ABSTRACT
BACKGROUND: Treatment-related myelodysplastic syndrome (t-MDS) is a rare late effect of cancer therapy. After alkylating agents, this typically occurs years after completion of therapy. Treatment of t-MDS in pediatrics is an allogeneic stem cell transplant, however, the prognosis remains poor. OBSERVATIONS: This case demonstrates t-MDS developing in a patient receiving treatment for pre-B acute lymphoblastic leukemia. This patient was treated with a combination of hematopoietic stem cell transplant and hypomethylating agents. CONCLUSIONS: These agents should be considered for use in patients with t-MDS, before transplant to limit additional chemotherapy and as maintenance therapy post-transplant to reduce the risk of relapse.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Humans , Child , Myelodysplastic Syndromes/therapy , Myelodysplastic Syndromes/drug therapy , Stem Cell Transplantation , Prognosis , Leukemia, Myeloid, Acute/drug therapyABSTRACT
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.
Subject(s)
Lymphoma, B-Cell , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Receptors, Chimeric Antigen , Antigens, CD19 , Humans , Immunotherapy, Adoptive/adverse effects , Leukapheresis , Lymphoma, B-Cell/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Receptors, Antigen, T-Cell , Receptors, Chimeric Antigen/genetics , T-LymphocytesABSTRACT
We generated MHC-independent chimeric antigen receptors (CARs) directed to the GD2 antigen expressed by neuroblastoma tumor cells and treated patients with this disease. Two distinguishable forms of this CAR were expressed in EBV-specific cytotoxic T lymphocytes (EBV-CTLs) and activated T cells (ATCs). We have previously shown that EBV-CTLs expressing GD2-CARs (CAR-CTLs) circulated at higher levels than GD2-CAR ATCs (CAR-ATCs) early after infusion, but by 6 weeks, both subsets became low or undetectable. We now report the long-term clinical and immunologic consequences of infusions in 19 patients with high-risk neuroblastoma: 8 in remission at infusion and 11 with active disease. Three of 11 patients with active disease achieved complete remission, and persistence of either CAR-ATCs or CAR-CTLs beyond 6 weeks was associated with superior clinical outcome. We observed persistence for up to 192 weeks for CAR-ATCs and 96 weeks for CAR-CTLs, and duration of persistence was highly concordant with the percentage of CD4(+) cells and central memory cells (CD45RO(+)CD62L(+)) in the infused product. In conclusion, GD2-CAR T cells can induce complete tumor responses in patients with active neuroblastoma; these CAR T cells may have extended, low-level persistence in patients, and such persistence was associated with longer survival. This study is registered at www.clinialtrials.gov as #NCT00085930.
Subject(s)
Adoptive Transfer/methods , Bone Neoplasms/therapy , Gangliosides/immunology , Genetic Therapy/methods , Neuroblastoma/therapy , Receptors, Antigen, T-Cell/genetics , Adolescent , Antigens, Tumor-Associated, Carbohydrate/immunology , Bone Marrow Neoplasms/genetics , Bone Marrow Neoplasms/immunology , Bone Marrow Neoplasms/therapy , Bone Neoplasms/genetics , Bone Neoplasms/immunology , Cell Line, Tumor , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Immunologic Memory/immunology , Male , Neoplasm, Residual/genetics , Neoplasm, Residual/immunology , Neoplasm, Residual/therapy , Neuroblastoma/genetics , Neuroblastoma/immunology , Receptors, Antigen, T-Cell/immunology , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , T-Lymphocytes, Cytotoxic/immunology , Young AdultABSTRACT
Immunocompromised individuals are at high risk for life-threatening diseases, especially those caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus. Conventional therapeutics are primarily active only against CMV, and resistance is frequent. Adoptive transfer of polyclonal cytotoxic T lymphocytes (CTLs) specific for CMV or EBV seems promising, but it is unclear whether this strategy can be extended to adenovirus, which comprises many serotypes. In addition, the preparation of a specific CTL line for each virus in every eligible individual would be impractical. Here we describe genetic modification of antigen-presenting cell lines to facilitate the production of CD4(+) and CD8(+) T lymphocytes specific for CMV, EBV and several serotypes of adenovirus from a single cell culture. When administered to immunocompromised individuals, the single T lymphocyte line expands into multiple discrete virus-specific populations that supply clinically measurable antiviral activity. Monoculture-derived multispecific CTL infusion could provide a safe and efficient means to restore virus-specific immunity in the immunocompromised host.
Subject(s)
CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Culture Techniques/methods , Immune System Diseases/blood , Immune System Diseases/therapy , Adenoviridae/metabolism , Adolescent , Adult , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/virology , Cells, Cultured , Child , Child, Preschool , Cytomegalovirus/metabolism , Female , Herpesvirus 4, Human/metabolism , Humans , Immunophenotyping , Male , Middle Aged , T-Lymphocytes/metabolismABSTRACT
We assessed minimal residual disease (MRD) detection and B-cell aplasia after tisagenlecleucel therapy for acute lymphoblastic leukemia (ALL) to define biomarkers predictive of relapse (N = 143). Next-generation sequencing (NGS) MRD detection >0 in bone marrow (BM) was highly associated with relapse. B-cell recovery [signifying loss of functional chimeric antigen receptor (CAR) T cells] within the first year of treatment was associated with a hazard ratio (HR) for relapse of 4.5 [95% confidence interval (CI), 2.03-9.97; P < 0.001]. Multivariate analysis at day 28 showed independent associations of BMNGS-MRD >0 (HR = 4.87; 95% CI, 2.18-10.8; P < 0.001) and B-cell recovery (HR = 3.33; 95% CI, 1.44-7.69; P = 0.005) with relapse. By 3 months, the BMNGS-MRD HR increased to 12 (95% CI, 2.87-50; P < 0.001), whereas B-cell recovery was not independently predictive (HR = 1.27; 95% CI, 0.33-4.79; P = 0.7). Relapses occurring with persistence of B-cell aplasia were largely CD19- (23/25: 88%). Detectable BMNGS-MRD reliably predicts risk with sufficient time to consider approaches to relapse prevention such as hematopoietic cell transplantation (HCT) or second CAR-T cell infusion. SIGNIFICANCE: Detectable disease by BMNGS-MRD with or without B-cell aplasia is highly predictive of relapse after tisagenlecleucel therapy for ALL. Clonotypic rearrangements used to follow NGS-MRD did not change after loss of CD19 or lineage switch. High-risk patients identified by these biomarkers may benefit from HCT or investigational cell therapies.See related commentary by Ghorashian and Bartram, p. 2.This article is highlighted in the In This Issue feature, p. 1.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma , Antigens, CD19 , Child , High-Throughput Nucleotide Sequencing , Humans , Neoplasm, Residual/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Receptors, Antigen, T-Cell , Recurrence , Young AdultABSTRACT
Infants with B-cell acute lymphoblastic leukemia (B-ALL) have poor outcomes because of chemotherapy resistance leading to high relapse rates. Tisagenlecleucel, a CD19-directed chimeric antigen receptor T-cell (CART) therapy, is US Food and Drug Administration approved for relapsed or refractory B-ALL in patients ≤25 years; however, the safety and efficacy of this therapy in young patients is largely unknown because children <3 years of age were excluded from licensing studies. We retrospectively evaluated data from the Pediatric Real-World CAR Consortium to examine outcomes of patients with infant B-ALL who received tisagenlecleucel between 2017 and 2020 (n = 14). Sixty-four percent of patients (n = 9) achieved minimal residual disease-negative remission after CART and 50% of patients remain in remission at last follow-up. All patients with high disease burden at time of CART infusion (>M1 marrow) were refractory to this therapy (n = 5). Overall, tisagenlecleucel was tolerable in this population, with only 3 patients experiencing ≥grade 3 cytokine release syndrome. No neurotoxicity was reported. This is the largest report of tisagenlecleucel use in infant B-ALL and shows that this therapy is safe and can be effective in this population. Incorporating this novel immunotherapy into the treatment of infant B-ALL offers a promising therapy for a highly aggressive leukemia.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma , Receptors, Chimeric Antigen , Antigens, CD19/immunology , Antigens, CD19/therapeutic use , Child , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Receptors, Antigen, T-Cell/therapeutic use , Receptors, Chimeric Antigen/therapeutic use , Retrospective Studies , United StatesABSTRACT
Chimeric antigen receptor (CAR) T-cell therapies that specifically target the CD19 antigen have emerged as a highly effective treatment option in patients with refractory B-cell hematological malignancies. Safety and efficacy outcomes from the pivotal prospective clinical trials of axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel and the retrospective, postmarketing, real-world analyses have confirmed high response rates and durable remissions in patients who had failed multiple lines of therapy and had no meaningful treatment options. Although initially administered in the inpatient setting, there has been a growing interest in delivering CAR-T cell therapy in the outpatient setting; however, this has not been adopted as standard clinical practice for multiple reasons, including logistic and reimbursement issues. CAR-T cell therapy requires a multidisciplinary approach and coordination, particularly if given in an outpatient setting. The ability to monitor patients closely is necessary and proper protocols must be established to respond to clinical changes to ensure efficient, effective and rapid evaluation either in the clinic or emergency department for management decisions regarding fever, sepsis, cytokine release syndrome and neurological events, specifically immune effector cell-associated neurotoxicity syndrome. This review presents the authors' institutional experience with the preparation and delivery of outpatient CD19-directed CAR-T cell therapy.
Subject(s)
Ambulatory Care , Antigens, CD19/immunology , Immunotherapy, Adoptive , Lymphoma, B-Cell/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Receptors, Chimeric Antigen/genetics , T-Lymphocytes/transplantation , Ambulatory Care/economics , Cost-Benefit Analysis , Hospital Costs , Humans , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/economics , Immunotherapy, Adoptive/mortality , Lymphoma, B-Cell/economics , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/mortality , Patient Safety , Precursor Cell Lymphoblastic Leukemia-Lymphoma/economics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Risk Assessment , Risk Factors , T-Lymphocytes/immunology , Treatment OutcomeABSTRACT
BACKGROUND: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated durable efficacy and a manageable safety profile in pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) in the ELIANA pivotal trial and real-world experience. Experience from investigator-led studies prior to ELIANA suggests that infections and inflammatory conditions may exacerbate the severity of cytokine release syndrome (CRS) associated with CAR-T cell therapy, leading to extreme caution and strong restrictions for on-study and commercial infusion of tisagenlecleucel in patients with active infection. CRS intervention with interleukin (IL)-6 blockade and/or steroid therapy was introduced late in the course during clinical trials due to concern for potential negative effect on efficacy and persistence. However, earlier CRS intervention is now viewed more favorably. Earlier intervention and consistency in management between providers may promote broader use of tisagenlecleucel, including potential curative therapy in patients who require remission and recovery of hematopoiesis for management of severe infection. MAIN BODY: Patient 1 was diagnosed with B-ALL at 23 years old. Fourteen days before tisagenlecleucel infusion, the patient developed fever and neutropenia and was diagnosed with invasive Mucorales infection and BK virus hemorrhagic cystitis. Aggressive measures were instituted to control infection and to manage prolonged cytopenias during CAR-T cell manufacturing. Adverse events, including CRS, were manageable despite elevated inflammatory markers and active infection. The patient attained remission and recovered hematopoiesis, and infections resolved. The patient remains in remission ≥1 year postinfusion.Patient 2 was diagnosed with pre-B-ALL at preschool age. She developed severe septic shock 3 days postinitiation of lymphodepleting chemotherapy. After receiving tisagenlecleucel, she experienced CRS with cardiac dysfunction and extensive lymphadenopathy leading to renovascular compromise. The patient attained remission and was discharged in good condition to her country of origin. She remained in remission but expired on day 208 postinfusion due to cardiac arrest of unclear etiology. CONCLUSIONS: Infusion was feasible, and toxicity related to tisagenlecleucel was manageable despite active infections and concurrent inflammation, allowing attainment of remission in otherwise refractory pediatric/young adult ALL. This may lead to consideration of tisagenlecleucel as a potential curative therapy in patients with managed active infections.
Subject(s)
Cytokine Release Syndrome/microbiology , Immunotherapy, Adoptive/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Receptors, Antigen, T-Cell/administration & dosage , Shock, Septic/microbiology , BK Virus/pathogenicity , Cell Line, Tumor , Child, Preschool , Disease Management , Female , Humans , Infusion Pumps , Mucormycosis/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/microbiology , Treatment Outcome , Young AdultABSTRACT
Tisagenlecleucel is indicated for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL). The tisagenlecleucel chimeric antigen receptor (CAR) contains a murine single-chain variable fragment domain; we examined the effects of humoral and cellular immune responses to tisagenlecleucel on clinical outcomes using 2 validated assays. Data were pooled from the ELIANA (registered at www.clinicaltrials.gov as #NCT02435849) and ENSIGN (#NCT02228096) trials in r/r B-ALL (N = 143) and the JULIET trial (#NCT02445248) in r/r DLBCL (N = 115). Humoral responses were determined by flow cytometric measurement of anti-murine CAR19 (mCAR19) antibodies in serum. Cellular responses were determined using T-cell production of interferon-γ in response to 2 different pools of mCAR19 peptides. Pretreatment anti-mCAR19 antibodies were detected in 81% of patients with r/r B-ALL and 94% of patients with r/r DLBCL. Posttreatment anti-mCAR19 antibodies were higher than patient-specific baseline in 42% of r/r B-ALL and 9% of r/r DLBCL patients. Pretreatment and posttreatment anti-mCAR19 antibodies did not affect tisagenlecleucel cellular kinetics, including maximum concentration and persistence (r2 < 0.05), clinical response (day-28 response, duration of response, and event-free survival), and safety. T-cell responses were consistent over time, with net responses <1% at baseline and posttreatment time points in a majority of patients and no effect on transgene expansion or persistence or outcomes. Presence of baseline and/or posttreatment anti-mCAR19 antibodies or T-cell responses did not alter the activity of tisagenlecleucel in patients with r/r B-ALL or r/r DLBCL.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Animals , Child , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Mice , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Progression-Free Survival , Receptors, Antigen, T-Cell/geneticsABSTRACT
HLA-matched sibling donor (MSD) stem cell transplantation can cure>60% of pediatric patients with acute lymphoblastic leukemia (ALL), but <30% of patients will have a sibling donor. Alternative donor (AD) transplantation can be curative but has a higher risk of graft-versus-host disease (GVHD). The addition of alemtuzumab (Campath 1-H) to AD transplants produces in vivo T cell depletion, which may reduce the risk for GVHD. We now report the outcome for 83 children with ALL (41 MSD, 42 AD) undergoing stem cell transplantation in first or second complete remission. All patients received myeloablative conditioning, including cyclophosphamide, cytarabine arabinoside, and total-body irradiation, with alemtuzumab administered to AD recipients. GVHD prophylaxis consisted of a calcineurin inhibitor with either short-course methotrexate or prednisone. Disease-free survival (DFS) for MSD recipients was 72.3% (95% confidence interval [CI], 55.4%-83.6%) versus 62.4% (95% CI, 45.2%-75.4%) for AD recipients. The 100-day mortality was 7.1% in the AD group and 2.4% in the MSD group. Relapse rates were identical (24%). Treatment-related mortality, principally viral infection, explained the difference in survival. For children undergoing stem cell transplantation (SCT) from alternative donors, alemtuzumab with a myeloablative conditioning regimen resulted in DFS comparable to MSD.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Neoplasm/administration & dosage , Antineoplastic Agents/administration & dosage , Donor Selection , Hematopoietic Stem Cell Transplantation , Living Donors , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Siblings , Transplantation Conditioning , Adolescent , Adult , Alemtuzumab , Antibodies, Monoclonal, Humanized , Child , Child, Preschool , Disease-Free Survival , Donor Selection/methods , Female , Graft Survival , Graft vs Host Disease/mortality , Humans , Infant , Male , National Health Programs , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Recurrence , Remission Induction , Retrospective Studies , Risk Factors , Survival Rate , Transplantation, Homologous , United StatesABSTRACT
Cytotoxic T lymphocytes (CTLs) directed to nonviral tumor-associated antigens do not survive long term and have limited antitumor activity in vivo, in part because such tumor cells typically lack the appropriate costimulatory molecules. We therefore engineered Epstein-Barr virus (EBV)-specific CTLs to express a chimeric antigen receptor directed to the diasialoganglioside GD2, a nonviral tumor-associated antigen expressed by human neuroblastoma cells. We reasoned that these genetically engineered lymphocytes would receive optimal costimulation after engagement of their native receptors, enhancing survival and antitumor activity mediated through their chimeric receptors. Here we show in individuals with neuroblastoma that EBV-specific CTLs expressing a chimeric GD2-specific receptor indeed survive longer than T cells activated by the CD3-specific antibody OKT3 and expressing the same chimeric receptor but lacking virus specificity. Infusion of these genetically modified cells seemed safe and was associated with tumor regression or necrosis in half of the subjects tested. Hence, virus-specific CTLs can be modified to function as tumor-directed effector cells.