Genetic landscapes and curative effect of CAR T-cell immunotherapy in patients with relapsed or refractory DLBCL.
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ABSTRACT:
SUBMITTER: Shi H
PROVIDER: S-EPMC10034568 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
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Genetic landscapes and curative effect of CAR T-cell immunotherapy in patients with relapsed or refractory DLBCL.
Shi Hui H Zheng Peihao P Liu Rui R Xu Teng T Yang Fan F Feng Shaomei S Guo Yuelu Y Ma Lixia L Liu Haidi H Lei Yang Y Li Ruiting R Deng Biping B Hou Shuling S Li Yang Y Zheng Qinlong Q Hu Kai K Ke Xiaoyan X
Blood advances 20230301 6
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Project description:Cellular therapies have transformed the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), which typically does not respond well to salvage chemotherapy. Recently, approximately 40% of r/r DLBCL patients across three different trials achieved a complete remission at 1 year after receiving treatment with autologous chimeric antigen receptor (CAR) T cells (auto-CARs). These successes have prompted studies of auto-CARs in second-line settings, in which axicabtagene ciloleucel and lisocabtagene maraleucel both showed improved event-free survival over autologous hematopoietic cell transplantation (AHCT). While encouraging, this data also highlights that 60% of patients relapse or progress following treatment with auto-CARs. Individual disease characteristics and logistical challenges of cell engineering also limit patients' eligibility for auto-CARs. Allogeneic CAR T cells (allo-CARs) may address some of these limitations as they may mitigate delays associated with auto-CARs, thereby reducing the need for bridging chemotherapies and increasing availability of cellular products for patients with aggressive lymphomas. By being sourced from healthy donors who have never been exposed to cytotoxic chemotherapy, allo-CARs can be created from T cells with better fitness. Allo-CARs made from specific cellular subsets (e.g., stem cell memory or naïve/early memory T cells) may also have increased efficacy and long-term persistence. Additionally, allo-CARs have been successfully created from other cell types, including natural killer cells, gamma-delta T-cells and induced pluripotent stem cells. These cell types can be engineered to target viral antigens, enabling precision targeting of virally driven DLBCL. As allogeneic donor cells can be banked and cryopreserved in batches, they can be made more readily available, potentially reducing logistical hurdles and costs compared to engineering auto-CARs. This may ultimately create a more sustainable platform for cell therapies. Challenges with allo-CARs that will need to be addressed include graft versus host disease, alloimmunization, potentially decreased persistence relative to auto-CARs, and antigen escape. In short, the adaptability of allo-CARs makes them ideal for treating patients with r/r DLBCL who have progressed through standard chemotherapy, AHCT, or auto-CARs. Here, we review the published literature on patients with r/r DLBCL treated with allogeneic CAR products manufactured from various cell types as well as forthcoming allogeneic CAR technologies.
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Project description:Genomic Analysis of Relapsed/Refractory DLBCL
| PRJNA1200818 | ENA
Project description:Genomic Analysis of Relapsed/Refractory DLBCL
| PRJNA1200817 | ENA
Project description:BackgroundPatients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma.MethodsIn a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×106 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months.ResultsA total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred.ConclusionsKTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).
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Project description:BackgroundRelapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis despite the availability of multiple treatment options. Preliminary evidence suggests that DLBCL may be responsive to programmed death ligand 1 (PD-L1)/programmed death 1 inhibitors.ObjectiveThe JAVELIN DLBCL study was conducted to assess whether a combination of agents could augment and sustain the antitumor immunity of avelumab, an anti-PD-L1 antibody, in R/R DLBCL.MethodsThis was a multicenter, randomized, open-label, parallel-arm study with a phase Ib and a phase III component. Reported here are the results from the phase Ib study, wherein 29 adult patients with DLBCL were randomized 1:1:1 to receive avelumab in combination with utomilumab (an immunoglobulin G2 4-1BB agonist) and rituximab (arm A), avelumab in combination with utomilumab and azacitidine (arm B), or avelumab in combination with bendamustine and rituximab (arm C). The primary endpoints were dose-limiting toxicities and objective response as assessed by the investigator per Lugano Response Classification criteria.ResultsOf the seven patients in arm A, one (14.3%) experienced two grade 3 dose-limiting toxicities (herpes zoster and ophthalmic herpes zoster); no dose-limiting toxicities were reported in arms B or C. No new safety concerns emerged for avelumab. One partial response was reported in arm A, three complete responses in arm C, and no responses in arm B. Given the insufficient antitumor activity in arms A and B and the infeasibility of expanding arm C, the study was discontinued before initiation of the phase III component.ConclusionsThe low level of clinical activity suggests that PD-L1 inhibitor activity may be limited in R/R DLBCL. CLINICALTRIALS.Gov identifierNCT02951156.
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