CAR-T Cell Infusion Research Articles

Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients.

Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CHpos and CHneg patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CHpos patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.

Prognostic Significance of Positron Emission Tomography Delta Radiomics Following Bridging Therapy in Patients with Large B-Cell Lymphoma Undergoing CAR T-Cell Therapy

CAR T-cell therapy is routinely used as a treatment option for relapsed/refractory large B-cell lymphoma (LBCL). Bridging therapy radiation therapy (bRT) is increasingly being utilized prior to chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL). It is unknown how the extent of debulking as a result of bRT impacts outcomes following CAR T-cell infusion. We hypothesized that the extent of debulking is prognostic of overall response to therapy. We reviewed patients with LBCL treated with bRT followed by commercially available CAR T-cell therapy between 2017 and 2022. Patients required a F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scan prior to bRT and between completion of bRT and CAR T-cell infusion. On each scan, metabolic tumor volume (MTV), maximum standardized uptake value (SUVmax), SUVmean, and total lesion glycolysis (TLG) were determined. Delta-radiomics based on changes of these values between scans in patients overall and irradiated sites were then calculated. Optimal cut points were determined using maximally selected log-rank. The primary endpoints were progression-free survival (PFS) and local control (LC), measured from CAR T-cell infusion by Kaplan-Meier and Fine-Gray competing risk survival analyses, respectively. Twenty-three patients with LBCL with 33 irradiated sites were reviewed. All metabolically active disease was treated in 10 patients. Median equivalent dose in 2 Gy fractions (EQD2) was 26 Gy (14-44). Median interval from bRT to PET was 9 days (2-30). Following bRT, 2 patients achieved complete responses, 16 had partial responses, and 5 had progressive disease. Five irradiated sites progressed through bRT. No local failures were observed when EQD2>32.5 Gy was given. LC was improved with EQD2>20 Gy (24 mo LC: 94.5% vs 68.6%; p = 0.075). Following BRT, median overall decreases in MTV, SUVmax, SUVmean, and TLG were 22.2 cc (63.1%), 8.9 (36.8%), 3.4 (31.1%), and 297.9 cc (75.8%), respectively. Median decreases in MTV, SUVmax, SUVmean, and TLG in irradiated sites were 15.6 cc (91.1%), 17.0 (74.6%), 6.8 (55.3%), and 157.0 cc (94.6%), respectively. PFS was significantly improved in patients with reductions of MTV of at least 36 cc (24 mo PFS: 69.2% vs 0%; p = 0.047) or SUVmax of at least 15 (24-mo PFS: 80.0% vs 28.1%; p < 0.001). LC was significantly improved in lesions with reductions of SUVmax of at least 14 (24-mo LC: 100% vs 67.3%; p < 0.001) or SUVmean of at least 7 (24-mo LC: 100% vs 74.4%; p < 0.001). bRT led to significant reductions in MTV, SUVmax, SUVmean, and TLG. The extent of these decreases correlated with improved PFS and LC. There appears to be a dose-response relationship. Larger cohorts should validate the value of interim PET following bRT, and associated changes in disease burden as a means of prognosticating patients. Future work might evaluate whether escalation of BT in patients with suboptimal response, using either systemic therapy or higher radiation doses, has an impact on outcomes.

Adenovirus-induced hemorrhagic cystitis after CD19-targeted chimeric antigen receptor T-cell therapy in a patient with large B-cell lymphoma.

Chimeric antigen receptor (CAR) T cells targeting CD19 have changed the treatment landscape of patients with relapsed/refractory diffuse large B-cell lymphoma. Infections are one of the most frequent complications after CAR T-cell therapy. Most of these infections are bacterial, although viral infections can also occur in this setting. Adenovirus-induced hemorrhagic cystitis is a rare infectious complication and is usually observed after bone marrow or solid organ transplantation. Herein we report a case of adenovirus-induced hemorrhagic cystitis in a patient experiencing urinary symptoms within the first month after CAR T-cell infusion. Based on our experience and a literature review, we discuss the diagnostic approach and potential treatment options for this infrequent infection after CAR T-cell therapy.

Application of thromboelastography to predict the severity of bleeding after chimeric antigen receptor (CAR)-T cell therapy in patients with hematological malignancy.

We aim to analyze the predictive value of thromboelastography on bleeding severity of patients with chimeric antigen receptor (CAR)-T cell therapy. A total of 80 patients with refractory/relapsed hematological malignancy were enrolled and divided into two groups: the severe bleeding group and the non-severe bleeding group. The thromboelastography data was collected on the day of CAR-T infusion and the 3rd, 7th, 10th, 13th, 17th, and 20th day after CAR-T cell infusion. The patients of the severe bleeding group had lower platelet (p < .007), maximum amplitude (p = .002), coagulation index (p = .005), and longer coagulation time (p = .019). Increasing trend in reaction time and coagulation time and decreasing trend in Alpha, maximum amplitude, and coagulation index on Days 0-10, opposite on Days 10-20. Univariate logistic regression analysis and multivariable logistic regression analysis showed maximum amplitude on the 3rd day after CAR-T cell infusion (MA3) (OR = 0.9; 95% CI = 0.84-0.95; p < .001) and cytokine release syndrome grade (OR = 2.57; 95% CI = 1.35-5.32; p = .006) were significantly associated with high bleeding severity. Thromboelastography was considered to be a good predictor of bleeding severity.

PET-based radiomics signature can predict durable responses to CAR T-cell therapy in patients with large B-cell lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment option for relapsed or refractory (R/R) large B-cell lymphoma (LBCL). However, only a subset of patients will present long-term benefit. In this study, we explored the potential of PET-based radiomics to predict treatment outcomes with the aim of improving patient selection for CAR T-cell therapy. We conducted a single-center study including 93 consecutive R/R LBCL patients who received a CAR T-cell infusion from 2018 to 2021, split in training set (73 patients) and test set (20 patients). Radiomics features were extracted from baseline PET scans and clinical benefit was defined based on median progression-free survival (PFS). Cox regression models including the radiomics signature, conventional PET biomarkers and clinical variables were performed for most relevant outcomes. A radiomics signature including 4 PET-based parameters achieved an AUC=0.73 for predicting clinical benefit in the test set, outperforming the predictive value of conventional PET biomarkers (total metabolic tumor volume [TMTV]: AUC=0.66 and maximum standardized uptake value [SUVmax]: AUC=0.59). A high radiomics score was also associated with longer PFS and OS in the multivariable analysis. In conclusion, the PET-based radiomics signature predicted efficacy of CAR T-cell therapy and outperformed conventional PET biomarkers in our cohort of LBCL patients.

Suppression of cytokine release syndrome during CAR-T-cell therapy via a subcutaneously injected interleukin-6-adsorbing hydrogel.

The infusion of chimaeric antigen receptor (CAR) T cells can trigger the release of life-threatening supraphysiological levels of pro-inflammatory cytokines. However, uncertainty regarding the timing and severity of such cytokine release syndrome (CRS) demands careful monitoring of the conditions required for the administration of neutralizing antibodies. Here we show that a temperature-sensitive hydrogel conjugated with antibodies for the pro-inflammatory cytokine interleukin-6 (IL-6) and subcutaneously injected before the infusion of CAR-T cells substantially reduces the levels of IL-6 during CRS while maintaining the therapy's antitumour efficacy. In immunodeficient mice and in mice with transplanted human haematopoietic stem cells, the subcutaneous IL-6-adsorbing hydrogel largely suppressed CAR-T-cell-induced CRS, substantially improving the animals' survival and alleviating their levels of fever, hypotension and weight loss relative to the administration of free IL-6 antibodies. The implanted hydrogel, which can be easily removed with a syringe following a cooling-induced gel-sol transition, may allow for a shift in the management of CRS, from monitoring to prevention.

Cytokine and reactivity profiles in SLE patients following anti-CD19 CART therapy

Chimeric antigen receptor (CAR) Tcells targeting CD19+ B cells have demonstrated efficacy in refractory systemic lupus erythematosus (SLE). Although initial clinical data suggest that anti-CD19 CAR Tcell therapy is well tolerated and highly effective, the immunologic consequences of CAR Tcell therapy in SLE patients remain unclear. We profiled serum in six refractory SLE patients prior to and 3months following CAR Tcell infusion. Three months post Tcell infusion, the inflammatory cytokines IL-6 and TNFα decreased in patient sera. This was accompanied by elevations in serum IL-7 and BAFF. Furthermore, SLE-associated antibodies dropped profoundly in five of six patients. Last, consistent with other reports of CD19 CAR T therapy in B cell malignancies, we were able to show marginal impact of anti-CD19 CART therapy on pre-existing humoral immune responses in SLE patients. Together, these results provide insights into the mechanisms of efficacy of anti-CD19 CAR Tcell therapy in SLE.

Significance of alkaline Phosphatase After Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma

BackgroundThe inexpensive and readily available biomarkers for cytokine release syndrome (CRS) grading and prognosis assessment in chimeric antigen receptor (CAR)-T therapy are currently lacking. This study examined the significance of alkaline phosphatase (ALP) after CAR-T therapy in patients with relapsed/refractory multiple myeloma (MM). MethodsThis cohort study included 27 patients with relapsed/refractory MM who were treated with CAR-T cells between December 2017 and October 2021. Patients were classified into 2 groups: normal ALP group (peak ALP <125 U/L, n = 10) and high ALP group (peak ALP ≥125 U/L, n = 17). ResultsWithin 1 month of CAR-T cell infusion, the incidence of ALP increases was 63%. We found that ALP levels began to rise in the second week, peaked in the third and fourth weeks, and began to decline in the second month. Moreover, the ALP levels in previous chemotherapy-responsive period were significantly lower than those after CAR-T therapy. Statistical analysis found that patients with increased ALP exhibited higher alanine aminotransferase and aspartate aminotransferase levels, higher and longer CAR-T cell proliferation, more serious CRS, higher cytokine and ferritin levels, and higher initial response rates. In addition, the duration of ALP increase was parallel to the duration of CAR-T expansion. Multivariable Cox‐regression analysis showed that peak ALP was the independent predictor for progression‐free survival (PFS) (HR = 0.029, 95% CI: 0.002-0.369). ConclusionsOur results suggest that the ALP levels after CAR-T therapy could serve as a suitable biomarker for monitoring CAR-T cell proliferation, CRS grading, and prognosis in patients with MM.

Anti-CD19 CAR T-cell consolidation therapy combined with CD19+ feeding T cells and TKI for Ph+ acute lymphoblastic leukemia.

We conducted a single-arm, open-label, single-center phase 1 study to assess the safety and efficacy of multicycle-sequential anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in combination with autologous CD19+ feeding T cells (FTCs) and tyrosine kinase inhibitor (TKI) as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19+ B-cell acute lymphoblastic leukemia. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another 3 cycles of CD19 CAR T-cell and CD19+ FTC infusions, followed by TKI as consolidation therapy. CD19+ FTCs were given at 3 different doses. The phase 1 results of the first 15 patients, including 2 withdrawals, are presented. The most common adverse events were cytopenia (13/13) and hypogammaglobinemia (12/13). There was no incidence of cytokine release syndrome above grade 2 or immune effector cell-associated neurotoxicity syndrome or grade 4 nonhematological toxicities. All 13 patients achieved complete remission, including 12 patients with a complete molecular response (CMR) at the data cutoff. The relapse-free survival was 84%, and the overall survival was 83% with a median follow-up of 27months. The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40months, whereas CD19+ FTCs vanished in 8 patients 3months after the last infusion. These findings could form the basis for the development of an allo-HSCT-free consolidation paradigm. This trial was registered at www.clinicaltrials.gov as #NCT03984968.

How can Cytokine-induced killer cells overcome CAR-T cell limits.

The successful treatment of patients affected by B-cell malignancies with Chimeric Antigen Receptor (CAR)-T cells represented a breakthrough in the field of adoptive cell therapy (ACT). However, CAR-T therapy is not an option for every patient, and several needs remain unmet. In particular, the production of CAR-T cells is expensive, labor-intensive and logistically challenging; additionally, the toxicities deriving from CAR-T cells infusion, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), have been documented extensively. Alternative cellular therapy products such as Cytokine-induced killer (CIK) cells have the potential to overcome some of these obstacles. CIK cells are a heterogeneous population of polyclonal CD3+CD56+ T cells with phenotypic and functional properties of NK cells. CIK cell cytotoxicity is exerted in a major histocompatibility complex (MHC)-unrestricted manner through the engagement of natural killer group 2 member D (NKG2D) molecules, against a wide range of hematological and solid tumors without the need for prior antigen exposure or priming. The foremost potential of CIK cells lies in the very limited ability to induce graft-versus-host disease (GvHD) reactions in the allogeneic setting. CIK cells are produced with a simple and extremely efficient expansion protocol, which leads to a massive expansion of effector cells and requires a lower financial commitment compared to CAR-T cells. Indeed, CAR-T manufacturing involves the engineering with expensive GMP-grade viral vectors in centralized manufacturing facilities, whereas CIK cell production is successfully performed in local academic GMP facilities, and CIK cell treatment is now licensed in many countries. Moreover, the toxicities observed for CAR-T cells are not present in CIK cell-treated patients, thus further reducing the costs associated with hospitalization and post-infusion monitoring of patients, and ultimately encouraging the delivery of cell therapies in the outpatient setting. This review aims to give an overview of the limitations of CAR-T cell therapy and outline how the use of CIK cells could overcome such drawbacks thanks to their unique features. We highlight the undeniable advantages of using CIK cells as a therapeutic product, underlying the opportunity for further research on the topic.

Metabolic PET/CT analysis of aggressive Non-Hodgkin lymphoma prior to Axicabtagene Ciloleucel CAR-T infusion: predictors of progressive disease, survival, and toxicity

PET/CT is used to evaluate relapsed/refractory non-Hodgkin lymphoma (NHL) prior to chimeric antigen receptor T-cell (CAR-T) infusion at two time points: pre-leukapheresis (pre-leuk) and pre-lymphodepletion chemotherapy (pre-LD). We hypothesized that changes in PET/CT between these time points predict outcomes after CAR-T. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and other metrics were calculated from pre-leuk and pre-LD PET/CT scans in patients with NHL who received axicabtagene ciloleucel, and assessed for association with outcomes. Sixty-nine patients were analyzed. While single time point PET/CT characteristics were not associated with risk of PD or death, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p < 0.05 for all). LASSO analysis identified increasing extranodal MTV and increasing TLG of the largest lesion as strong predictors of death (AUC 0.74). Greater pre-LD total MTV was associated with higher risk of grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS) (p = 0.042). Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of progression and death. A two variable risk score stratifies prognosis prior to CAR-T infusion and may inform risk-adapted strategies.

Development of a Multiscale Mechanistic Modelling Framework Integrating Differential Cellular Kinetics of CAR-T Cell Subsets and Immunophenotypes in Cancer Patients.

Chimeric antigen receptor (CAR) T-cell subsets and immunophenotypic composition of the pre-infusion product, as well as their longitudinal changes following infusion, are expected to affect CAR-T cell expansion, persistence, and clinical outcomes. Herein, we sequentially evolved our previously described cellular kinetic-pharmacodynamic (CK-PD) model to incorporate CAR-T cell product-associated attributes by utilizing published preclinical and clinical datasets from two affinity variants (FMC63 and CAT19 scFv) anti-CD19 CAR-T cells. In step 1, a unified cell-level PD model was used to simultaneously characterize the in vitro killing datasets of two CAR-Ts against CD19+ cell lines at varying effector: target (E: T) ratios. In step 2, an augmented CK-PD model for anti-CD19 CAR-Ts was developed, by integrating CK dataset(s) from two bioanalytical measurements (qPCR and flow cytometry) in cancer patients. The model described the differential in vivo expansion properties of CAR-T cell subsets. The estimated expansion rate constant was ~1.12-fold higher for CAR+CD8+ cells in comparison to CAR+CD4+ T cells. In step 3, the model was extended to characterize the disposition of four Immunophenotypic populations of CAR-T cells, including stem-cell memory (TSCM ), central memory (TCM ), effector memory (TEM ) and effector (TEFF ) cells. The model adequately characterized the longitudinal changes in immunophenotypes post anti-CD19 CAR-T cell infusion in acute lymphocytic leukemia paediatric patients. Polyclonality in the pre-infusion product was identified as a categorical covariate influencing differentiation of immunophenotypes. In the future, this model could be leveraged a priori towards optimizing the composition of CAR-T cell infusion product, and further understand the CK-PD relationship in patients.

Point-of-care anti-CD19 chimeric antigen receptor T-cell therapy for relapsed/refractory follicular lymphoma

Patients with relapsed/refractory follicular lymphoma (R/R-FL) often require multiple treatment lines. We performed a phase 1b/2 single-center clinical trial of autologous point-of-care anti-CD19 chimeric antigen receptor (CAR) T-cells in R/R-FL patients treated patients with ≥ 2 treatment lines. All 26 patients enrolled received CAR T-cell infusion at a median of 11 days after leukapheresis. Seventy-seven percent of patients had POD24. At enrollment, disease stage was III-IV in 85% of the patients, 77% had high-risk FLIPI score, and 77% had progressive disease. Grade III-IV cytokine release and immune effector cell-associated neurotoxicity syndromes occurred in 12% and 16% of the patients, respectively. Overall response rate at 1-month was 88%. The median follow-up was 15.4 months. One-year overall and progression-free survival were 100% and 63%, respectively. In conclusion, point-of-care CAR T-cell, manufactured within 11 days, induced a high response rate with an acceptable safety profile in patients with high-risk R/R-FL.

Chimeric antigen receptor T-cell therapy in hematologic malignancies: Successes, challenges, and opportunities.

The success of chimeric antigen receptor T-cell (CAR-T) therapy in hematologic malignancies has realized a longstanding effort toward harnessing the immune system to fight cancer in a truly personalized fashion. Second generation chimeric antigen receptors (CAR) incorporating co-stimulatory molecules like 4-1BB or CD28 were able to overcome some of the hindrances with initial CAR constructs resulting in efficacious products. Many second-generation CAR-T products have been approved in the treatment of relapsed/refractory hematologic malignancies including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia. However, challenges remain in optimizing the manufacturing, timely access, limiting the toxicity from CAR-T infusions and improving sustainability of responses derived with CAR-T therapy. Here, we summarize the clinical trial data leading to approval CAR-T therapies in MM and NHL, discuss the limitations with current CAR-T therapy strategies and review emerging strategies for overcoming these limitations.

CRISPR/Cas9: A Powerful Strategy to Improve CAR-T Cell Persistence.

As an emerging treatment strategy for malignant tumors, chimeric antigen receptor T (CAR-T) cell therapy has been widely used in clinical practice, and its efficacy has been markedly improved in the past decade. However, the clinical effect of CAR-T therapy is not so satisfying, especially in solid tumors. Even in hematologic malignancies, a proportion of patients eventually relapse after receiving CAR-T cell infusions, owing to the poor expansion and persistence of CAR-T cells. Recently, CRISPR/Cas9 technology has provided an effective approach to promoting the proliferation and persistence of CAR-T cells in the body. This technology has been utilized in CAR-T cells to generate a memory phenotype, reduce exhaustion, and screen new targets to improve the anti-tumor potential. In this review, we aim to describe the major causes limiting the persistence of CAR-T cells in patients and discuss the application of CRISPR/Cas9 in promoting CAR-T cell persistence and its anti-tumor function. Finally, we investigate clinical trials for CRISPR/Cas9-engineered CAR-T cells for the treatment of cancer.

A comprehensive analysis of adverse events in the first 30 days of phase 1 pediatric CAR T-cell trials

AbstractThe tremendous success of chimeric antigen receptor (CAR) T cells in children and young adults (CAYAs) with relapsed/refractory B-cell acute lymphoblastic leukemia is tempered by toxicities such as cytokine release syndrome (CRS). Despite expansive information about CRS, profiling of specific end-organ toxicities secondary to CAR T-cell therapy in CAYAs is limited. This retrospective, single-center study sought to characterize end-organ specific adverse events (AEs) experienced by CAYAs during the first 30 days after CAR T-cell infusion. AEs graded using Common Terminology Criteria for Adverse Events were retrospectively analyzed for 134 patients enrolled in 1 of 3 phase 1 CAR T-cell trials (NCT01593696, NCT02315612, and NCT03448393), targeting CD19 and/or CD22. A total of 133 patients (99.3%) experienced at least 1 grade ≥3 (≥Gr3) AE across 17 organ systems, of which 75 (4.4%) were considered dose- or treatment-limiting toxicities. Excluding cytopenias, 109 patients (81.3%) experienced a median of 3 ≥Gr3 noncytopenia (NC) AEs. The incidence of ≥Gr3 NC AEs was associated with the development and severity of CRS as well as preinfusion disease burden (≥ 25% marrow blasts). Although those with complete remission trended toward experiencing more ≥Gr3 NC AEs than nonresponders (median, 4 vs 3), nonresponders experiencing CRS (n = 17; 37.8%) had the highest degree of NC AEs across all patients (median, 7 vs 4 in responders experiencing CRS). Greater understanding of these toxicities and the ability to predict which patients may experience more toxicities is critical as the array of CAR T-cell therapies expand. This retrospective study was registered at www.clinicaltrials.gov as NCT03827343.

Time-Dependent Prognostic Value of Serological and Measurable Residual Disease Assessments after Idecabtagene Vicleucel.

This is one of the first studies evaluating the impact of CR and MRD dynamics after CAR T therapy in relapsed/refractory multiple myeloma. These data help interpret the prognostic significance of serological and MRD responses at early and late time points after CAR T-cell infusion. See related commentary by Landgren and Kazandjian, p. 346 . This article is featured in Selected Articles from This Issue, p. 337.

Development of a radiomic-clinical nomogram for prediction of survival in patients with diffuse large B-cell lymphoma treated with chimeric antigen receptor T cells.

In our current work, an 18F-FDG PET/CT radiomics-based model was developed to assess the progression-free survival (PFS) and overall survival (OS) of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received chimeric antigen receptor (CAR)-T cell therapy. A total of 61 DLBCL cases receiving 18F-FDG PET/CT before CAR-T cell infusion were included in the current analysis, and these patients were randomly assigned to a training cohort (n = 42) and a validation cohort (n = 19). Radiomic features from PET and CT images were obtained using LIFEx software, and radiomics signatures (R-signatures) were then constructed by choosing the optimal parameters according to their PFS and OS. Subsequently, the radiomics model and clinical model were constructed and validated. The radiomics model that integrated R-signatures and clinical risk factors showed superior prognostic performance compared with the clinical models in terms of both PFS (C-index: 0.710 vs. 0.716; AUC: 0.776 vs. 0.712) and OS (C-index: 0.780 vs. 0.762; AUC: 0.828 vs. 0.728). For validation, the C-index of the two approaches was 0.640 vs. 0.619 and 0.676 vs. 0.699 for predicting PFS and OS, respectively. Moreover, the AUC was 0.886 vs. 0.635 and 0.778 vs. 0.705, respectively. The calibration curves indicated good agreement, and the decision curve analysis suggested that the net benefit of radiomics models was higher than that of clinical models. PET/CT-derived R-signature could be a potential prognostic biomarker for R/R DLBCL patients undergoing CAR-T cell therapy. Moreover, the risk stratification could be further enhanced when the PET/CT-derived R-signature was combined with clinical factors.

γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial

γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma. We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 106 CAR T cells, 150 × 106 CAR T cells, 300 × 106 CAR T cells, and 450 × 106 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals. 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 106 CAR+ cells, and the recommended phase 2 dose was not reached. Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials. Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health.

Chimeric antigen receptor T-cell treatment patterns in relapsed or refractory large B-cell lymphoma.

Aim: To investigate real-world chimeric antigen receptor (CAR) T-cell therapy treatment patterns. Patient & methods: Relapsed/refractory large B-cell lymphomapatients who received CAR T-cell therapy were identified. Patient characteristics, setting of CAR T-cell infusion, incidence of CAR T-cell therapy-associated adverse eventsand healthcare resource utilization were assessed. Results: Of 1175 patients, 83% were infused inpatient. Within threedays postinfusion, inpatient-infused patients had a significantly higher risk of CAR T-associated adverse events (hazard ratio: 2.67; 95% CI: 2.09-3.42) compared with outpatient-infused patients. By day 30, 67% of outpatient-infused patients were hospitalized at least once. Conclusion: These findings suggest that physicians were able to select lower-risk patients for outpatient infusion, but postinfusion hospitalizations still occur.