Anti-CD19 chimeric antigen receptor (CAR) T cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application. Here we generated a new ...anti-CD19 CAR molecule (CD19-BBz(86)) derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains. We found that CD19-BBz(86) CAR T cells produced lower levels of cytokines, expressed higher levels of antiapoptotic molecules and proliferated more slowly than the prototype CD19-BBz CAR T cells, although they retained potent cytolytic activity. We performed a phase 1 trial of CD19-BBz(86) CAR T cell therapy in patients with B cell lymphoma (ClinicalTrials.gov identifier NCT02842138 ). Complete remission occurred in 6 of 11 patients (54.5%) who each received a dose of 2 × 10
-4 × 10
CD19-BBz(86) CAR T cells. Notably, no neurological toxicity or CRS (greater than grade 1) occurred in any of the 25 patients treated. No significant elevation in serum cytokine levels after CAR T cell infusion was detected in the patients treated, including in those who achieved complete remission. CD19-BBz(86) CAR T cells persistently proliferated and differentiated into memory cells in vivo. Thus, therapy with the new CD19-BBz(86) CAR T cells produces a potent and durable antilymphoma response without causing neurotoxicity or severe CRS, representing a safe and potent anti-CD19 CAR T cell therapy.
To investigate the effectiveness and safety of using chimeric antigen receptor (CAR) T cell therapies targeting CD19 in patients with diffuse large B-cell lymphoma (DLBCL).
PubMed, Embase, and the ...Cochrane Library were searched for reports published from database inception up to July 2021. The present meta-analysis included clinical response outcomes, survival outcomes, and safety analyses. For qualitative analysis that could not be combined, the data were presented in a tabular form. Subgroup analyses were also performed according to the costimulatory domains, generic names, and study designs.
Twenty-seven studies (1,687 patients) were included. The pooled 12-months overall survival (OS) rate was 63% (95%CI: 56-70%). The pooled best overall response (BOR) was 74.0% (95%CI: 67-79%), with a best complete response (BCR) of 48% (95%CI: 42-54%) and a 3-months CR rate (CRR) of 41% (95%CI: 35-47%). The subgroup analyses by costimulatory domain suggested statistically significant differences in BOR and BCR, whereas not in the 12-months OS rate and 3-months CRR. Among the patients evaluable for safety, 78% (95%CI: 68-87%), 6% (95%CI: 3-10%), 41% (95%CI: 31-52%), and 16% (95%CI: 10-24%) experienced cytokine release syndrome (CRS), severe CRS, neurotoxicity, and severe neurotoxicity, respectively. Compared with the CD28 costimulatory domain, the 4-1BB-based products showed a better safety profile on any-grade CRS (
< 0.01), severe CRS (
= 0.04), any-grade neurotoxicity (
< 0.01), and severe neurotoxicity (
< 0.01).
Anti-CD19 CAR-T cell immunotherapy has promising effectiveness and tolerable severe AE profile in DLBCL patients. 4-1BB-based CAR-T cells have a similar 12-months OS rate and 3-months CRR with CD28-based products but a better safety profile. The costimulatory domain might not affect the survival outcomes.
The genetic predisposition to lymphoma is not fully understood. We identified 13 lymphoma-cancer families (2011-2021), in which 27 individuals developed lymphomas and 26 individuals had cancers. ...Notably, male is the predominant gender in lymphoma patients, whereas female is the predominant gender in cancer patients (p = .019; OR = 4.72, 95% CI, 1.30-14.33). We collected samples from 18 lymphoma patients, and detected germline variants through exome sequencing. We found that germline protein truncating variants (PTVs) were enriched in DNA repair and immune genes. Totally, we identified 31 heterozygous germline mutations (including 12 PTVs) of 25 DNA repair genes and 19 heterozygous germline variants (including 7 PTVs) of 14 immune genes. PTVs of ATM and PNKP were found in two families, respectively. We performed whole genome sequencing of diffuse large B cell lymphomas (DLBCLs), translocations at IGH locus and activation of oncogenes (BCL6 and MYC) were verified, and homologous recombination deficiency was detected. In DLBCLs with germline PTVs of ATM, deletion and insertion in CD58 were further revealed. Thus, in lymphoma-cancer families, we identified germline defects of both DNA repair and immune genes in lymphoma patients.
Background
The treatment outcomes and prognosis of lymphoma are affected by various factors such as hospital types. This study was to describe the temporal trend in the survival of lymphoma in an ...academic center in China.
Methods
A total of 3840 consecutive patients with lymphoma diagnosed between 1996 and 2015 were reviewed. Eighty patients were excluded, and finally, 3760 patients were analyzed in this study. The cohort was divided into four groups according to calendar periods at diagnosis: 1996‐2000, 2001‐2005, 2006‐2010, and 2010‐2015. The overall survival (OS) rates among the four groups were compared.
Results
The 5‐ and 10‐year OS for the whole cohort were 62% and 52%, respectively. The 5‐year OS of patient with classic Hodgkin lymphoma (cHL), mature B‐cell lymphoma (BCL), and peripheral T‐cell lymphoma (PTCL) were 79%, 63%, and 50%, respectively. Among mature BCL, the 5‐year OS was highest in follicular lymphoma (77.8%), followed by Burkitt lymphoma (76.5%), marginal zone lymphoma (74.1%), diffuse large B‐cell lymphoma (61.5%), small lymphocytic lymphoma/chronic lymphocytic leukemia (55.1%), and mantle cell lymphoma (44.3%). Among PTCL, the 5‐year OS was highest in ALK+anaplastic large cell lymphoma (79.0%), followed by ALK−anaplastic large cell lymphoma (63.1%), natural killer/T‐cell lymphoma (57.7%), angioimmunoblastic T‐cell lymphoma (34.9%, and peripheral T‐cell lymphoma not otherwise specified (27.6%). Significant improvement in the survival of lymphoma was observed, with the 5‐year OS increasing from 48% in 1996‐2000 to 65% in 2011‐2015 (P < .001). The 5‐year OS of patients with cHL, mature BCL, and PTCL changed from 55%, 49%, and 41% in 1996‐2000 to 79%, 65%, and 51% in 2011‐2015, respectively (P values were .014, .002, and .592, respectively).
Conclusion
The survival of most types of lymphoma such as cHL and mature BCL, rather than PTCL, was improved significantly during the past two decades.
Increase in overall survival of lymphoma from 1996 to 2015.
CD19-targeted chimeric antigen receptor-T (CAR-T) cells with CD28 or 4-1BB (28z CAR-T and BBz CAR-T) have shown great promise to treat relapsed or refractory (r/r) B cell non-Hodgkin’s lymphoma ...(B-NHL). However, comparison of their clinical outcomes has never been reported. This study investigated their efficacy and adverse events in B-NHL therapy. Six patients with r/r B-NHL were initially enrolled and infused with 28z or BBz CAR-T cells at a dose of 0.75–5 × 105/kg. These CAR-T cells showed similar antitumor efficacies, with a complete response (CR) rate of 67% within 3 months. BBz CAR-T was well tolerated. However, severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in the 28z CAR-T cohort, resulting in the termination of further evaluation of 28z CAR-T. Three more patients were enrolled to investigate BBz CAR-T cells in-depth at an escalated dose (1 × 106/kg). All cases achieved CR within 3 months, and only grade 1/2 adverse events occurred. This study suggests that 4-1BB is more beneficial for the clinical performance of CAR-T cells than CD28 in CD19-targeted B-NHL therapy, at least under our manufacturing process.
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Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab ...era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1-3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.
What is known and objective
Anti‐CD19 CAR‐T cell therapy is effective in B‐cell lymphoma. However, it is rarely used in lymphoma combined with other malignant tumours.
Case description
A ...relapsed/refractory follicular lymphoma (r/r FL) patient underwent anti‐CD19 CAR‐T cell therapy and achieved complete response to lymphoma. However, gastric adenocarcinoma (GAC) was diagnosed during the cellular therapy. After infusion of CAR‐T cells, he received curative treatment for GAC, and maitained complete response in both r/r FL and GAC after the treatment.
What is new and conclusion
Anti‐CD19 CAR‐T therapy is an effective treatment for r/r FL, also provided opportunity for the sequential therapy of GAC, and remained significant quality of life afterwards.
PET/CT showed the lymphoma achieved complete response through CD19 CAR‐T therapy, and gastric cancer progressed during the therapy.
Background
Despite numerous chimeric antigen receptor T‐cell (CAR‐T) trials conducted in China, no CAR‐T has been registered in the country. Furthermore, China law and regulations restrict the export ...of patient material for CAR‐T manufacture abroad. Relma‐cel (JWCAR029), an anti‐CD19 product produced with a commercial‐ready process in China, was evaluated in the first prospective, single‐arm, multicenter, pivotal study of CAR‐T therapy conducted under Chinese IND to support an NMPA‐accepted BLA submission in relapsed/refractory (r/r) LBCL (NCT04089215).
Methods
Patients were randomized to receive either 100 × 106 (low dose, n = 27) or 150 × 106 (high dose, n = 32) CAR+ T‐cells as a single infusion following lymphodepleting chemotherapy (fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 daily × 3), and then, monitored for efficacy and safety outcomes and pharmacokinetics. The primary endpoint was ORR at 3 months, as assessed by the investigators. Secondary endpoints included DOR, PFS, OS, and adverse event frequency/severity and cell expansion kinetics.
Results
As of the data cutoff on 17 June 2020, 68 patients were enrolled, and 59 were treated. Among the 58 efficacy‐evaluable patients, the primary endpoint of 3 month ORR was 60.3% (95% CI, 46.6–73.0), excluding the null hypothesis rate of 20%. Any grade and severe grade CRS occurred in 47.5% and 5.1%, respectively, and any grade and severe grade neurotoxicity events occurred in 20.3% and 5.1%.
Conclusions
Relma‐cel met the primary endpoint analysis and demonstrated a high rate of durable responses and low rate of CAR‐T‐associated toxicities in patients with r/r LBCL in a multicenter trial supporting regulatory submission in China.
The RELIANCE Trial provided the first demonstration of licensure‐quality CAR‐T manufacturing and clinical trial data generation in r/r patients originating in China. The results with relma‐cel demonstrate similar preliminary response rates and PK profiles while providing the potential for an improved toxicity profile in heavily‐pre‐treated patients with r/r DLBCL having poor risk features relative to other CD19‐specific CAR‐Ts approved in the US and EU.
Classical Hodgkin lymphoma (cHL) is a highly curable disease, while novel therapy is needed for refractory or relapsed (R/R) patients. This phase II trial aimed to evaluate the role of camrelizumab ...plus gemcitabine and oxaliplatin (GEMOX) in R/R cHL patients.
Transplant-eligible patients with R/R cHL were enrolled and received two 14-day cycles of camrelizumab 200 mg intravenously (IV) and two 28-day cycles of camrelizumab 200 mg IV, gemcitabine 1000 mg/m
IV, and oxaliplatin 100 mg/m
IV on days 1 and 15. Patients with partial response (PR) or stable disease received an additional cycle of combination therapy. Those who achieved complete response (CR) or PR proceeded to autologous stem cell transplantation (ASCT). The primary endpoint was the CR rate at the end of protocol therapy before ASCT.
Forty-two patients were enrolled. At the end of protocol therapy, the objective response rate and CR rate were 94.9% (37/39) and 69.2% (27/39) in the evaluable set, and 88.1% (37/42) and 64.3% (27/42) in the full analysis set, respectively. Twenty-nine patients (69.0%) proceeded to ASCT, and 4 of 5 patients with PR achieved CR after ASCT. After a median follow-up of 20.7 months, the 12-month progression-free survival rate was 96.6% and the 12-month overall survival rate was 100%. Grade 3 or higher treatment emergent adverse events occurred in 28.6% of patients (12/42), mainly hematological toxicity.
Camrelizumab combined with GEMOX constitutes an effective salvage therapy for R/R cHL, proving to be relatively well-tolerated and facilitating ASCT in most patients, thus promoting sustained remission.
ClinicalTrials.gov NCT04239170. Registered on January 1, 2020.
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