Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma.
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ABSTRACT:
SUBMITTER: Shalabi H
PROVIDER: S-EPMC5927974 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionGeographic access to novel oncology therapies, and the extent to which it may vary by potential sites of care, regions, and population characteristics, is poorly understood. We examined how expanding access to chimeric antigen receptor (CAR) T cell therapy administration sites impacts patient travel distances and time.MethodsWe used geographic information system techniques to calculate shortest travel distance and time between patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) and the nearest CAR T cell therapy administration site in three scenarios: academic hospitals; academic and community multispecialty hospitals; and academic and community multispecialty hospitals plus nonacademic specialty oncology network centers. Main outcome measures were differences in travel distance and time among the scenarios and the relationship between travel time and socioeconomic status, race, rural-urban areas, and non-Hodgkin lymphoma clusters. Non-Hodgkin lymphoma incidence, socioeconomic status, and administration centers were derived from governmental/publicly available data sources.ResultsOf 3922 patients eligible for CAR T cell therapy, more than 37% had to travel more than 1 h to the nearest academic hospital. Average travel time and distance were significantly reduced by 23% and 30% (P < 0.001), respectively, when access was expanded to include community hospitals plus a broader range of oncology specialty treatment centers. Compared to academic hospitals alone, increasing access to include community hospitals decreased time and distance by 7% and 8% (P < 0.01), respectively. In addition, there would be a lower proportion of sites operating as the only care provider within 25 miles if access was expanded outside of academic hospitals only. Longer travel time was associated with lower socioeconomic status.ConclusionMany patients with DLBCL have long travel times to an academic hospital that administers CAR T cell therapy. Expanding access to care through site-of-care planning will help address regional, rural-urban, and sociodemographic equity in the geographic allocation of CAR T cell therapy.
| S-EPMC8408091 | biostudies-literature
Project description: Not available
| S-EPMC8436585 | biostudies-literature
Project description:A human single-chain variable fragment (scFv) antibody library was expressed on the surface of human T cells after transduction with lentiviral vectors (LVs). The repertoire was fused to a first-generation T cell receptor ζ (TCRζ)-based chimeric antigen receptor (CAR). We used this library to isolate antibodies termed CARbodies that recognize antigens expressed on the tumor cell surface in a proof-of-principle system. After three rounds of activation-selection there was a clear repertoire restriction, with the emergence dominant clones. The CARbodies were purified from bacterial cultures as soluble and active proteins. Furthermore, to validate its potential application for adoptive cell therapy, human T cells were transduced with a LV encoding a second-generation costimulatory CAR (CAR(v2)) bearing the selected CARbodies. Transduced human primary T cells expressed significant levels of the CARbodies-based CAR(v2) fusion protein on the cell surface, and importantly could be specifically activated, after stimulation with tumor cells. This approach is a promising tool for the generation of antibodies fully adapted to the display format (CAR) and the selection context (cell synapse), which could extend the scope of current adoptive cell therapy strategies with CAR-redirected T cells.Molecular Therapy-Nucleic Acids (2013) 2, e93; doi:10.1038/mtna.2013.19; published online 21 May 2013.
| S-EPMC4817937 | biostudies-literature
Project description:Anti-CD19 chimeric antigen receptor T cell therapy (CAR19) represents a critical treatment modality for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, the majority of patients subsequently experience disease progression following CAR19, and data are limited on assessing the best salvage regimen for these patients. This study aimed to evaluate outcomes in R/R DLBCL patients with progressive disease post-CAR19 and to assess variables that predict response to salvage therapy. We performed a retrospective analysis of all patients with DLBCL who received CAR19 at our institution between January 2018 and February 2021, collecting data on demographic characteristics, disease characteristics, best response to CAR19, date of relapse or progression, and first salvage therapy and response to salvage. We analyzed patients according to whether they responded to CAR19 (responders) or did not (nonresponders). Salvage regimens were classified into 6 groups for analysis. Primary endpoints included overall survival (OS) and progression-free survival (PFS), calculated using the Kaplan-Meier method. Cox models were fit to evaluate the effect of prognostic factors. Among the 120 patients who received CAR19 during the analysis period were 69 responders who achieved a complete or partial response to CAR19 and 51 nonresponders, including 44 with stable or progressive disease and 7 who died before assessment. Thirty responders relapsed and 26 received salvage therapy, and 24 nonresponders received salvage therapy. The primary salvage regimens included lenalidomide-based regimens (n = 17; 34%), BTKi (n = 10; 20%), checkpoint inhibitor-based (n = 7; 14%), chemo-immunotherapy (n = 5; 10%), allogeneic hematopoietic stem cell transplantation (n = 5; 10%), and others (n = 6; 12%). There was no significant difference in OS based on salvage regimen (P = .4545). Responders who received salvage therapy had significantly longer OS than nonresponders (median OS not reached versus 10.9 months; P = .0187), and response to CAR19 and elevated lactate dehydrogenase level at time of salvage treatment were the only two statistically significant prognostic factors after accounting for other variables. Responders to CAR19 had significantly better outcomes with salvage therapy compared with nonresponders to CAR19. There was no significant difference in outcomes based on salvage regimen. Future research is needed to assess the best salvage regimen post-CAR19 failure.
| S-EPMC9284421 | biostudies-literature
Project description:T cells expressing anti-CD19 chimeric antigen receptors (CARs) can induce complete remissions (CRs) of diffuse large B cell lymphoma (DLBCL). The long-term durability of these remissions is unknown. We administered anti-CD19 CAR T cells preceded by cyclophosphamide and fludarabine conditioning chemotherapy to patients with relapsed DLBCL. Five of the seven evaluable patients obtained CRs. Four of the five CRs had long-term durability with durations of remission of 56, 51, 44, and 38 months; to date, none of these four cases of lymphomas have relapsed. Importantly, CRs continued after recovery of non-malignant polyclonal B cells in three of four patients with long-term complete remissions. In these three patients, recovery of CD19+ polyclonal B cells took place 28, 38, and 28 months prior to the last follow-up, and each of these three patients remained in CR at the last follow-up. Non-malignant CD19+ B cell recovery with continuing CRs demonstrated that remissions of DLBCL can continue after the disappearance of functionally effective anti-CD19 CAR T cell populations. Patients had a low incidence of severe infections despite long periods of B cell depletion and hypogammaglobulinemia. Only one hospitalization for an infection occurred among the four patients with long-term CRs. Anti-CD19 CAR T cells caused long-term remissions of chemotherapy-refractory DLBCL without substantial chronic toxicities.
| S-EPMC5628864 | biostudies-literature
Project description: Not available
| S-EPMC9325766 | biostudies-literature
Project description:Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR-T cells (CAR-Ts) against leukemia and lymphoma has encouraged development of CAR-T therapies for MM. Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited. B-cell maturation antigen is expressed by normal and malignant plasma cells. CAR-Ts targeting B-cell maturation antigen have demonstrated significant antimyeloma activity in early clinical trials. Toxicities in these trials, including cytokine release syndrome, have been similar to toxicities observed in CAR-T trials for leukemia. Targeting postulated CD19+ myeloma stem cells with anti-CD19 CAR-Ts is a novel approach to MM therapy. MM antigens including CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain are under investigation as CAR targets. MM is genetically and phenotypically heterogeneous, so targeting of >1 antigen might often be required for effective treatment of MM with CAR-Ts. Integration of CAR-Ts with other myeloma therapies is an important area of future research. CAR-T therapies for MM are at an early stage of development but have great promise to improve MM treatment.
| S-EPMC5731088 | biostudies-literature
Project description:Lymphocytes such as T-cells can be genetically transduced to express a synthetic chimeric antigen receptor (CAR) that re-directs their cytotoxic activity against a tumour-expressed antigen of choice. Autologous (patient-derived) CAR T-cells have been licensed to treat certain relapsed and refractory B-cell malignancies, and numerous CAR T-cell products are in clinical development. As living gene-modified cells, CAR T-cells exhibit unique pharmacokinetics, typically proliferating within the recipient during the first 14 days after administration before contracting in number, and sometimes exhibiting long-term persistence. The relationship between CAR T-cell dose and exposure is highly variable, and may be influenced by CAR design, patient immune function at the time of T-cell harvest, phenotype of the CAR T-cell product, disease burden, lymphodepleting chemotherapy and subsequent immunomodulatory therapies. Recommended CAR T-cell doses are typically established for a specific product and indication, although for some products, stratification of dose based on disease burden may mitigate toxicity while maintaining efficacy. Re-evaluation of CAR T-cell dosing may be necessary following changes to the lymphodepleting regimen, for different disease indications, and following significant manufacturing changes, if product comparability cannot be demonstrated. Dose escalation trials have typically employed 3 + 3 designs, although this approach has limitations, and alternative phase I trial designs may facilitate the identification of CAR T-cell doses that strike an optimal balance of safety, efficacy and manufacturing feasibility.
| S-EPMC7444796 | biostudies-literature
Project description:Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable despite the advent of numerous new drugs such as proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. There is an unmet need to develop novel therapies for refractory/relapsed MM. In the past few years, chimeric antigen receptor (CAR)-modified T cell therapy for MM has shown promising efficacy in preclinical and clinical studies. Furthermore, the toxicities of CAR-T cell therapy are manageable. This article summarizes recent developments of CAR-T therapy in MM, focusing on promising targets, new technologies, and new research areas. Additionally, a comprehensive overview of antigen selection is presented along with preliminary results and future directions of CAR-T therapy development.
| S-EPMC6873434 | biostudies-literature
Project description:Clinical trials of chimeric antigen receptors (CARs) targeting CD19 have produced impressive results in hematological malignancies, including diffuse large B-cell lymphoma (DLBCL). However, a notable number of patients with DLBCL fail to achieve remission after CD19 CAR T-cell therapy and may therefore require a dual targeted CAR T-cell therapy. A 31-year-old man with refractory DLBCL was assessed in the present case report. The patient was treated with sequential infusion of single CD19 CAR T cells followed by dual CD19/CD22-targeted CAR T cells. The outcome was that the patient achieved partial remission after the first single CD19 CAR T-cell infusion and complete remission after the dual CD19/CD22-targeted CAR T-cell infusion. Grade 1 cytokine release syndrome (CRS) was observed after the single CD19 CAR T-cell infusion, while grade 3 CRS and hemophagocytic syndrome were observed after the dual targeted CAR T-cell infusion, but these adverse effects alleviated after the treatments. To the best of our knowledge, the present case report is the first to describe the successful application of dual CD19/CD22-targeted CAR T-cell therapy for the treatment of refractory DLBCL. The report suggests that dual CD19/CD22-targeted CAR T-cell therapy may represent a promising option for the treatment of refractory DLBCL; however, caution should be taken due to potential CRS development.
| S-EPMC7405542 | biostudies-literature