-
Cytotherapy Sep 2022Chimeric antigen receptor (CAR) T-cell therapy is an individualized immunotherapy that genetically reprograms a patient's T cells to target and eliminate cancer cells.... (Review)
Review
Chimeric antigen receptor (CAR) T-cell therapy is an individualized immunotherapy that genetically reprograms a patient's T cells to target and eliminate cancer cells. Tisagenlecleucel is a US Food and Drug Administration-approved CD19-directed CAR T-cell therapy for patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia and r/r diffuse large B-cell lymphoma. Manufacturing CAR T cells is an intricate process that begins with leukapheresis to obtain T cells from the patient's peripheral blood. An optimal leukapheresis product is essential to the success of CAR T-cell therapy; therefore, understanding factors that may affect the quality or T-cell content is imperative. CAR T-cell therapy requires detailed organization throughout the entire multistep process, including appropriate training of a multidisciplinary team in leukapheresis collection, cell processing, timing and coordination with manufacturing and administration to achieve suitable patient care. Consideration of logistical parameters, including leukapheresis timing, location and patient availability, when clinically evaluating the patient and the trajectory of their disease progression must be reflected in the overall collection strategy. Challenges of obtaining optimal leukapheresis product for CAR T-cell manufacturing include vascular access for smaller patients, achieving sufficient T-cell yield, eliminating contaminating cell types in the leukapheresis product, determining appropriate washout periods for medication and managing adverse events at collection. In this review, the authors provide recommendations on navigating CAR T-cell therapy and leukapheresis based on experience and data from tisagenlecleucel manufacturing in clinical trials and the real-world setting.
Topics: Antigens, CD19; Humans; Immunotherapy, Adoptive; Leukapheresis; Lymphoma, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 35718701
DOI: 10.1016/j.jcyt.2022.05.003 -
Journal of Clinical Oncology : Official... Sep 2020Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma...
PURPOSE
Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication.
PATIENTS AND METHODS
Data were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution's guidelines. Responses were assessed as per Lugano 2014 classification.
RESULTS
Of 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel-treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis.
CONCLUSION
The safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.
Topics: Adult; Aged; Aged, 80 and over; Antigens, CD19; Biological Products; Clinical Trials, Phase II as Topic; Comorbidity; Cytokine Release Syndrome; Female; Humans; Immunotherapy, Adoptive; L-Lactate Dehydrogenase; Leukapheresis; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Organizational Policy; Patient Selection; Progression-Free Survival; Recurrence; Retrospective Studies; Severity of Illness Index; Standard of Care; Survival Rate; Young Adult
PubMed: 32401634
DOI: 10.1200/JCO.19.02104 -
Tidsskrift For Den Norske Laegeforening... Aug 2014
Topics: Adult; Female; Humans; Leukapheresis; Leukocytosis; Middle Aged
PubMed: 25096431
DOI: 10.4045/tidsskr.13.1559 -
Transfusion and Apheresis Science :... Oct 2023Significant advances in procedural information displayed by current apheresis machines have been made, but analyses of cell collection efficiency (CE) still rely on...
Significant advances in procedural information displayed by current apheresis machines have been made, but analyses of cell collection efficiency (CE) still rely on calculations done by apheresis professionals. Accordingly, understanding CE equations can support the optimization of apheresis techniques and identification of incidents that could impact the procedure's effectiveness. This report summarizes classical and novel CE analyses applied to apheresis exemplified by an actual case of hematopoietic progenitor cell collection. In addition to the apheresis yield and most common CE and CE formulas, we present the instantaneous and corrected CE, fold enrichment, collection throughput, collection rate and its variants, average inlet rate, classical and adjusted captured cells, recruitment pool, recruitment factor, recruitment coefficient, blood component loss, predictive apheresis yield, and performance ratio calculations. Moreover, the mathematical relationship between these CE equations is also shown, which can be helpful in many apheresis procedures.
Topics: Humans; Leukapheresis; Blood Component Removal; Hematopoietic Stem Cells; Antigens, CD34
PubMed: 37438245
DOI: 10.1016/j.transci.2023.103758 -
Transplantation and Cellular Therapy Sep 2023Tisagenlecleucel is approved for the treatment of relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) in patients up to age 25 years based on the...
Tisagenlecleucel is approved for the treatment of relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) in patients up to age 25 years based on the results of a pivotal trial (ELIANA) in pediatric and young adult patients. However, that trial did not include patients age <3 years because of the challenges posed by leukapheresis of very young and low-weight patients. Data on leukapheresis material and manufacturing outcomes among patients age <3 years have been collected since the time of global regulatory approval. Here we report leukapheresis characteristics and manufacturing outcomes for tisagenlecleucel produced for patients age <3 years in US and non-US commercial settings. Qualified patients with r/r B-ALL were age <3 years at the time of request for commercial tisagenlecleucel, with manufacturing data starting after August 30, 2017 (date of first US Food and Drug Administration approval). Leukapheresis and manufacturing outcomes data were stratified by age and weight. CD3 cell count and CD3/total nucleated cell (TNC) percentages were obtained from the leukapheresis material; leukocyte subpopulations were obtained via quality control vials. Of the 146 tisagenlecleucel quality control batches analyzed for CD3 cell count and CD3/TNC%, 86 batches (84 patients) were from US sites and 60 batches were from non-US sites. The median patient age and weight were 1.2 years and 10.4 kg at US sites and 1.5 years and 10.5 kg at non-US sites. Globally, 137 of 146 batches (94%) were manufactured within specifications across 16 countries. Among tisagenlecleucel batches manufactured in the United States between 2017 and 2021, there was a trend toward increasing CD3 counts, CD3/TNC%, and manufactured dose of chimeric antigen receptor (CAR) T cells; there was no difference in median days of collection by patient age or weight. Globally, a trend toward 1 or more potential additional collection days was observed for patients weighing ≤10 kg. Leukapheresis and tisagenlecleucel manufacturing in pediatric patients with r/r B-ALL age <3 years, including infants (<1 year), and low weight are feasible. As global experience with leukapheresis and patient identification for CAR-T cell therapy increased over time, a corresponding improvement in tisagenlecleucel manufacturing success has been observed. Clinical outcome data for these patients are currently being explored.
Topics: Child, Preschool; Humans; Immunotherapy, Adoptive; Leukapheresis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell
PubMed: 37311511
DOI: 10.1016/j.jtct.2023.06.007 -
Blood Transfusion = Trasfusione Del... Nov 2023Chimeric antigen receptor (CAR) T-cell therapy relies on T cells engineered to target specific tumor antigens such as CD-19 in B-cell malignancies. In this setting, the...
Chimeric antigen receptor (CAR) T-cell therapy relies on T cells engineered to target specific tumor antigens such as CD-19 in B-cell malignancies. In this setting, the commercially available products have offered a potential long-term cure for both pediatric and adult patients. Yet manufacturing CAR T cells is a cumbersome, multistep process, the success of which strictly depends on the characteristics of the starting material, i.e., lymphocyte collection yield and composition. These, in turn, might be affected by patient factors such as age, performance status, comorbidities, and previous therapies. Ideally, CAR T-cell therapies are a one-off treatment; therefore, optimization and the possible standardization of the leukapheresis procedure is critical, also in view of the novel CAR T cells currently under investigation for hematological malignancies and solid tumors. The most recent Best Practice recommendations for the management of children and adults undergoing CAR T-cell therapy provide a comprehensive guide to their use. However, their application in local practice is not straightforward and some grey areas remain. An Italian Expert Panel of apheresis specialists and hematologists from the centers authorized to administer CAR T-cell therapy took part in a detailed discussion on the following: 1) pre-apheresis patient evaluation; 2) management of the leukapheresis procedure, also in special situations represented by low lymphocyte count, peripheral blastosis, pediatric population <25 kg, and the COVID-19 outbreak; and 3) release and cryopreservation of the apheresis unit. This article presents some of the important challenges that must be faced to optimize the leukapheresis procedure and offers suggestions as to how to improve it, some of which are specific to the Italian setting.
Topics: Humans; Child; Adult; Immunotherapy, Adoptive; Leukapheresis; Receptors, Chimeric Antigen; Lymphocytes; Neoplasms; Cell- and Tissue-Based Therapy
PubMed: 37146295
DOI: 10.2450/BloodTransfus.471 -
Cytotherapy Sep 2017Chimeric antigen receptor (CAR) T-cell therapy is an investigational immunocellular therapy that reprograms a patient's cytotoxic T cells to engage and eliminate... (Review)
Review
Chimeric antigen receptor (CAR) T-cell therapy is an investigational immunocellular therapy that reprograms a patient's cytotoxic T cells to engage and eliminate malignant cells. CAR T-cell therapies targeting the CD19 antigen have demonstrated high efficacy in clinical trials for patients with B-cell malignancies and may potentially be available on a broader scale in the future. CAR T-cell therapy begins with the collection of a sufficient number of T cells from a patient's peripheral blood through leukapheresis. Several factors must be considered when patients undergo leukapheresis for CAR T-cell therapy, including age and prior therapies. The leukapheresis material is shipped to a manufacturing facility, followed by return of the CAR T cells to the treatment center. Careful coordination of a multidisciplinary team composed of physicians, nurses, pharmacists and other hospital personnel is critical for the proper care of the patient before, during and after CAR T-cell therapy. CAR T-cell therapy has been associated with adverse events (AEs) such as cytokine release syndrome, which requires rapid attention by the emergency department, intensive care unit and hospital pharmacy. In this review, we discuss several aspects of institutional preparation for leukapheresis, CAR T-cell infusion and AE management based on our experience with clinical trials of the CD19 CAR T-cell therapy CTL019.
Topics: Antigens, CD19; B-Lymphocytes; Cell Transplantation; Cell- and Tissue-Based Therapy; Clinical Trials as Topic; Hematologic Neoplasms; Humans; Immunotherapy; Leukapheresis; Pharmacy Service, Hospital; Receptors, Antigen, T-Cell; Recombinant Proteins; T-Lymphocytes, Cytotoxic
PubMed: 28754600
DOI: 10.1016/j.jcyt.2017.06.001 -
Journal of Hematology & Oncology Jul 2023Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report...
BACKGROUND
Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL).
METHODS
Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 10 and 50 × 10 CARTs/m. Leukapheresis, manufacturing and administration of CARTs were performed in-house.
RESULTS
For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response.
CONCLUSION
In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www.
CLINICALTRIALS
gov as NCT03676504.
Topics: Humans; Adult; Neurotoxicity Syndromes; Leukapheresis; Adaptor Proteins, Signal Transducing; Antigens, CD19
PubMed: 37481608
DOI: 10.1186/s13045-023-01470-0 -
International Journal of Medical... 2021Current standard vaccine testing protocols take approximately 10-24 months of testing before a vaccine can be declared successful. Sometimes by the time a successful... (Review)
Review
Current standard vaccine testing protocols take approximately 10-24 months of testing before a vaccine can be declared successful. Sometimes by the time a successful vaccine is out for public use, the outbreak may already be over. With no vaccine or antiviral drug available to treat the infected, we are left with the age-old methods of isolation, quarantine, and rest, to arrest such a viral outbreak. Convalescent blood therapy and covalent plasma therapy have often proved effective in reducing mortality, however, the role of innate and adaptive immune cells in these therapies have been overlooked. Antigen presenting cells (APCs), CD4+ T memory cells, CD8+ T memory cells, and memory B-Cells all play a vital role in sustainable defense and subsequent recovery. This report incorporates all these aspects by suggesting a novel treatment therapy called selective convalescent leukapheresis and transfusion (SCLT) and also highlights its potential in vaccination. The anticipated advantages of the proposed technique outweigh the cost, time, and efficiency of other available transfusion and vaccination processes. It is envisioned that in the future this new approach could serve as a rapid emergency response to subdue a pathogen outbreak and to stop it from becoming an epidemic, or pandemic.
Topics: Antigen-Presenting Cells; Antiviral Agents; Blood Transfusion; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 Vaccines; Cytokines; Humans; Immunization, Passive; Immunologic Factors; Immunotherapy; Leukapheresis; Pandemics; SARS-CoV-2; COVID-19 Serotherapy
PubMed: 34522165
DOI: 10.7150/ijms.46363 -
Cancer Control : Journal of the Moffitt... Jan 2015Disease complications associated with certain malignancies may be mediated by cells or soluble molecules that traffic in the bloodstream. Because of this, therapeutic... (Review)
Review
BACKGROUND
Disease complications associated with certain malignancies may be mediated by cells or soluble molecules that traffic in the bloodstream. Because of this, therapeutic apheresis (TA) methodologies have been used to selectively remove or manipulate specific molecules, antibodies, or cellular elements to treat the underlying pathological process. For some disorders, TA is utilized as a rapid-acting and short-term adjunct to conventional chemotherapy or immunotherapy. For others, a series of scheduled treatments is recommended for optimal management. In all cases, the risks, benefits, and costs must be strongly considered.
METHODS
The current literature and published guidelines were reviewed to summarize the use of TA in the management of certain complications of cancer.
RESULTS
Although TA is relatively safe and useful as a first-line or salvage modality for some disorders, few prospective, randomized clinical trials exist and the majority of evidence is derived from observational studies. Expert-based, clinical practice guidelines have been developed to inform hematology/oncology professionals and apheresis physicians about the efficacy and limitations of TA for malignancy-related indications.
CONCLUSIONS
Certain oncological conditions respond to TA and consensus guidelines are available to support clinical decision-making. However, well-designed, prospective intervention trials are needed to better define the role of TA for a variety of disorders.
Topics: Blood Component Transfusion; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukapheresis; Neoplasms; Paraproteinemias; Plasma Exchange; Plateletpheresis
PubMed: 25504280
DOI: 10.1177/107327481502200109