efficacy and safety in the licensing trial lacked corresponding real-world data.ConclusionBoth axicabtagene ciloleucel and tisagenlecleucel showed considerable efficacy in practice, but need special attention with respect to life-threatening toxicity that can occur in certain situations. Lisocabtagene maraleucel demonstrated excellent efficacy and safety profiles in the licensing trial, but lacked corresponding real-world data. Additional data on the three products are needed in rare histological subtypes to benefit a broader patient population.

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Section: Subgroup Analysis Based On the Type Of Tumormentioning

confidence: 99%

Efficacy and Safety of CAR-T Cell Products Axicabtagene Ciloleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel for the Treatment of Hematologic Malignancies: A Systematic Review and Meta-Analysis

Meng

Wu²,

Sun³

et al. 2021

Front. Oncol.

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“…This approach could potentially overcome manufacturing issues like the low cell numbers collected from lymphopenic patients, long culture times to produce sufficient T cells, and/or poor ex vivo expansion of T cells. [85][86][87][88] Acute exercise under some conditions can result in a biphasic response, whereby cell populations can drop below baseline levels in the hours following Open access the completion of the exercise. This phenomenon likely reflects a protective effect of immune cells redistributing into various organ sites as part of a response to stress.…”

Section: Adoptive T Cell Therapiesmentioning

confidence: 99%

Exercise and the immune system: taking steps to improve responses to cancer immunotherapy

Gustafson

Wheatley‐Guy

Rosenthal

et al. 2021

J Immunother Cancer

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The remarkable success of cancer immunotherapies has provided new hope to cancer patients. Unfortunately, a significant proportion of patients remain unable to respond to immunotherapy or maintain durable clinical responses. The lack of objective responses likely results from profound immune dysfunction often observed in patients with cancer. There is substantial evidence that exercise and physical activity can reduce incidence and improve outcomes in cancer patients. As the immune system is highly responsive to exercise, one potential avenue to improve immune function is through exercise and physical activity. A single event of dynamic exercise results in the substantial mobilization of leukocytes with increased functional capacities into the circulation. Chronic, or long-term, exercise leads to higher physical fitness in terms of greater cardiorespiratory function and/or muscle strength and endurance. High aerobic capacity, as measured by maximal oxygen uptake, has been associated with the reduction of dysfunctional T cells and improvements in the abundance of some T cell populations. To be sure, however, the mechanisms of exercise-mediated immune changes are both extensive and diverse. Here, we examine the evidence and theorize how acute and chronic exercise could be used to improve responses to cancer immunotherapies including immune checkpoint inhibitors, dendritic cell vaccines, natural killer cell therapies, and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells. Although the parameters of optimal exercise to yield defined outcomes remain to be determined, the available current data provide a compelling justification for additional human studies and clinical trials investigating the adjuvant use of exercise in immuno-oncology.

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“…In selected patients with low lymphocyte counts, apheresis of an adequate quantity of autologous T-cells for CAR T-cell manufacturing might be challenging. Fortunately, with a continuous improvement in lymphapheresis protocols, sufficient yields of lymphocytes might be expected in most patients [59]. Of note, CAR T-cells from aged donors are of impaired quality including shorter persistence and less memory-like phenotypes and one may speculate that there might also be an association with more extensive pre-treatment burden [60].…”

Section: Hematological Limitations: Lymphopenia and Autoimmune Diseasesmentioning

confidence: 99%

CAR T-Cells for CNS Lymphoma: Driving into New Terrain?

Karschnia

Blobner

Teske

et al. 2021

Cancers

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Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphoma and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have proven as a promising therapeutic avenue in hematological B-cell malignancies including diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and mantle-cell lymphoma. CARs endow an autologous T-cell population with MHC-unrestricted effectivity against tumor target antigens such as the pan B-cell marker CD19. In PCNSL, compelling and long-lasting anti-tumor effects of such therapy have been shown in murine immunocompromised models. In clinical studies on CAR T-cells for CNS lymphoma, only limited data are available and often include both patients with PCNSL but also patients with secondary CNS lymphoma. Several clinical trials on CAR T-cell therapy for primary and secondary CNS lymphoma are currently ongoing. Extrapolated from the available preliminary data, an overall acceptable safety profile with considerable anti-tumor effects might be expected. Whether these beneficial anti-tumor effects are as long-lasting as in animal models is currently in doubt; and the immunosuppressive tumor microenvironment of the brain may be among the most pivotal factors limiting efficacy of CAR T-cell therapy in CNS lymphoma. Based on an increasing understanding of CAR T-cell interactions with the tumor cells as well as the cerebral tissue, modifications of CAR design or the combination of CAR T-cell therapy with other therapeutic approaches may aid to release the full therapeutic efficiency of CAR T-cells. CAR T-cells may therefore emerge as a novel treatment strategy in primary and secondary CNS lymphoma.

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Current Challenges in Providing Good Leukapheresis Products for Manufacturing of CAR-T Cells for Patients with Relapsed/Refractory NHL or ALL

Cited by 42 publications

References 33 publications

Efficacy and Safety of CAR-T Cell Products Axicabtagene Ciloleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel for the Treatment of Hematologic Malignancies: A Systematic Review and Meta-Analysis

Efficacy and Safety of CAR-T Cell Products Axicabtagene Ciloleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel for the Treatment of Hematologic Malignancies: A Systematic Review and Meta-Analysis

Exercise and the immune system: taking steps to improve responses to cancer immunotherapy

CAR T-Cells for CNS Lymphoma: Driving into New Terrain?

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