Long-term remission in multiply relapsed enteropathy-associated T-cell lymphoma following CD30 CAR T-cell therapy.
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ABSTRACT:
SUBMITTER: Voorhees TJ
PROVIDER: S-EPMC7724914 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
Publications
Long-term remission in multiply relapsed enteropathy-associated T-cell lymphoma following CD30 CAR T-cell therapy.
Voorhees Timothy J TJ Ghosh Nilanjan N Grover Natalie N Block Jared J Cheng Catherine C Morrison Kaitlin K Ivanova Anastasia A Dotti Gianpietro G Serody Jonathan J Savoldo Barbara B Beaven Anne W AW
Blood advances 20201201 23
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Project description:PurposeChimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL).MethodsWe conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety.ResultsForty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent.ConclusionHeavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies.
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Project description:BackgroundLong-term outcome is unfavourable for relapsed/refractory (r/r) lymphoma patients who are resistant to salvage chemotherapy, even after subsequent autologous stem-cell transplantation (ASCT). Although anti-CD30 chimeric antigen receptor (CAR30) T-cell therapy induces high response rates in these patients, the duration of response is relatively limited.MethodsThis open-label, single-center and single-arm pilot study investigated the safety and efficacy of ASCT in tandem with CAR30 T-cell infusion in r/r CD30+ lymphoma. The primary endpoint was safety and key secondary endpoint was overall response rate, overall survival, progression-free survival, and duration of response.ResultsFive classical Hodgkin lymphoma (cHL) patients and 1 anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) patient were enrolled. The median age was 24 years. No patient had prior ASCT. Three patients (50.0%) relapsed for ≥ 2 times and 3 patients (50.0%) had primary refractory diseases. All had a Deauville score of 4 or 5, and 5 patients (83.3%) had a stable or progressive disease (SD/PD) at enrollment. All patients received myeloablative chemotherapy and infused CD34-positive hematopoietic stem cells (HSCs) and CAR30 T cells in tandem, with a median dose of 3.9 × 106/kg and 7.6 × 106/kg, respectively. Five paitents presented with cytokine release syndrome (CRS), all of which were grade 1. No neurotoxicity was observed. All patients had successful HSCs engraftment and reached an objective response, including 5 (4 cHL and 1 ALCL, 83.3%) with a complete response (CR) and 1 with a partial response (PR). With a median follow-up of 20.4 (range, 12.1-34.4) months, all remained alive and maintained their responses.ConclusionOur work demonstrates the combined administration of ASCT and CAR30 T-cell therapy is well-tolerate and highly effective in r/r cHL and ALCL, even in PET-positive or chemorefractory patients who are expected to have inferior outcome after ASCT, although further large-scaled validation in prospective clinical trial is warranted. Trial registration The trial was registered with the Chinese Clinical Trial Registry (ChiCTR, number ChiCTR2100053662).
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Project description:Chimeric antigen receptor (CAR)-T cells targeting CD30 have demonstrated high response rates with durable remissions observed in a subset of patients with relapsed/refractory CD30+ hematologic malignancies, particularly classical Hodgkin lymphoma. This therapy has low rates of toxicity including cytokine release syndrome with no neurotoxicity observed in our phase 2 study. We collected patient-reported outcomes (PROs) on patients treated with CD30 directed CAR-T cells to evaluate the impact of this therapy on their symptom experience. We collected PROs including PROMIS (Patient-Reported Outcomes Measurement Information System) Global Health and Physical Function questionnaires and selected symptom questions from the NCI PRO-CTCAE in patients enrolled on our clinical trial of CD30-directed CAR-T cells at procurement, at time of CAR-T cell infusion, and at various time points post treatment. We compared PROMIS scores and overall symptom burden between pre-procurement, time of infusion, and at 4 weeks post infusion. At least one PRO measurement during the study period was found in 23 out of the 28 enrolled patients. Patient overall symptom burden, global health and mental health, and physical function were at or above baseline levels at 4 weeks post CAR-T cell infusion. In addition, PROMIS scores for patients who participated in the clinical trial were similar to the average healthy population. CD30 CAR-T cell therapy has a favorable toxicity profile with patient physical function and symptom burden recovering to at least their baseline pretreatment health by 1 month post infusion. Trial registration number: NCT02690545.
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Project description:Mantle cell lymphoma (MCL) is a rare type of B-cell Non-Hodgkin lymphoma (NHL) affecting predominantly male patients. While complete remissions following first-line treatment are frequent, most patients ultimately relapse, with a usually aggressive further disease course. The use of cytarabine-comprising induction chemotherapy and autologous stem cell transplantation, Rituximab maintenance, Bruton's tyrosine kinase (BTK) inhibitors and CAR T therapy has substantially improved survival. Still, options for patients relapsing after CAR T therapy are limited and recommendations for the treatment of these patients are lacking. We report two cases of patients with mantle cell lymphoma who relapsed after CAR T therapy and were treated with the bispecific CD20/CD3 T cell engaging antibody glofitamab. Both patients showed marked increases of circulating CAR T cells and objective responses after glofitamab administration. Therapy was tolerated without relevant side effects in both patients. One patient completed all 12 planned cycles of glofitamab therapy and was alive and without clinical progression at the last follow-up. The second patient declined further treatment after the first cycle and succumbed to disease progression. We review the literature and investigate possible mechanisms involved in the observed responses after administration of glofitamab, such as proliferation of CAR T cells, anti-tumor effects of the bispecific antibody and the role of other possibly contributing factors. Therapy with bispecific antibodies might offer an effective and well-tolerated option for patients with mantle cell lymphoma relapsing after CAR T therapy.
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Project description:BackgroundRelapsed/refractory classic Hodgkin lymphoma (R/R cHL) remains challenging to treat, and anti-CD30 chimeric antigen receptor T (CAR-T) cell therapy may be effective. This meta-analysis investigates the efficacy and safety of anti-CD30 CAR-T cell therapy for treating R/R cHL.MethodsA systematic literature search of PubMed, Cochrane, Embase, ClinicalTrials.gov, and Web of Science databases was conducted until February 2024. The odds ratio (OR) with a 95% confidence interval (CI) was analysed using Review Manager 5.4. Outcomes including overall response rate (ORR), complete response (CR), partial response (PR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted for meta-analysis. We used the Methodological Index for Non-Randomized Studies (MINORS) to evaluate the quality of the included literature.ResultsA total of 151 participants from 8 records were included. Meta-analysis showed the ORR of CD30 CAR-T cell therapy for R/R cHL was 57% (95%CI 0.36-0.76, P = 0.50), with a CR of 34% (95%CI 0.13-0.64, P = 0.29) and a PR of 32% (95%CI 0.15-0.55, P = 0.12). With the median follow-up range from 9.5 to 71.5 months, the 1-year PFS was 39% (95% CI 0.30-0.49, P = 0.04), and the 1-year OS was 89% (95% CI 0.65-0.97, P = 0.005). The most common hematologic AE was leukopenia (72%, 95% CI: 0.50-0.87), and the most common non-hematological AE was cytokine release syndrome (CRS) (43%, 95% CI: 0.14-0.76). The grade ≥ 3 AEs was 66% (95%CI 0.06-0.98, I2 = 93%, P = 0.70), 34% (95%CI 0.07-0.78, I2 = 85%, P = 0.51) in neutropenia and thrombocytopenia, respectively. All AEs were tolerable and resolved with treatment.ConclusionCurrent evidence suggests that anti-CD30 CAR-T cell therapy is effective and safe in treating R/R cHL and is worth considering as a viable therapeutic option.
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