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Blood Mar 2022Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small...
Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198.
Topics: Antigens, CD19; Cytokine Release Syndrome; Humans; Immunotherapy, Adoptive; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Recurrence
PubMed: 34699592
DOI: 10.1182/blood.2021011895 -
Cell Reports. Medicine Apr 2022John Maher has worked on CAR T cell immunotherapy with a primary focus on solid tumors for over 20 years. In this Q&A, Cell Reports Medicine interviewed him about his...
John Maher has worked on CAR T cell immunotherapy with a primary focus on solid tumors for over 20 years. In this Q&A, Cell Reports Medicine interviewed him about his journey in this arena and next steps.
Topics: Humans; Immunotherapy; Immunotherapy, Adoptive; Neoplasms
PubMed: 35522096
DOI: 10.1016/j.xcrm.2022.100595 -
Blood Advances Apr 2022Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In...
Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range, <1 to 26), response rate of 86% (n = 131 of 152), 12-month OS of 75.1% (95% confidence interval [CI], 67.6% to 82.6%), and 12-month CIR of 36.4% (95% CI, 27.5% to 45.2%). Optimal fludarabine exposure was determined as AUC ≥13.8 mg × h/L. In multivariable analyses, patients with AUC <13.8 mg × h/L had a 2.5-fold higher CIR (hazard ratio [HR], 2.45; 95% CI, 1.34-4.48; P = .005) and twofold higher risk of relapse or loss of BCA (HR, 1.96; 95% CI, 1.19-3.23; P = .01) compared with those with optimal fludarabine exposure. High preinfusion disease burden was also associated with increased risk of relapse (HR, 2.66; 95% CI, 1.45-4.87; P = .001) and death (HR, 4.77; 95% CI, 2.10-10.9; P < .001). Personalized PK-directed dosing to achieve optimal fludarabine exposure should be tested in prospective trials and, based on this analysis, may reduce disease relapse after CAR T-cell therapy.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Immunotherapy, Adoptive; Infant; Prospective Studies; Recurrence; Retrospective Studies; Vidarabine; Young Adult
PubMed: 34788386
DOI: 10.1182/bloodadvances.2021006418 -
Blood Jun 2022Few studies have described chimeric antigen receptor (CAR) T-cell therapy for patients with B-cell acute lymphoblastic leukemia (B-ALL) with central nervous system... (Clinical Trial)
Clinical Trial
Few studies have described chimeric antigen receptor (CAR) T-cell therapy for patients with B-cell acute lymphoblastic leukemia (B-ALL) with central nervous system leukemia (CNSL) because of concerns regarding poor response and treatment-related neurotoxicity. Our study included 48 patients with relapsed/refractory B-ALL with CNSL to evaluate the efficacy and safety of CD19-specific CAR T cell-based therapy. The infusion resulted in an overall response rate of 87.5% (95% confidence interval [CI], 75.3-94.1) in bone marrow (BM) disease and remission rate of 85.4% (95% CI, 72.8-92.8) in CNSL. With a median follow-up of 11.5 months (range, 1.3-33.3), the median event-free survival was 8.7 months (95% CI, 3.7-18.8), and the median overall survival was 16.0 months (95% CI, 13.5-20.1). The cumulative incidences of relapse in BM and CNS diseases were 31.1% and 11.3%, respectively, at 12 months (P = .040). The treatment was generally well tolerated, with 9 patients (18.8%) experiencing grade ≥3 cytokine release syndrome. Grade 3 to 4 neurotoxic events, which developed in 11 patients (22.9%), were associated with a higher preinfusion disease burden in CNS and were effectively controlled under intensive management. Our results suggest that CD19-specific CAR T cell-based therapy can induce similar high response rates in both BM and CNS diseases. The duration of remission in CNSL was longer than that in BM disease. CD19 CAR T-cell therapy may provide a potential treatment option for previously excluded patients with CNSL, with manageable neurotoxicity. The clinical trials were registered at www.clinicaltrials.gov as #NCT02782351 and www.chictr.org.cn as #ChiCTR-OPN-16008526.
Topics: Acute Disease; Antigens, CD19; Burkitt Lymphoma; Central Nervous System Neoplasms; Cytokine Release Syndrome; Humans; Immunotherapy, Adoptive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 35338773
DOI: 10.1182/blood.2021013733 -
Molecular Therapy : the Journal of the... Apr 2019Adoptive T cell therapy is a form of cellular therapy that utilizes human immune cells, often empowered by the expression of recombinant proteins, to attack selected... (Review)
Review
Adoptive T cell therapy is a form of cellular therapy that utilizes human immune cells, often empowered by the expression of recombinant proteins, to attack selected targets present on tumor or infected cells. T cell-based immunotherapy has been progressing over the past several decades, and reached a milestone with the recent US Food and Drug Administration (FDA) approval of chimeric antigen receptor T cell therapy for relapsed and refractory leukemia and lymphoma. Although most studies have used viral vectors, a growing number of researchers have come to appreciate in vitro-transcribed (IVT) mRNA for the development, testing, and application of T cell-based immunotherapeutics. IVT mRNA offers inherent safety features, highly efficient recombinant protein translation, and the ability to control pharmacokinetic properties of the therapy. In this review, we discuss the history of IVT mRNA in adoptive T cell therapy, from tumor-infiltrating lymphocytes and T cell receptor-based therapies to chimeric antigen receptor therapy and gene-editing techniques, as well as prior and ongoing clinical trials.
Topics: Animals; Cell- and Tissue-Based Therapy; Gene Editing; Genetic Vectors; Humans; Immunotherapy, Adoptive; In Vitro Techniques; Lymphocytes, Tumor-Infiltrating; Mice; Neoplasms; RNA, Messenger; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Transcription, Genetic
PubMed: 30819612
DOI: 10.1016/j.ymthe.2019.01.018 -
Current Problems in Cancer Feb 2022Approaches to immunologic therapies in myelodysplastic syndromes (MDS) have generally fallen into 2 categories: therapies that target immune effector cells and enhance... (Review)
Review
Approaches to immunologic therapies in myelodysplastic syndromes (MDS) have generally fallen into 2 categories: therapies that target immune effector cells and enhance or direct an antileukemic effect, and therapies which target immunological markers on MDS progenitors themselves. Examples of the former include immune checkpoint inhibitors, immunomodulatory therapies, and vaccines, among others, while examples of the latter include antibody-drug conjugate therapies and naked antibodies; while bispecific antibodies and modified T-cells (such as CAR-T therapies) bridge both therapeutic modalities. In this review, we will discuss the rationale for the above therapies, clinical results to date, and potential future directions for investigation.
Topics: Humans; Immunotherapy; Immunotherapy, Adoptive; Medical Oncology; Myelodysplastic Syndromes; Neoplasms
PubMed: 34980485
DOI: 10.1016/j.currproblcancer.2021.100824 -
Irish Journal of Medical Science Feb 2021Cancer is a major burden on the healthcare system, and new therapies are needed. Recently, the development of immunotherapies, which aim to boost or use the immune... (Review)
Review
Cancer is a major burden on the healthcare system, and new therapies are needed. Recently, the development of immunotherapies, which aim to boost or use the immune system, or its constituents, as a tool to fight malignant cells, has provided a major new tool in the arsenal of clinicians and has revolutionized the treatment of many cancers.Cellular immunotherapies are based on the administration of living cells to patients and have developed hugely, especially since 2010 when Sipuleucel-T (Provenge), a DC vaccine, was the first cellular immunotherapy to be approved by the FDA. The ensuing years have seen two further cellular immunotherapies gain FDA approval: tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta).This review will give an overview of the principles of immunotherapies before focusing on the major forms of cellular immunotherapies individually, T cell-based, natural killer (NK) cell-based and dendritic cell (DC)-based, as well as detailing some of the clinical trials relevant to each therapy.
Topics: Humans; Immunotherapy; Immunotherapy, Adoptive; Neoplasms
PubMed: 32607912
DOI: 10.1007/s11845-020-02264-w -
International Journal of Molecular... Aug 2020Hematological malignancies define a highly heterogeneous set of blood-, bone marrow-, and organ-associated diseases with highly variable prognoses that constantly...
Hematological malignancies define a highly heterogeneous set of blood-, bone marrow-, and organ-associated diseases with highly variable prognoses that constantly relapse upon treatment [...].
Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Resistance, Neoplasm; Drug Therapy, Combination; Hematologic Neoplasms; Humans; Immunotherapy; Immunotherapy, Adoptive; Molecular Targeted Therapy
PubMed: 32847013
DOI: 10.3390/ijms21176091 -
Technology in Cancer Research &... 2023Adoptive cell immunotherapy (ACT) is an innovative promising treatment for tumors. ACT is characterized by the infusion of active anti-tumor immune cells (specific and... (Review)
Review
Adoptive cell immunotherapy (ACT) is an innovative promising treatment for tumors. ACT is characterized by the infusion of active anti-tumor immune cells (specific and non-specific) into patients to kill tumor cells either directly or indirectly by stimulating the body's immune system. The patient's (autologous) or a donor's (allogeneic) immune cells are used to improve immune function. Chimeric antigen receptor (CAR) T cells (CAR-T) is a type of ACT that has gained attention. T cells from the peripheral blood are genetically engineered to express CARs that rapidly proliferate and specifically recognize target antigens to exert its anti-tumor effects. Clinical application of CAR-T therapy for hematological tumors has shown good results, but adverse reactions and recurrence limit its applicability. Tumor infiltrating lymphocyte (TIL) therapy is effective for solid tumors. TIL therapy exhibits T cell receptor (TCR) clonality, superior tumor homing ability, and low targeted toxicity, but its successful application is limited to a number of tumors. Regardless, TIL and CAR-T therapies are effective for treating cancer. Additionally, CAR-natural killer (NK), CAR-macrophages (M), and TCR-T therapies are currently being researched. In this review, we highlight the current developments and limitations of several types of ACT.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Receptors, Antigen, T-Cell; Neoplasms; Immunotherapy
PubMed: 38037341
DOI: 10.1177/15330338231204198 -
Blood Jul 2022
Topics: Germany; Humans; Immunotherapy, Adoptive; Lymphoma, B-Cell
PubMed: 35900785
DOI: 10.1182/blood.2022016277