Determinants of response and resistance to CAR T cell therapy

Publication date: Available online 6 November 2019Source: Seminars in Cancer BiologyAuthor(s): Stefanie Lesch, Mohamed-Reda Benmebarek, Bruno L. Cadilha, Stefan Stoiber, Marion Subklewe, Stefan Endres, Sebastian KoboldAbstractThe remarkable success of chimeric antigen receptor (CAR)-engineered T cells in pre-B cell acute lymphoblastic leukemia (ALL) and B cell lymphoma led to the approval of anti-CD19 CAR T cells as the first ever CAR T cell therapy in 2017. However, with the number of CAR T cell-treated patients increasing, observations of tumor escape and resistance to CAR T cell therapy with disease relapse are demonstrating the current limitations of this therapeutic modality. Mechanisms hampering CAR T cell efficiency include limited T cell persistence, caused for example by T cell exhaustion and activation-induced cell death (AICD), as well as therapy-related toxicity. Furthermore, the physical properties, antigen heterogeneity and immunosuppressive capacities of solid tumors have prevented the success of CAR T cells in these entities. Herein we review current obstacles of CAR T cell therapy and propose strategies in order to overcome these hurdles and expand CAR T cell therapy to a broader range of cancer patients.
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research

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Keserű Richard Moriggl Signal transducer and activator of transcription (STAT)3 and STAT5 are important transcription factors that are able to mediate or even drive cancer progression through hyperactivation or gain-of-function mutations. Mutated STAT3 is mainly associated with large granular lymphocytic T-cell leukemia, whereas mutated STAT5B is associated with T-cell prolymphocytic leukemia, T-cell acute lymphoblastic leukemia and γδ T-cell-derived lymphomas. Hyperactive STAT3 and STAT5 are also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukem...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
Chimeric antigen receptor (CAR)-T cell therapy is a new and powerful class of cancer immunotherapy [1,2]. Clinical trials of CAR-T cell therapy targeting the B-cell marker CD19 have shown promising results for the treatment of hematologic malignancies, including acute lymphoblastic leukemia (ALL) [3 –7], chronic lymphocytic leukemia (CLL) [8,9], and non-Hodgkin lymphoma (NHL) [10,11]. CAR-T cell therapy targeting B-cell maturation antigen (BCMA) has also been demonstrated to be effective for treating multiple myeloma (MM) [12–15].
Source: Biology of Blood and Marrow Transplantation - Category: Hematology Authors: Source Type: research
nski J, Urbano-Ispizua A, Hayden PJ, Kröger N Abstract Chimeric antigen receptor T-cells are a novel class of anti-cancer therapy in which autologous or allogeneic T-cells are engineered to express a chimeric antigen receptor targeting a membrane antigen. In Europe, Tisagenlecleucel (KymriahTM) is approved for the treatment of refractory/relapsed Acute Lymphoblastic Leukaemia in children and young adults as well as relapsed/refractory Diffuse Large B-cell Lymphoma; Axicabtagene ciloleucel (YescartaTM) is approved for the treatment of relapsed/refractory high-grade B-cell Lymphoma and Primary Mediastinal B-cel...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research
Infectious diseases are still a significant cause of morbidity and mortality worldwide. Despite the progress in drug development, the occurrence of microbial resistance is still a significant concern. Alternative therapeutic strategies are required for non-responding or relapsing patients. Chimeric antigen receptor (CAR) T cells has revolutionized cancer immunotherapy, providing a potential therapeutic option for patients who are unresponsive to standard treatments. Recently two CAR T cell therapies, Yescarta® (Kite Pharma/Gilead) and Kymriah® (Novartis) were approved by the FDA for the treatments of certain types ...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
ConclusionWe suggest a one ‐compartment population model with first‐order elimination to capture the pharmacokinetic profile for basiliximab for this patient population.
Source: Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL RESEARCH ARTICLE Source Type: research
We present a novel, TdT and CD3 negative, aggressive early T-cell precursor LBL (ETP-LBL) initially misdiagnosed as a high grade B-cell lymphoma due to expression of CD79a and the erroneous detection of BCL2/IGH fusion. The patient was eventually evaluated using molecular diagnostic techniques, including fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) assays that demonstrated PICALM-MLLT10 fusion and a NOTCH1 mutation in the absence of BCL2/IGH fusion. The use of NGS, specifically mate-pair sequencing (MPseq), subsequently confirmed an in-frame PICALM-MLLT10 fusion. Our retrospective analysis...
Source: Cancer Genetics - Category: Cancer & Oncology Source Type: research
Abstract Adoptive immunotherapy of cancer using T cells expressing chimeric antigen receptors (CARs) is now an approved treatment for non-Hodgkin lymphoma (NHL) and B cell acute lymphoblastic leukemia (B-ALL), inducing high response rates in patients. The infusion products are generated by using retro- or lentiviral transduction to induce CAR expression in T cells followed by an in vitro expansion protocol. However, use of viral vectors is cumbersome and is associated with increased costs due to the required high titers, replication-competent retrovirus (RCR) detection and production/use in a biosafety level 2 cul...
Source: Mol Biol Cell - Category: Molecular Biology Authors: Tags: Methods Mol Biol Source Type: research
We describe three clinical scenarios in which CAR T- cell immunotherapy interfered with HIV-1 testing including: (1) routine infectious disease screening prior to stem cell transplantation in a 16-year-old female with B-cell acute lymphoblastic leukemia, status post CAR T- cell treatment (2) routine infectious disease screening prior to 2nd CAR T- cell collection in a 65-year-old male with diffuse large B-cell lymphoma who failed initial CAR T- cell treatment and (3) routine infectious risk assessment following an occupational health exposure from a 58 -year-old male with multiple myeloma, status post CAR T- cell treatment...
Source: Clinical Lymphoma and Myeloma - Category: Cancer & Oncology Authors: Tags: J Clin Microbiol Source Type: research
Conclusion: The cumulative incidence of malnutrition in Finnish pediatric cancer patients is comparable to that reported in other populations. The nutritional status of patients with acute myeloid leukemia, CNS tumors, or solid tumors should be monitored with extra care to facilitate early intervention in the case of impending malnutrition.What is known:•Both malnutrition and obesity are associated with reduced survival and increased drug toxicity in pediatric cancer patients.What is new:•Overall, 28 % of Finnish children receiving chemotherapy for cancer suffer from malnutrition during the first 42 months follow...
Source: European Journal of Pediatrics - Category: Pediatrics Source Type: research
ConclusionsIn conclusion, our study shows that BIV subtype is heterogeneous group of leukemia including not only the BL, but also BCP-ALL. In ambiguous cases, only a combination of multiple immunophenotypic, cytomorphologic, and genetic diagnostic technologies can allow the precise discrimination of BL and BCP-ALL and selection of the appropriate treatment scheme.
Source: Journal of Cancer Research and Clinical Oncology - Category: Cancer & Oncology Source Type: research
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