CAR-T Cell Infusion Research Articles

Efficacy and safety of novel multiple-chain DAP-CAR-T cells targeting mesothelin in ovarian cancer and mesothelioma: a single-arm, open-label and first-in-human study.

Despite remarkable achievements in applying chimeric antigen receptor (CAR)-T cells to treat hematological malignancies, they remain much less effective against solid tumors, facing several challenges affecting their clinical use. We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma. In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity. We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME. Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma. ChiCTR.org.cn, ChiCTR2100046544 . May 21, 2021.

A case of acute macular neuroretinopathy as atipycal ICANS manifestation after CAR-T cell infusion

A case of acute macular neuroretinopathy as atipycal ICANS manifestation after CAR-T cell infusion

DDEL-10. MICROBUBBLE-ENHANCED FOCUSED ULTRASOUND REGULATES THE ENRICHMENT OF INFLAMMATORY PATHWAYS IN THE BLOOD-BRAIN BARRIER AND IMPROVES CAR T CELL ACCUMULATION IN GLIOMAS

Abstract A major challenge to brain cancer immunotherapy is posed by the rate-limiting obstacles to the systemic delivery of cytotoxic T cells, such as chimeric antigen receptor (CAR) T cells, in brain tumors posed by the blood brain barrier (BBB). Although the BBB can be bypassed by direct infusion of CAR-T cells in brain tumors, these approaches offer only short-term benefits, since they cannot affect distant tumor cell infiltrations, as evidenced by tumor relapse. Circulating microbubbles (MB) upon ultrasound (US) exposure (sonication) can exert mechanical stress in brain vessels to trigger a range of responses, including local increase in the BBB permeability and activation of inflammatory signaling and phenotypes. We hypothesize that ultrasound frequency tuned at MB resonance inside brain capillaries can transiently modulate the BBB signaling and function to improve CAR-T cell trafficking in glioma tumors. RNAseq and immunostaining of protein expression reveal that at frequencies just above microbubble resonance inside vessels (1.5MHz for 2µm MB), where maximum vessel wall shear stress is observed, there is a marked enrichment of inflammatory markers in the endothelial cells of brain vessels, including P-selectin and ICAM-1. Consistent with these findings, we observed that under high frequency excitation (1.5MHz), there is a 5-fold increase in the accumulation of EGFRvIII CAR-T cells in orthotopic EGFRvIII murine glioma tumors as compared not sonicated controls. We also found that over 85% of the tumor-infiltrating CAR-T cells express PSGL-1 and LFA-1 receptors, which interact with P-selectin and ICAM-1 to facilitate T cell extravasation. Together, these findings demonstrate that tuning the US frequency can improve CAR-T cell trafficking, potentially through upregulation of cell adhesion molecules in the glioma tumor microenvironment, and further support the functional relevance and potential clinical significance of the observed immuno-mechano-biological changes.

Acute kidney injury in hematological patients treated with CAR-T cells: risk factors, clinical presentation and impact on outcomes.

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies, yet it carries significant risks, including acute kidney injury (AKI). In this study, we investigated the risk factors and clinical impact of AKI in patients undergoing CAR-T cell therapy. This retrospective study involved hematologic patients treated with CAR-T therapy. Clinical and laboratory data were collected, and clinical outcomes were monitored during follow-up after CAR-T infusion. AKI was defined according to KDIGO criteria. The outcome measures included early mortality, overall survival (OS), and disease-free survival (DFS). Among the 48 patients analyzed, 14 (29%) developed AKI, with a mean onset of 6 days after CAR-T infusion. The risk of AKI was associated with baseline performance status (OR 8.65, IC95% 6.2-12, p = 0.032) and the development of severe cytokine release syndrome post-therapy (OR 16.4 95%CI 1.9-138.5, p = 0.01). Patients with AKI more frequently required intensive care. Furthermore, severe AKI was independently associated with worse clinical outcomes, including reduced OS and DFS (HR 18.2, 95%CI 2.6-27.3, p = 0.003). Additionally, patients who developed AKI post-CAR-T therapy were more likely to progress to chronic kidney disease during follow-up. In conclusion, frail patients undergoing CAR-T therapy are at an increased risk of developing AKI, which can significantly affect both short- and long-term outcomes. Preventive strategies and early recognition of AKI are essential in these patients.

Timeline and outcomes of viral and fungal infections after Chimeric Antigen Receptor (CAR) T-cell therapy: A large database analysis

ObjectivesThis large database analysis aims to describe the incidence, timeline, and risk factors for viral and fungal infections after chimeric antigen receptor (CAR) T-cell therapy. MethodsWe queried a global research network database, TriNetX, for patients who received CAR T-cell therapy, who were identified and followed for the development of viral and fungal infections. Baseline demographic, oncologic history, laboratory data and medication histories were collected. We evaluated risk factors for respiratory viral infections (RVI), herpesvirus, fungal infections and mortality using Cox regression. ResultsA total of 2,256 patients who received CAR T-cell therapy were included, 1,867 (82.7%) were CD19-targeted and 400 (17.7%) were BCMA-targeted. Following CAR T-cell infusion, RVI were the most prevalent (23.3%) with a median onset of 160 days (IQR 52-348 days), while herpesvirus and fungal infections were less frequent, occurring in 13.6% and 11.4% of cases with median onsets of 71 (IQR 18-252) and 73 days (IQR 14-236 days), respectively. On multivariable Cox regression, independent predictors of RVI included acute lymphoblastic leukemia (ALL, HR 1.61), prior hematopoietic cell transplant (HCT, HR 1.29), cytokine release syndrome (CRS, HR 1.41), hemophagocytic lymphohistiocytosis (HLH, HR 1.96), and glucocorticoids (HR 3.37). Prior HCT (HR 2.00), hypogammaglobulinemia (HR 1.51), immune-effector cell-associated neurotoxicity syndrome (ICANS, HR 1.52), and HLH (HR 1.99) were associated with a higher risk of herpesviruses. Independent predictors of fungal infections included prior HCT (HR 1.59), CRS (HR 1.58) and hypogammaglobulinemia (HR 1.40). Idecabtagene vicleucel was associated with a lower risk of herpesvirus and fungal infections (HR 0.39 and 0.44, respectively). ConclusionsIn a large cohort of CAR T-cell therapy recipients, respiratory viral infections were the most common but occurred later, while herpesvirus and fungal infections were less frequent but occurred earlier. Prospective studies investigating prophylaxis and pre-emptive monitoring strategies are needed in this population.

Cancer cachexia and weight loss before CAR T-cell therapy for lymphoma are independently associated with poor outcomes

AbstractChimeric antigen receptor (CAR) T-cell therapy has transformed the care of lymphoma, yet many patients relapse. Several prognostic markers have been associated with CAR T-cell outcomes, such as tumor burden, response to bridging chemotherapy, and laboratory parameters at the time of lymphodepletion or infusion. The effect of cancer cachexia and weight loss before CAR T cells on toxicity and outcomes is not well understood. Here, we present a retrospective single-institution cohort study of 259 patients with lymphoma treated with CAR T cells between 2017 and 2023. We observed that patients with >5% decrease in their body mass index in the 3 months preceding CAR T-cell treatment (weight loss group; all meeting one of the commonly accepted definitions of cancer cachexia) had higher disease burden and inflammatory parameters (C-reactive protein, ferritin, interleukin-6, and tumor necrosis factor α) at the time of lymphodepletion and CAR T-cell infusion. Patients with weight loss experienced higher rates of grade 3+ neurotoxicity and early hematotoxicity, but those effects were not seen upon multivariable adjustment. However, in both univariate and multivariable analysis, patients with weight loss had worse response rates, overall survival, and event-free survival, indicating that weight loss is an independent poor prognostic factor. Our data suggest that weight loss in the 3 months preceding CAR T-cell therapy represents a worrisome “alarm signal” and a potentially modifiable factor, alongside tumor burden and inflammation, and warrants further investigation in patients treated with CAR T-cell therapy.

Symptoms of Hematologic Tumors Patients after CAR-T Therapy: a Systematic Review and Meta-Analysis.

Patients with hematologic neoplasms after Chimeric antigen receptor T-cell (CAR-T) therapy have multiple syndromes, with corresponding symptoms. The review aimed to integrate the severity and incidences of symptoms in these patients, and to investigate the difference of the symptoms among different geographic locations, types of hematological tumors, evaluating instruments, and evaluating time, to provide a theoretical basis for symptom management. A literature search of PubMed, Web of Science, Embase, the Cochrane Library, China National Knowledge Internet, SinoMed, VIP, and WANFANG DATA was performed for studies reporting symptom scores or symptom incidences of these patients published before November 9, 2023. Heterogeneity between studies was assessed by Higgins' I2. A random effects model was used for studies with I2 > 50%. Methodological quality of included studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist. Eight studies were included. Among the reported symptoms, sleep disturbance, fatigue and depression were of higher severity, with the standardized scores exceeding 50. Sadness, problem with concentration, problem with memory, cough and nausea were the top five symptoms in incidence, which exceeded 50%. The symptom scores and incidences assessed by the patient-reported outcomes were higher. Within 90 days of CAR-T infusion, these patients reported a significantly higher severity and incidence of multiple symptoms. Patients with hematologic neoplasms treated by CAR-T suffer from multiple symptoms, including depression, fatigue, and so on. Instruments used to evaluate symptoms and the evaluating time may influence the outcome of symptom assessment.

Glycolytic activity following anti-CD19 CAR-T cell infusion in non-Hodgkin lymphoma.

Energy metabolism of chimeric antigen receptor-T cells (CAR-T) activation in humans remains unexplored. As a glycolytic activity surrogate, we investigated the dynamics of peripheral blood (PB) lactate in the first weeks post-CAR-T infusion. In 17 patients treated with CD28 harbording anti-CD19 CAR-T for relapsed/refractory non-Hodgkin lymphomas, PB lactate levels increased following CAR-T infusion. Elevated lactate levels correlated with longer CAR-T persistence and higher CD8+/CD4+ ratio. Peripheral blood lactate kinetics may reflect immune cells activation and be useful for bedside monitoring.

A matter of inflammation: CAR T-cell therapy and atrial fibrillation

Abstract Background Chimeric antigen receptor (CAR) T-cell therapy has been revolutionary in the treatment of blood cancers, but has been associated with arrhythmias such as atrial fibrillation (AF). Whether the incidence of AF has changed over time and if contributing risk factors are present remains to be defined. Methods Leveraging the Mayo Electronic Medical Record, we extracted a cohort of patients who underwent CAR T-cell therapy between 2016 and 2022. From this cohort, we identified those who had a diagnosis of AF at any point. We then defined the endpoint of interest as the first episode of new or recurrent AF during or after CAR T-cell infusion. Fine and Gray subdistribution hazard modeling was used to calculate the association of patient characteristics to the endpoint of interest. Variables with P<0.20 in univariate modeling were chosen for the multivariate model. Significance was defined as P<0.05. Results There were 328 patients who underwent CAR T-cell therapy between 2016 and 2022. Of this cohort, 27 (8.2%) patients had a pre-existing diagnosis of AF, of which 6 had recurrence of AF after CAR T (22.2%), while 21 (77.8%) did not. Of the 301 patients without a prior history of AF, 8 (2.7%) patients developed new-onset AF after CAR T. The majority of the 14 new or recurrent AF events (4.3% overall incidence) occurred within 30 days of receiving CAR T (N=10, 71.4%), the remainder after 180 days (Figure 1). No trend in declining incidence over time was noted. Prior AF, neurotoxicity, and inflammation (cytokine release syndrome and macrophage activating syndrome-like (MAS-L)) were strongly associated with the risk of developing new or recurrent AF (Table 1). Only presence of MAS-L remained an independent predictor in the multivariate model (HR 15.4, 95% CI 3.9-61.2, P<0.001). Conclusion AF is mainly seen early following CAR T-cell therapy, and mainly in association with severe inflammatory responses. Early and aggressive treatment of CRS and MAS-L may be recommendable for patients undergoing CAR-T therapy, especially for those with a prior history of AF.

Distance to CAR-T Treatment Center Does Not Impede Delivery.

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable efficacy in relapsed or refractory large B cell lymphoma, but real-world evidence is needed to confirm safety and efficacy when facing the unique challenges of a wide geographical catchment area. We reviewed patients treated with commercially available CAR-T at a medium-sized single center in Canada (The Ottawa Hospital) between December 2020 and July 2022 (Canadian implementation started in 2020). Fifty-one patients (59% male, median age 62) traveled a median distance of 655 km (range 3-3659) for treatment. Median time from apheresis to CAR-T infusion was 36 days (range 26-81). With a median follow-up of 383 days (95% CI: 333-480), median progression-free survival (PFS) and overall survival (OS) were 257 days (95% CI: 92-NE) and 422 days (95% CI: 106-NE), respectively. The median PFS for out-of-province patients was 115 days (95% CI: 91-NE) versus 280 days for in-province patients (95% CI: 142-NE), p = 0.12. Multivariate analysis demonstrated that distance from treatment center (p = 0.05) and refractory disease status (p = 0.003) were independently associated with shorter PFS. The time from the last disease progression to CAR-T referral was longer for out-of-province patients, but there was no difference in the time of referral to CAR-T consult, apheresis, or CAR-T infusion between in-province and out-of-province patients. Our results confirm that despite the complexity of CAR-T therapy administration, Ottawa can effectively provide commercial CAR-T therapy in a timely fashion for patients from across the country.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR), Growth Differentiation Factor-15 (GDF-15), and Soluble C5b-9 (sC5b-9) Levels Are Significantly Associated with Endothelial Injury Indices in CAR-T Cell Recipients

Endothelial injury indices, such as Endothelial Activation and Stress Index (EASIX), modified EASIX (m-EASIX), and simplified EASIX (s-EASIX) scores, have been previously associated with chimeric antigen receptor-T (CAR-T) cell immunotherapy complications. Soluble urokinase-type plasminogen activator receptor (suPAR), growth differentiation factor-15 (GDF-15), and soluble C5b-9 (sC5b-9) have been described as markers of endothelial injury post-hematopoietic stem cell transplantation. In the current study, we examined whether suPAR, GDF-15, and sC5b-9 levels were associated with endothelial injury indices in adult CAR-T cell recipients. The levels of these markers were measured in patients before CAR-T cell infusion and in healthy individuals with immunoenzymatic methods. We studied 45 CAR-T cell recipients and 20 healthy individuals as the control group. SuPAR, GDF-15, and sC5b-9 levels were significantly higher in the patients’ group compared to the healthy control group (p < 0.001, in all comparisons). SuPAR levels at baseline were associated with the m-EASIX scores calculated at the same time point (p = 0.020), while suPAR and GDF-15 concentrations were correlated with EASIX scores at day 14 post-infusion (p < 0.001 in both comparisons). Moreover, sC5b-9 levels were correlated with the s-EASIX scores at infusion (p = 0.008) and the EASIX scores at day 14 (p = 0.005). In our study, sC5b9, suPAR, and GDF-15 levels were found to reflect endothelial injury in CAR-T cell recipients.

Efficacy and safety of CAR-T therapy targeting CLL1 in patients with extramedullary diseases of acute myeloid leukemia

BackgroundsThe incidence of extramedullary diseases (EMDs) in patients diagnosed with acute myeloid leukemia (AML) is approximately 10–20%. These patients exhibit a significantly distinct etiology, therapeutic response, and prognosis compared to patients without EMDs. CLL1 CAR-T therapy has been demonstrated satisfactory efficacy and safety in the treatment of refractory and relapsed AML patients. However, concerns have been raised regarding the potential impact of extramedullary niduses on the effectiveness of CLL1 CAR-T therapy.MethodsA total of 47 patients were enrolled in this study, including 27 patients with isolated AML tumor bone marrow infiltration and 20 patients with both extramedullary and bone marrow infiltration of AML. CLL1 CAR-T cells were manufactured and subjected to rigorous quality control in the hematology laboratory of Tianjin First Central Hospital. The efficacy and adverse reactions were assessed following CAR-T cell infusion, while expansion of CAR-T cells, levels of cytokines releasing, and other indicators were closely monitored.ResultsAmong the 20 patients with EMDs and the 27 individuals without EMDs, complete remission in bone marrow was achieved by 65.00% and 81.48% of patients, respectively. Meanwhile, among the patients with EMDs, 55.00% achieved complete remission while 10.00% achieved partial remission when assessing the efficacy of CLL1 CAR-T cells against extramedullary niduses. Although the overall survival, progression-free survival, and duration of remission period appeared to be shorter for patients with EMDs compared to those without EMDs, this difference did not reach statistical significance. The incidence rates of complications were comparable between both groups. Meanwhile, there were no significant differences observed in the levels of CAR-T cell expansion and accompanying cytokines release between patients with and without EMDs.ConclusionsOur study findings have demonstrated the efficacy of CLL1 CAR-T therapy in the treatment of AML patients with EMDs, while also indicating manageable occurrence rates of complications within a tolerable range. The CLL1 CAR-T therapy, serving as an ideal strategy for AML patients irrespective of the presence of EMDs, effectively ameliorates the conditions of AML patients and provides them with an opportunity to undergo curative hematopoietic stem cell transplantation while significantly enhancing their prognosis.

Prognostic significance of fludeoxyglucose positron emission tomography delta radiomics following bridging therapy in patients with large B-cell lymphoma undergoing CAR T-cell therapy.

Bridging 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 cytoreduction during bRT impacts outcomes. We retrospectively reviewed patients with LBCL treated with bRT followed by CAR T-cell therapy. Metabolic tumor volume (MTV), maximum standardized uptake value (SUVmax), SUVmean, and total lesion glycolysis (TLG) were extracted from F18-fluorodeoxyglucose positron emission tomography (PET) scans acquired prior to bRT and between completion of bRT and CAR T-cell infusion. Delta radiomics based on changes of these values were then calculated. The association between delta radiomics and oncologic outcomes [progression-free survival (PFS), freedom from distant progression (FFDP), and local control (LC)] were then examined. Thirty-three sites across 23 patients with LBCL were irradiated. All metabolically active disease was treated in 10 patients. Following bRT, median overall decreases (including unirradiated sites) 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. Median follow-up was 15.2 months. A decrease in SUVmax of at least 54% was associated with improved PFS (24-month PFS: 83.3% vs. 28.1%; p = 0.037) and FFDP (24-month FFDP: 100% vs. 62.4%; p < 0.001). A decrease in MTV of at least 90% was associated with improved FFDP (24-month FFDP: 100% vs. 62.4%; p < 0.001). LC was improved in sites with decreases in SUVmax of at least 71% (24-month LC: 100% vs. 72.7%; p < 0.001). Decreases of MTV by at least 90% (100% vs. 53.3%; p = 0.038) and TLG by at least 95% (100% vs. 56.3%; p = 0.067) were associated with an improved complete response rate. bRT led to substantial reductions in MTV, SUVmax, SUVmean, and TLG. The relative extent of these decreases correlated with improved outcomes after CAR T-cell infusion. Prospective cohorts should validate the value of interim PET following bRT for quantifying changes in disease burden and associated prognosis.

EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma

BackgroundChimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release...

EASIX and m-EASIX predict CRS and ICANS in pediatric and AYA patients after CD19-CAR T-cell therapy

AbstractCytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are complications of CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy. The Endothelial Activation and Stress Index (EASIX) and modified EASIX (m-EASIX) scores have been retrospectively proven to be predictive of CRS and ICANS in adult CAR T-cell recipients. However, these scores have not been evaluated in pediatric cohorts. We retrospectively report on 76 pediatric and adolescent and young adult (AYA) patients with relapsed/refractory B-cell acute lymphoblastic leukemia treated with CD19-CAR T cells at St. Jude Children’s Research Hospital or John’s Hopkins Hospital. Data included patient, disease, and treatment characteristics. EASIX and m-EASIX scores were calculated at days –5 before, 0, and +3 after CAR T-cell infusion. CRS and ICANS occurred in 47 and 17 patients, respectively. At all evaluated time points, the median EASIX scores were higher for patients who developed severe CRS and any grade ICANS, and the median m-EASIX scores were higher in patients who developed severe CRS and severe ICANS than those with no/mild CRS/ICANS. Receiver operating characteristic curve analysis showed that both scores were strong predictors of CRS, especially severe CRS, at all time points. Any grade and severe ICANS were best predicted by both scores at day +3. m-EASIX uniformly outperformed EASIX, except for predicting any grade ICANS. Our results validate the potential utility of EASIX and m-EASIX scores for predicting CAR T-cell–related complications for pediatric and AYA patients.

Long-Term Survival and Immune Reconstitution of Donor-Derived Chimeric Antigen Receptor T-Cell Therapy for Childhood Molecular Relapse of B-Cell Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

Measurable residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an independent risk factor for relapse in patients with acute lymphoblastic leukemia (ALL). This study aimed to assess the efficacy, safety, and immune reconstitution of chimeric antigen receptor T-cell (CAR-T) therapy in patients with molecular relapse after allo-HSCT. Eleven patients with molecular relapse of B-cell-ALL who underwent CAR-T therapy after allo-HSCT were enrolled. The rate of MRD negativity after a month of CAR-T infusion was 81.8%. Patients who bridged to second-HSCT after CAR-T therapy (n = 3) showed a trend of higher 3-year leukemia-free survival and 3-year overall survival than those who did not (n = 8; 100% vs. 75.0%; 95% CI, 45.0–104.9%; p = 0.370). No treatment-related mortalities were observed. Among patients who did not bridge to second-HSCT and remained in complete remission until the last follow-up (n = 6), five of them had not recovered normal immunoglobulin concentrations with a median follow-up of 43 months. CAR-T therapy may be a safe and effective treatment strategy to improve survival after allo-HSCT; however, the problem of prolonged hypogammaglobulinemia in patients who do not bridge to second-HSCT is worth noting.

Enhanced platelet function through CAR-T cell therapy in relapsed/refractory multiple myeloma

The influence of chimeric antigen receptor T (CAR-T) cell therapy on platelet function in relapsed/refractory (R/R) multiple myeloma (MM) has not been thoroughly investigated. Our cohort comprised fifty MM patients treated with CAR-T cells. The mean platelet closure time (PCT) induced by collagen/adenosine diphosphate (CADP) in peripheral blood was significantly prolonged before lymphodepletion (195.24 ± 11.740 s) and notably reduced post-CAR-T cell therapy (128.02 ± 5.60 s), with a statistically significant improvement (67.22, 95% CI 46.91–87.53, P < 0.001). This post-treatment PCT was not significantly different from that of healthy controls (10.64, 95% CI 1.11–22.40, P > 0.05). Furthermore, a pronounced enhancement in PCT was observed in patients with a response greater than partial remission (PR) following CAR-T cell infusion compared to pre-treatment values (P < 0.001). An extended PCT was also associated with a less favorable remission status. In patients with cytokine release syndrome (CRS) grades 0–2, those with a PCT over 240.5 s exhibited a shorter progression-free survival (PFS), with median PFS times of 10.2 months for the PCT > 240.5 s group versus 22.0 months for the PCT ≤ 240.5 s group. Multivariate analysis revealed that a PCT value exceeding 240.5 s is an independent prognostic factor for overall survival (OS) in R/R MM patients after CAR-T cell therapy. The study demonstrates that CAR-T cell therapy enhances platelet function in R/R MM patients, and PCT emerges as a potential prognostic biomarker for the efficacy of CAR-T cell therapy.

CD19-Directed CAR T-Cells in a Patient With Refractory MOGAD: Clinical and Immunologic Follow-Up for 1 Year.

In MOG antibody-associated disease (MOGAD), relapse prevention and the treatment approach to refractory symptoms are unknown. We report a patient with refractory MOGAD treated with CD19-directed CAR T-cells. CD19-directed CAR T-cells (ARI-0001) were produced in-house by lentiviral transduction of autologous fresh leukapheresis and infused after a conventional lymphodepleting regimen. A 18-year-old man developed 2 episodes of myelitis associated with serum MOG-IgG, which were followed by 6 episodes of left optic neuritis (ON) and sustained the presence of MOG-IgG over 6 years despite multiple immunotherapies. After the sixth episode of ON, accompanied by severe residual visual deficits, CAR T-cell treatment was provided without complications. Follow-up of cell counts showed complete depletion of CD19+ B cells at day +7; reconstituted B cells at day +141 showing a naïve B-cell phenotype, and low or absent memory B cells and plasmablasts for 1 year. MOG-IgG titers have remained undetectable since CAR T-cell infusion. The patient had an early episode of left ON at day +29, when MOG-IgG was already negative, and since then he has remained free of relapses without immunotherapy for 1 year. This clinical case shows that CD19-directed CAR T-cell therapy is well-tolerated and is a potential treatment for patients with refractory MOGAD. This provides Class IV evidence. It is a single observational study without controls.

Point of care CD19 chimeric antigen receptor (CAR) T-cells for relapsed/refractory acute myeloid leukemia (AML) with aberrant CD19 antigen expression

Relapsed/refractory (r/r) acute myeloid leukemia (AML) is associated with poor prognosis. CD19 is a B-cell marker, is aberrantly expressed in AML, mostly with t(8; 21)(q22; q22.1). Here we report the results of a phase 2 study giving point of care produced CD19 CAR T- cells for r/r AML with aberrant expression of CD19 (NCT04257175). Lymphodepletion included fludarabine and cyclophosphamide The response was evaluated by bone marrow (BM) aspiration on day 28. Six patients (5 adults and 1 child) were included. Median number of previous chemotherapy lines was 4 (range, 3–8) and four patients received CAR T-cells 8–18 months post allogeneic hematopoietic stem cell transplantation (allo-HSCT). Cytokine release syndrome (CRS) of any grade occurred in all patients, and 1 patient had grade 3 CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2 patients at low grades. Tocilizumab was administered to 2 patients and corticosteroids to 3 patients. Four patients achieved a complete remission (CR), while 2/6 progressed (PD). Three patients (2 with CR and 1 with PD) underwent allo-HSCT (it was the second transplant in 2) 2–5 months post CAR T-cells infusion. The median duration of response in patients achieving CR was 8.5 (range; 3–14) months. However, all patients eventually died within 5 (1–18) months.In conclusion, CD19 CAR T- cell treatment for AML is feasible and safe. However, the response is short and should be followed by allo-HSCT. Hopefully, future long term results will be improved by combining the CAR T- cell therapy with the emerging novel effective anti-leukemic compounds.

Use of Eltrombopag to Improve Thrombocytopenia and Tranfusion Requirement in Anti-CD19 CAR-T Cell-Treated Patients.

Background/Objectives: Immune effector cell-associated hematotoxicity (ICAHT) is a frequent adverse event after chimeric antigen receptor (CAR)-T cell therapy. Grade ≥ 3 thrombocytopenia occurs in around one-third of patients, and many of them become platelet transfusion-dependent. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) able to accelerate megakaryopoiesis, which has been used successfully in patients with bone marrow failure and immune thrombocytopenia (ITP). Its role in managing thrombocytopenia and other cytopenias in CAR-T cell-treated patients has been scarcely addressed. Our aim was to report the safety and efficacy of this approach in patients included in the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC) registry. Methods: This is a retrospective, multicenter, observational study. Patients who developed platelet transfusion dependence subsequently to CAR-T cells and received eltrombopag to improve platelet counts were recruited in 10 Spanish hospitals. Results: Thirty-eight patients were enrolled and followed up for a median (interquartile range [IQR]) of 175 (99, 489) days since CAR-T cell infusion. At the moment eltrombopag was indicated, 18 patients had thrombocytopenia and another severe cytopenia, while 8 patients had severe pancytopenia. After 32 (14, 38) days on eltrombopag, 29 (76.3%) patients recovered platelet transfusion independence. The number of platelet units transfused correlated with the time needed to restore platelet counts higher than 20 × 109/L (Rho = 0.639, p < 0.001). Non-responders to eltrombopag required more platelet units (58 [29, 69] vs. 12 [6, 26] in responders, p = 0.002). Nineteen out of twenty-three (82.6%) patients recovered from severe neutropenia after 22 (11, 31) days on eltrombopag. Twenty-nine out of thirty-five (82.9%) patients recovered red blood cell (RBC) transfusion independence after 29 (17, 44) days. Seven patients recovered all cell lineages while on treatment. No thromboembolic events were reported. Only two transient toxicities (cholestasis, hyperbilirubinemia) were reported during eltrombopag treatment, none of which compelled permanent drug withdrawal. Conclusions: Eltrombopag could be safely used to manage thrombocytopenia and accelerate transfusion independence in CAR-T cell-treated patients.